research articles on ovarian cancer

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Research Results and Study Updates

See Advances in Ovarian Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

FDA approved mirvetuximab soravtansine-gynx (Elahere) to treat people with advanced, platinum-resistant ovarian cancer whose tumors overproduce a protein called FR-α. The full approval was based on the results of a large, randomized trial called MIRASOL, which showed Elahere improved survival for these people.

Researchers have developed tiny “drug factories” that produce an immune-boosting molecule and can be implanted near tumors. The pinhead-sized beads eliminated tumors in mice with ovarian and colorectal cancer and will soon be tested in human studies.

New results from a large study show that trametinib (Mekinist) is an effective treatment for low-grade serous ovarian cancer. The findings are the first strong evidence that this rare type of ovarian cancer should be treated differently from other forms of the disease.

For patients with recurrent ovarian cancer who meet strict criteria, additional surgery may improve survival, results from a large clinical trial show.

A microRNA—a molecule made by cells to turn genes on and off—called miR-181a may help high-grade serous ovarian cancer form, a study has found. The scientists think the microRNA could potentially help doctors detect ovarian cancer earlier.

Three recently launched NCI-supported studies could help researchers better understand the causes of racial/ethnic disparities in ovarian cancer. The ultimate goal is to eliminate disparities and improve survival for all women with the disease.

Secondary surgery for women with recurrent ovarian cancer does not improve how long those women live, findings from a large trial show. The results call into question the current standard of practice for these patients.

In three large clinical trials of women with newly diagnosed ovarian cancer, treatment with a PARP inhibitor as first-line therapy, maintenance therapy, or both, extended the length of time before participants’ cancers came back or got worse.

Many women diagnosed with ovarian and breast cancer are not undergoing tests for inherited genetic mutations that can provide important information to help guide decisions about treatment and longer-term cancer screening, a new study has found.

Surgery to remove all the lymph nodes in the area around an advanced ovarian tumor did not improve survival in a recent randomized clinical trial. The study also found systematic lymphadenectomy was associated with more frequent serious complications.

In a recent trial, the PARP inhibitor olaparib substantially delayed ovarian cancer from coming back after the first line of chemotherapy. Could the findings change the standard of care for newly diagnosed ovarian cancer with a BRCA mutation?

FDA has expanded its approval of rucaparib (Rubraca) as a maintenance therapy for women with recurrent ovarian, fallopian tube, or primary peritoneal cancer whose tumors shrank after subsequent treatment with a platinum-based chemotherapy.

Scientists have struggled to come up with a simple test to detect endometrial and ovarian cancers early, when they are most likely to respond to treatment. Can a liquid biopsy test called PapSEEK change that?

The experimental vaccine targets a protein found at elevated levels in about 90% of the most common type of ovarian cancer. If validated in human studies, researchers believe the vaccine may be particularly useful for women who carry BRCA1 and BRCA2 gene mutations.

A new study provides more evidence that the most common form of ovarian cancer may originate in the fallopian tubes, and that there is a window of nearly 7 years between development of fallopian tube lesions and the start of ovarian cancer.

A large international study suggests that the presence of certain immune cells within the tumors of some patients with ovarian cancer are associated with improved survival.

FDA has granted regular approval to olaparib tablets (Lynparza®) as maintenance treatment for patients with recurrent ovarian cancer who are having partial or complete responses to platinum-based chemotherapy.

Results from the first large prospective study of breast and ovarian cancer risk in women with inherited mutations in the BRCA 1 or BRCA2 genes confirm the high risks estimated from earlier, retrospective studies.

The FDA approved the PARP inhibitor niraparib for use as a maintenance therapy for some women with advanced ovarian cancer.

The FDA has approved rucaparib for women with BRCA-positive advanced ovarian cancer based on findings from two small clinical trials showing that it shrank tumors.

ORIGINAL RESEARCH article

Mutation characteristics of cancer susceptibility genes in chinese ovarian cancer patients.

1 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
2 BGI Genomics, Shenzhen, China
3 Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
4 Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
5 BGI Research, Beijing, China

Introduction: The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2 . However, a wider range of genes related to the DNA damage response pathways has not been fully explored.

Methods: To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes.

Results: In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R : c.359T>C and PRKDC : c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis.

Conclusion: In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.

Introduction

Ovarian cancer is a malignant gynecological tumor that seriously threatens the life and health of women. Among gynecological tumors worldwide, the incidence rate ranks third, and the mortality rate ranks first all year round. Global cancer statistics show that in 2020 ( 1 ), there were 313959 new cases of ovarian cancer and 207252 deaths worldwide. Among gynecological tumors in China ( 2 ), both incidence and mortality rank third, with more than 57090 new cases of ovarian cancer and 39306 deaths in 2020. By compiling cancer data in China in recent years ( 3 ), it can be found that the incidence rate of ovarian cancer is increasing annually.

Due to the special anatomical location of the ovary and the insidious onset of ovarian cancer, effective early screening methods are still lacking ( 4 , 5 ). Therefore, 75% of patients are already in an advanced stage when diagnosed and have extensive intraperitoneal metastasis ( 6 – 8 ). Cancer susceptibility genes are significantly associated with ovarian carcinogenesis ( 9 ). In terms of family history, approximately 5-10% of patients with ovarian cancer have first-degree relatives with a history of ovarian cancer. Several studies have shown that, from the perspective of susceptibility genes, BRCA1/2 is significantly associated with the occurrence of ovarian cancer ( 10 ). For example, women who have inherited BRCA1 mutations have a lifetime risk of developing ovarian cancer ranging from 40% to 60%, while those with BRCA2 mutations have a lifetime risk of 11% to 27% ( 11 ). A review of published patient data from the United States, the United Kingdom, and Australia found that in ovarian cancer ( 12 ), the frequency of BRCA1 mutations in different countries ranged from 3.4% to 47%, and the frequency of BRCA2 mutations ranged from 1% to 12%. A clinical study of ovarian cancer patients at Fujian Medical University Cancer Hospital revealed that 17.1% of patients carried BRCA1 pathogenic mutations and 5.3% carried BRCA2 pathogenic mutations ( 13 ); additionally, three Chinese-specific high-frequency BRCA1 mutations, c.5470_5477delATTGGGCA, c.981_982delAT, c.3770 _3771delAG, were reported. Meanwhile, compared with those of individuals in the normal population, the risk ratio of individuals carrying BRCA1 mutations was 34.6 for those aged younger than and 42.4 for those aged older than 50 years. A meta-analysis of published data from 1999 to 2017 ( 14 ), with technical platforms including PCR, Sanger sequencing, and high-throughput sequencing, included a total of 35178 cases of BRCA1/2 testing in the Chinese population, of which the carrier rate of ovarian cancer was 21.8%. Owing to limitations in sample size, sampling regions, and differences in detection platforms, current studies can’t comprehensively and accurately profile the BRCA1/2 mutations of ovarian cancer in the Chinese population.

DNA damage repair (DDR) refers to the cellular response in which damaged DNA molecules in cells maintain the relative stability of genetic information and restore the structure of normal DNA sequences through the cooperation of multiple proteins ( 15 ). The human cell has multiple mechanisms for DNA damage repair ( 16 ), such as homologous recombination repair (HRR), mismatch repair (MMR), Fanconi anemia, and base excision repair. Alterations in genes involved in DNA damage repair are closely associated with the occurrence, progression, and drug resistance of cancer ( 17 ). Poly (ADP-ribose) polymerase (PARP) inhibitors based on defects in the HRR pathway have been approved for marketing by the FDA. A study of 449 epithelial ovarian cancer gene mutations from Peking Union Medical College Hospital ( 18 ), including 28 HRR-related genes, 4 MMR genes, and 4 hereditary tumor-related genes, found that 107 patients carried BRCA1/2 germline mutations, the other 31 patients were carriers of germline mutations in other DDR-related genes, and all RAD51D germline mutation carriers were patients younger than 40 years. A multigene germline mutation analysis of ovarian cancer patients at the University of Washington revealed that 18% of patients carried pathogenic mutations in susceptibility genes and that PALB2 and BARD1 were significantly associated with the occurrence of ovarian cancer ( 19 ). A survey initiated by Myriad Genetics, Inc., which enrolled patients undergoing genetic testing for hereditary tumor risk between 2013 and 2022, analyzed the relationship between pathogenic mutations and the occurrence of multiple cancers and revealed that PTEN pathogenic mutations resulted in a 3.77-fold increase in the risk of developing ovarian cancer ( 20 ). The impact of HRR-related genes on the occurrence of ovarian cancer has been widely researched. However, the mutations of other DNA damage repair genes in the Chinese ovarian cancer population and their relationship with patient characteristics have not been thoroughly investigated.

Clinical multigene testing, which can assess the risk of ovarian cancer, and provide data support for future cancer prevention, diagnosis, treatment, and optimal management, plays a crucial role in the treatment of ovarian cancer. In this study, we gathered data on multigene germline mutations from Chinese ovarian cancer patients and created a dataset of ovarian cancer germline mutations in the Chinese population. Secondly, based on the germline mutation characteristics of ovarian cancer in the Chinese population, the high-frequency mutations and genes in the Chinese population were analyzed. Finally, combined with family history, age of onset, and region, we analyzed and identified genes associated with family history, early onset of cancer, and geographical characteristics, and attempted to elucidate the mechanism between mutations and ovarian cancer occurrence.

Materials and methods

Sample selection and dataset construction.

From the previously published literature, we searched for ovarian cancer studies that performed germline testing of 171 genes ( Supplementary Table S1 ) at the BGI Shenzhen Clinical Diagnostic Laboratory. All samples were obtained with informed consent, and a total of 3 studies met the criteria ( 21 – 23 ). Mutation data was obtained from the authors based on a reasonable request. And mutation detection methods were described in detail in the Supplementary Material 1 . The mutation results and clinical information from the three studies were pooled, and samples with missing age, family history of cancer, or regional information were excluded. The data of 1171 ovarian cancer samples that can represent ovarian cancer in the Chinese population were retained. The average depth was over 100X and the coverage at 30X exceeded 95% for each sample. The sequencing coverage and quality statistics for each sample were summarized in Supplementary Table S2 .

Mutation filtering and annotation

Single nucleotide variations (SNVs), and insertions and deletions (INDELs) were selected that were localized in all exons and intron-exon boundaries (± 20 bp) of the genes. Mutations with fewer than 5 supporting reads, a mutation frequency less than 20%, or a population frequency greater than 5% in the population polymorphism databases GnomAD, ExAC, and 1k Genomes were excluded ( 24 – 26 ). The final mutation results for each sample were obtained. According to the genetic variation classification standards and guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) ( 27 , 28 ), mutations were classified into five categories, pathogenic, likely pathogenic, variant of unknown significance (VUS), likely benign and benign. Patients with likely pathogenic or pathogenic mutations were defined as those carrying deleterious mutations.

Statistical analysis

All the statistical analyses and plots were performed using R (version 3.6.3). Pearson’s χ2-test and Fisher’s exact test were used to determine the statistical significance of categorical variables. Student’s t test was used to compare continuous variables, such as age at diagnosis, between two groups. All P values reported were two-sided, and a P value of less than 0.05 was considered statistically significant. False discovery rates were calculated using the Benjamini-Hochberg procedure; FDR < 0.05 was used as the threshold for significance after correction for multiple hypothesis testing.

Participant characteristics

The study included 1171 patients with qualified testing data ( Table 1 ). These samples include all seven regions in China and can represent the characteristics of the Chinese ovarian cancer population. The age range of the enrolled patients was 12~86 years old ( Supplementary Figure S1 ), the median age was 54 years old, and 247 patients had a family history of cancer. According to the statistics of clinical data, there was no significant correlation between family history of cancer and age of cancer onset. BRCA- positive patients were defined as those with likely pathogenic and/or pathogenic mutations in BRCA1/2 , and 103 (8.8%) out of 1171 ovarian cancer patients were BRCA -positive.

Table 1 Participant characteristics of the cohort.

Characteristics of all mutations

Among the 1171 patients, a total of 19435 mutations were detected ( Supplementary Table S3 ), with an average of more than 16 mutations per patient. These mutations contained 5657 types, of which 94.38% (5345) of which were SNPs, and the remaining 312 were INDELs. Categorized by mutation effect, the most common types were missense mutations (3105), followed by synonymous mutations (1704), 491 splice-site mutations, 177 frameshift mutations, 72 INDELs within coding frames, and 108 nonsense mutations. In the cohort, there were a total of 48 mutations present in 39 genes, each carried by more than 5% of the patients, and the five highest frequency mutations were in the following order: MC1R , c.359T>C; ERCC5 , c.1586G>C; PRSS1 , c.72C>T; BARD1 , c.1075_1095del; and KIT , c.1638A>G. Meanwhile, we applied fit Chi-square calculation to evaluate these mutations with ovarian cancer risk and found MC1R:c.359T>C, ERCC5:c.1586G>C and PRSS1:c.72C>T that significantly fails to conform Hardy-Weinberg equilibrium (P-value<0.05). Notably, nearly 48% (23/48) of the high-frequency mutations were synonymous. We used the PATHVIEW software package ( 29 ) for the 39 genes and found that they were significantly enriched in DNA damage response repair pathways such as fanconi anemia pathway, homologous recombination, mismatch repair, nucleotide excision repair, and base excision repair ( Supplementary Figure S2A ).

Mutations were detected in each of the 171 genes within the assay ( Supplementary Table S4 ). The most common gene, PRKDC , was detected in 612 patients (approximately 52%), and the least common gene, MAX , was detected in only 1 patient. Genes with a high prevalence of mutations in more than 10% of the cohort were selected, and a total of 30 genes were obtained ( Figure 1 ). The top 10 genes with high incidence were PRKDC , BRCA2 , BRCA1 , FANCI , ERCC5 , SLX4 , PTCH1 , MC1R , BARD1 , and RET . The 30 genes were significantly enriched in the fanconi anemia pathway (P value 2.55e-13, FDR 5.15e-11) and mismatch repair (P value 2.40e-10, FDR 2.42e-8) ( Supplementary Figure S2B ). An exploration of the distribution of mutation sites within genes showed single or multiple hotspot mutations in high-incidence mutated genes ( Figure 2 ), such as BRCA1 : c.2566T>C (p.Y856H), BRCA2 : c.10234A>G (p.I3412V), ERCC5 : c.1586G>C (p.C529S), FANCI : c.2011A>G (p.I671V), PRKDC : c.10681T>A (p.L3561M), and BARD1 : c.1075_1095del (p.L359_P365del), suggesting that these sites were associated with ovarian cancer occurrence in China.

Figure 1 Mutation spectrum of high-frequency mutant genes.

Figure 2 Mutation site of high-frequency mutant gene. (A) BRCA1 . (B) BRCA2 . (C) BARD1 . (D) ERCC5 . (E) FANCI . (F) PRKDC .

Compared with other high-frequency mutated genes ( Figure 1 ), more INDEL mutations were detected in BRCA1 , BRCA2 , PRKDC , BARD1 , MSH6 , RECQL4 , and MSH3 genes, and more splice-site mutations were detected in the BRCA1 , MSH6 , MUTYH , and TSC2 genes, which tended to cause greater functional changes. BRCA1 , BRCA2 , and BARD1 are core genes of the homologous recombination repair pathway ( 30 ), and MSH6 and MSH3 are core genes of the mismatch repair pathway ( 31 ). The National Comprehensive Cancer Network (NCCN) guidelines ( 32 ) recommended screening for mutations in RAD51D , EPCAM , and RAD51C , which were detected in 5%, 4%, and 2% of the population, respectively. However, only the high-frequency mutated genes, BRCA1 and BRCA2 , were within the scope of NCCN-recommended screening. It implied that the mutated genes of ovarian cancer in the Chinese population differed significantly from those recommended by NCCN for ovarian cancer screening in both European and American populations.

Characteristics of deleterious mutations

According to the classification of mutation function, a total of 954 (16.9%) were annotated as likely pathogenic or pathogenic mutations in 1041 patients ( Supplementary Table S3 ). The top 10 genes with most deleterious mutations in the Chinese ovarian cancer population were MC1R (12%), MLH1 (9%), PRKDC (8%), KIF1B (8%), FANCM (7%), FANCI (6%), PRSS1 (6%), SDHA (6%), BRCA2 (6%), and CFTR (5%) ( Supplementary Figure S3 ). In addition, deleterious BRCA1 mutations were detected with a frequency of about 3%, and BRCA1 and BRCA2 were detected in 103 patients (8.8%) patients. Pathway enrichment of these high-frequency genes showed that they were significantly enriched in the fanconi anemia pathway (P value 1.03e-06, FDR 2.00e-04). Analysis of the distribution of mutation sites within genes revealed the presence of single or multiple hotspot mutations in high-frequency mutation genes ( Supplementary Figure S4 ), such as MC1R : c.359T>C (p.I120T), MLH1 : c.1151T>A (p.V384D), PRKDC : c.10681T>A (p.L3561M), ERCC5 : c.640C>T (p.R214C), ERCC5 : c.767A>G (p.Q256R), PTCH1 : c.2222C>T (p.A741V), and RECQL4 : c.212A>G (p.E71G), suggesting that these sites were related to the occurrence and progression of ovarian cancer in China. The mutations observed were primarily missense mutations and were predominantly heterozygous, indicating that the dosage of the mutation had a significant impact on normal functional execution.

Considering only the NCCN-recommended ovarian cancer screening genes, it was noticed that no mutations were detected in the recommended EPCAM and STK11 genes. Compared with the two American cohorts (cohorts A and B) ( 19 , 33 ), and the four Chinese cohorts (cohorts C-F) ( 13 , 18 , 34 , 35 ) ( Supplementary Table S5 ), it was observed that the detection rates of the two cohorts in the United States were 18.10% and 18.81%, respectively. For the four cohorts in the Chinese population, the detection rate of Cohort C was 27.20%, and the other three cohorts were tested for only the BRCA1 and BRCA2 genes, with detection rates of 22.40%, 17.00%, and 28.40%, respectively. The detection rate of this study cohort was 28.35%, which was close to that of previous Chinese cohorts. Further analysis of the deleterious mutations in NCCN-recommended screening genes in foreign and domestic cohorts revealed that the BRCA1 and BRCA2 genes were generally detected at high frequencies in the American and Chinese populations ( Figure 3 ), and the difference was that the MLH1 gene carried the highest frequency of deleterious mutations in this cohort. Meanwhile, it was discovered that all high-frequency mutation genes in the American population were within the screening scope recommended by the NCCN guidelines, while the high-frequency mutation genes in the Chinese cohort of ovarian cancer, such as MC1R , PRKDC , KIF1B , FANCM , FANCI , PRSS1 , and SDHA , were not included in the scope of the NCCN guidelines, indicating that the NCCN guidelines based on the European and American populations were not suitable for ovarian cancer genetic screening in the Chinese population.

Figure 3 Detection rate of pathogenic mutations in NCCN ovarian cancer screening genes in different populations.

Among the 130 patients without detecting deleterious mutations, the high-frequency mutation genes were similar to those of all cohort populations, and pathway enrichment analysis showed that these genes were also significantly enriched in the fanconi anemia pathway (P value 1.60e-06, FDR 3.24e-04). Compared with the 1041 patients carrying deleterious mutations, there was no significant difference in age distribution (t-test P value 0.84) or family history of cancer (chi-square test P value 0.70). At the same time, it was identified that the genes with significantly high frequency in the group carrying deleterious mutations were mainly enriched in the homologous recombination (P value 1.02e-05, FDR 2.06e-03) and fanconi anemia pathway (P value 7.12e-05, FDR 7.20e-03).

Characteristics of BRCA1/2 gene mutations

A total of 190 BRCA1 mutations and 169 BRCA2 mutations were detected in the enrolled ovarian cancer population. Among the high-frequency BRCA1 and BRCA2 mutations, except for BRCA1 :c.5470_5477delATTGGGCA (5.85% of all BRCA1 mutations, 20/342), which was a pathogenic mutation, the others were all missense mutations annotated as benign. Further analysis revealed that BRCA1 : c.2566T>C (p.Y856H) accounted for 12.87% of all BRCA1 mutations ( Supplementary Figures S5A, B ), and BRCA2 : c.8187G>T (p.K2729N) constituted 9.36% of all BRCA2 mutations ( Supplementary Figures S5C, D ), were significantly higher in the East Asian population than in other populations, and were geographically characteristic BRCA1/2 mutation in the Chinese ovarian cancer population. However, BRCA2 :c.10234A>G (p. I3412V) comprised 23.15% of all BRCA2 mutations ( Supplementary Figures S5E, F ), with a frequency of 2.40% in East Asian populations and 8.03% in this ovarian cancer cohort. Notably, its prevalence exceeds 10% in normal populations in the Americas and Africa, displaying that it was not a geographically characteristic mutation in the Chinese population.

Co-mutation in BRCA1 and BRCA2 occurred in 99 patients, representing 8.5% (99/1171) of the entire cohort. Analysis of the characteristics of the BRCA1 and BRCA2 co-mutation group and other patients, it was observed that there was no statistical difference in family history distribution (chi-square test, P value 0.68). However, in terms of age ( Supplementary Figure S6 ), the group carrying BRCA1 and BRCA2 co-mutations had a significantly earlier age of cancer onset than the rest patients (mean age, 51 VS 54.5 years, Wilcoxon test P value 7.30e-03). Similar results have been reported in multiple studies ( 34 , 36 ), implying that BRCA1 and BRCA2 were associated with the early onset of cancer.

Comparative analysis of the difference in ovarian cancer mutation genes between the BRCA1/2 mutation group and the non-mutation group uncovered that FAM175A , EMSY , PTCH1 , and HNF1B were significantly highly mutated in the group without BRCA1/2 mutations ( Supplementary Figure S7A ), particularly PTCH1 : c.3907C>T (p.R1303C) ( Supplementary Figure S7B ). When considering only the difference in deleterious mutations between the two groups, it was found that FAM175A was equally significant in the group without BRCA1/2 mutations ( Supplementary Figure S7C ).

Mutations associated with family history

Ovarian cancer exhibited a notable pattern of family inheritance and aggregation, primarily attributed to the transmission of tumor-associated germline mutations to the offspring along with the reproductive process. The enrollment cohort consisted of 247 samples with a family history of cancer and 924 samples without. By comparing the differences in mutation genes between the two groups ( Figure 4A ), it was observed that the XPA and NF2 genes were significantly more frequently mutated in the group with a family history of cancer (P <0.05), while the ERCC5 and TSC1 genes were more common in the group without a family history of cancer (P <0.05). Analysis of the mutation sites in these genes revealed that the TSC1 gene had a significantly higher frequency of mutation c.250G>A (p.A84T) in the population without a family history ( Figure 4B ).

Figure 4 Differences of mutated genes in groups with and without cancer family history. (A) all mutations. (B) difference of TSC1 mutation sites in groups with and without cancer family history.

Mutations associated with age of diagnosis

The analysis of hereditary mutations in each sample revealed a decrease in the total number of mutations as onset age increased within the patient population ( Supplementary Figure S8A ), suggesting that the occurrence of ovarian cancer in the younger age group was mainly related to genetic factors. According to the age distribution of the cohort, the patients in the first quartile of the age range (47 years and younger) were categorized into the younger age group and were compared with the group older than 47 years. Fisher’s exact test was performed on the mutations of each gene in the two age groups ( Supplementary Figure S8B ). The results showed that ERCC4 , CHEK2 , and PDGFRA were significantly more mutated in the younger group (P value<0.05), while POLH was significantly more common in the older group.

Mutations associated with native place

Regional characteristics of cancer-related mutation genes were highly prevalent due to differences in the ancestral genetic backgrounds of various regions. In the cohort, a Fisher’s exact test was conducted on each mutated gene between a single region and other regions ( Figure 5A ). The results showed that MEN1 was significantly more highly mutated in the East China group, MXI1 gene in the Southwest China group, TMEM127 and FH in the South China population, RPA1 in the North China population, and CDH1 , CHEK2 , FAM175A , and EXT2 in the Northeast population. ERCC4 and HMMR were significantly more common in the non-North China population, while POLH was more common in the non-South China population. The pathway enrichment revealed that high-frequency mutated genes in North China were significantly enriched in the fanconi anemia pathway (p-value 6.20e-07, FDR 1.25e-04), homologous recombination (p-value 7.15e-07, FDR 7.22e-04), nucleotide excision repair (P value 3.49e-05, FDR 2.35e-03), mismatch repair (P value 4.82e-04, FDR 0.02), while in South China, in the fanconi anemia pathway (P value 2.12e-05, FDR 4.28e-03). When only deleterious mutations were considered ( Supplementary Figure S9 ), CDH1 and FAM175A were significantly more frequently mutated in the Northeastern population, while ERCC4 was in non-North China populations, and the PRKDC in non-South China populations. The results indicated that differences in the geographic scope of China also led to differences in cancer susceptibility genes for ovarian cancer.

Figure 5 Differences of mutation genes among different location. (A) difference of mutated gene between a single region and other regions. (B) difference of MEN1 mutation sites between the East China and the reset. (C) difference of POLH mutation sites between the South China and the reset. (D) difference of ERCC4 mutation sites between the North China and the reset. (E) difference of PRKDC deleterious mutation sites between the South China and the reset.

By analyzing the mutation carrier rates of the differential genes, we found that MEN1 : c.209A>C (p.D70A) was highly prevalent in the East China population ( Figure 5B ), while MEN1 : c.1523G>A (p.G508D) and c.527G>A (p.R176Q) in the populations of other regions. Furthermore, a significant high-frequency mutation, POLH : c.1433C>T (p.T478M) ( Figure 5C ), was observed in non-South China populations and ERCC4 : c.241G>T (p.V81F) in non-North China populations ( Figure 5D ). The pathogenic PRKDC : c.10681T>A (p.L3561M) mutation was significantly more common in the non-South China population ( Figure 5E ). The presence of highly mutated genes in different regions suggested that precise treatment of ovarian cancer in the Chinese population should be based on characteristic mutation data specific to this population.

By gathering germline mutation data from 1171 ovarian cancer samples across China, a mutation database of susceptibility genes was constructed based on the genetic background of the Chinese population. Our findings revealed that high-frequency mutated genes had hotspot mutations. In order of prevalence, mutated genes with a frequency of more than 16% in the enrolled ovarian cancer cohort population were, PRKDC , BRCA2 , BRCA1 , FANCI , ERCC5 , SLX4 , PTCH1 , MC1R , BARD1 , and RET . Compared with the NCCN guidelines on ovarian cancer screening genes based on the genetic characteristics of the European and American populations, we observed that the guideline-recommended genes RAD51D , EPCAM , and RAD51C were only detected in less than 5% of the population, while genes with high-frequency mutations in the Chinese population, such as PRKDC , FANCI , and ERCC5 , were not included in the screening scope. Considering only deleterious mutations, it showed that the carrying rates of deleterious mutations of the ovarian cancer screening genes recommended by the NCCN guidelines also varied significantly across different ethnic groups. Furthermore, the high-frequency mutated genes in the American population fell within the screening range recommended by the NCCN guidelines, while the high-frequency mutated genes, MC1R , PRKDC , and KIF1B in the Chinese ovarian cancer cohort were not covered. The results highlighted that the mutation characteristics of the Chinese ovarian cancer population were significantly different from those of the European and American populations. Therefore, it was imperative to formulate genetic screening guidelines for ovarian cancer that aligned with the genetic characteristics of the Chinese population.

BRCA1 deleterious mutations were detected in 40 samples (3.42%) and BRCA2 deleterious mutations in 68 samples (5.81%). In previous studies of ovarian cancer in China, the carrying rates of BRCA1 were generally higher than our results. Three Chinese population cohort studies ( 13 , 34 , 35 ) showed that the carrier frequencies of BRCA1 ranged from 13.1% to 20.8% and those of BRCA2 were between 3.9% and 7.6%. In two studies of the American population ( 19 , 37 ), the frequencies of BRCA1 were 8.6% and 9.5%, respectively, while the frequencies of BRCA2 were 5.2% and 5.1%. The low BRCA1 positive rate in our cohort was attributed to the geographical differences in the enrollment cohort and the high-grade serous carcinoma in the other study population, suggesting that the deleterious mutations of BRCA1 were associated with a greater incidence of malignant ovarian cancer.

The prevalence of mutations at different sites in genes varied greatly among different populations. Three geographically characteristic mutations were identified in this study: BRCA1 : c.5533_5540del (p.I1845Dfs*3), which was detected in 38 samples in this cohort (1.69%), has been identified as a founder mutation in four studies of Chinese ovarian cancer populations ( 13 , 14 , 34 , 35 ), and was confirmed to have appeared in the Han Dynasty of China 2000 years ago ( 36 ); BRCA1 : c.2566T>C (p.Y856H), which was detected in 93 (4.13%) samples in the current cohort, and was also identified as the founder mutation in one Chinese population study of ovarian cancer ( 14 ); and BRCA2 : c.8187G>T (p.K2729N), which was detected in 74 (3.28%) samples in the current cohort, with no similar reports in China. Whether this mutation is a founder mutation requires further research. Among the founder mutations identified in previous studies of ovarian cancer in the Chinese population, except for c.1081delG, c.2612C>T, c.3548A>G, c.4837A>G, and c.5154G>A in the BRCA1 , and c.3337C>T in the BRCA2 , the rest of the mutations were detected in a few samples, and could not be presumed to be geographically specific mutations. Possible reasons for this include small enrollment cohorts in other studies and samples from a particular region or a particular subtype of cancer. Moreover, founder mutations identified in other ethnic groups ( 38 , 39 ), such as Europeans and Americans, were not detected at high frequencies in this cohort, indicating that there were obvious differences in the genetic backgrounds of different ethnic groups.

Ovarian cancer had the characteristics of high familial incidence, and the results of our cohort showed that XPA and NF2 were associated with familial inheritance of ovarian cancer. XPA is a core gene for nucleic acid excision repair and has been extensively studied ( 40 , 41 ). The NF2 is a tumor suppressor gene, and the encoded protein is a linker protein between cytoskeletal components and proteins in the cell membrane, which is involved in regulating contact-dependent inhibition of cell proliferation and plays a key role in intercellular adhesion and transmembrane signaling ( 42 ). Mutations in the NF2 are associated with tumorigenesis and metastasis ( 43 ). Previous studies have focused on somatic mutations in NF2 and found that these mutations are highly prevalent mainly in brain tissue ( 44 ), with a frequency of only 1% in the ovarian cancer population. Another study ( 45 ) revealed that the frequency of NF2 detection in the ovarian cancer population was 2.56%, which is close to the germline carrier frequency in the current cohort (2.31%). The germline mutation of NF2 in ovarian cancer has rarely been studied, and the relationship between germline mutations in NF2 and familial inheritance of ovarian cancer requires further investigation.

Age is a crucial factor influencing the occurrence of cancer. As age increased, the number of germline mutations tended to decrease, but there was a noticeable difference in germline mutation genes between younger and older cancer patients. We identified significant high-frequency mutations in the ERCC4 , CHEK2 , and PDGFRA genes in young patients with ovarian cancer. The CHEK2 gene is involved in cell cycle checkpoint regulation and is a tumor suppressor gene ( 46 ). The gene is activated by DNA damage and encodes a protein that inhibits the CDC25C phosphatase, blocking entry into the mitotic phase and resulting in the cell cycle arrest in the G1 phase. In addition, the protein interacts with and phosphorylates the BRCA1 protein, causing its activation after DNA damage. However, there are few studies on the association of CHEK2 mutations and age at the onset of ovarian cancer. A study ( 47 ) in Poland containing 2012 ovarian cancer patients showed that the average age of the ovarian cancer group with CHEK2 was 38 years, while the average age of the CHEK2 -negative ovarian cancer group was 49 years.

In conclusion, this study constructed a comprehensive and accurate susceptibility gene dataset of ovarian cancer in the Chinese population and provided abundant data for the formulation of genetic screening and treatment guidelines for ovarian cancer tailored to the population. Moreover, the Chinese ovarian cancer population had characteristic high-frequency mutated genes and hotspots. Additionally, this study was the first to conduct an association analysis of patient characteristics across 171 genes, including DDR pathway-related genes, and identified characteristic mutated genes and sites linked to age, family history of cancer, and specific geographic regions. For further research, on the one hand, it is necessary to combine comprehensive clinical records and multi-omics information to accurately identify mutations associated with ovarian cancer. On the other hand, additional functional validation studies are needed to confirm the detailed mechanism of susceptibility genes and cancer occurrence and to provide data support for medical policy formulation, drug development, and clinical patient treatment.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by Medical Ethics Committee of West China Second University Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

Author contributions

JW: Writing – original draft, Visualization, Software, Methodology, Investigation, Formal analysis, Data curation. KF: Writing – original draft, Data curation. MZ: Writing – original draft, Data curation. LL: Writing – original draft, Formal analysis. MN: Writing – review & editing, Formal analysis. HS: Writing – review & editing. RY: Writing – review & editing, Funding acquisition, Conceptualization. MT: Writing – review & editing, Conceptualization.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study is supported by the Key Project of Sichuan Provincial Department of Science and Technology (19YFS0532): “Study on the key factors affecting the diagnosis and treatment of major diseases in obstetrics and gynecology”, and the project of Chengdu Science and Technology administration (2021-YF05-01725-SN): “Study on the mechanism of platinum-resistance chemotherapy in ovarian cancer”.

Acknowledgments

We thank Di Shao for providing sample information for this study. And we thank the patients for their participation and support of the study.

Conflict of interest

Authors JW, LL, MN and MT are employees of BGI Genomics that produces the panel test used in this study. HS was employed by BGI Research.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2024.1395818/full#supplementary-material

Supplementary Material 1 | Mutation detection methods.

Supplementary Figure 2 | Pathway enrichment results. (A) the 39 genes with high frequency mutations. (B) the 30 most common mutated genes.

Supplementary Figure 4 | Mutation site of genes with high-frequency deleterious mutation. (A) MC1R . (B) MLH1 . (C) PRKDC . (D) ERCC5 . (E) PTCH1 . (F) RECQL4.

Supplementary Figure 5 | Comparison of BRCA1 and BRCA2 high-frequency mutations in the enrollment cohort and the detection frequency of GnomAD database. (A) Frequency of BRCA1 c.2566T>C in different population. (B) Frequency of BRCA1 c.2566T>C in Chinese ovarian cancer patients and normal people. (C) Frequency of BRCA2 c.8187G>T in different population. (D) Frequency of BRCA2 c.8187G>T in Chinese ovarian cancer patients and normal people. (E) Frequency of BRCA2 c.10234A>G in different population. (F) Frequency of BRCA2 c.10234A>G in Chinese ovarian cancer patients and normal people. AFR, African/African American; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, European (Finnish); NFE, European (non-Finnish); OTH, Other.

Supplementary Figure 7 | Mutation gene differences between BRCA and non- BRCA groups. (A) all mutations. (B) difference of PTCH1 mutation sites between BRCA and non- BRCA groups. (C) deleterious mutations.

Supplementary Figure 8 | Differences in mutation genes among the different age. (A) The distribution of number of sample mutations at different ages. (B) Differences in mutation genes between the younger group and the older group.

Abbreviations

ACMG, American College of Medical Genetics and Genomics; BRCA1, Breast cancer susceptibility gene 1; BRCA2, Breast cancer susceptibility gene 2; DDR, DNA damage repair; ESP, Exome Sequencing Project; ExAC, The Exome Aggregation Consortium; FDR, False discovery rate; GnomAD, The Genome Aggregation Database; HRD, homologous recombination defect; HRR, Homologous recombination repair; InDel, Insertion and deletion; MMR, Mismatch repair; NCCN, National Comprehensive Cancer Network; OR, Odds Ratio; PARPi, poly ADP-ribose polymerase inhibitors; SNP, single nucleotide polymorphism.

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Keywords: cancer genomics, cancer susceptibility genes, target capture sequencing, germline mutations, ovarian cancer

Citation: Wang J, Fu K, Zhang M, Liang L, Ni M, Sun H-X, Yin R and Tang M (2024) Mutation characteristics of cancer susceptibility genes in Chinese ovarian cancer patients. Front. Oncol. 14:1395818. doi: 10.3389/fonc.2024.1395818

Received: 04 March 2024; Accepted: 03 May 2024; Published: 16 May 2024.

Reviewed by:

Copyright © 2024 Wang, Fu, Zhang, Liang, Ni, Sun, Yin and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Rutie Yin, [email protected] ; Meifang Tang, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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A closer look at ovarian cancer screening

How common is ovarian cancer?

Ovarian cancer is a rare disease with about 10 cases occurring for every 100,000 women annually in the U.S. The National Cancer Institute estimates that about 1% of women will develop ovarian cancer during their lifetime.

What tests can help detect ovarian cancer?

The most relevant tools for finding ovarian cancer are imaging tests, such an ultrasound, and tumor markers that can be found in the blood, such as cancer antigen 125 , or CA 125.

Ultrasounds are good at identifying cysts or other masses growing on the ovaries. The challenging part is that these masses are quite common, and most are not cancers. While the appearance of an ovarian mass can give some clues about its chance of cancer, it's often difficult to tell the difference between masses that are cancers and those that are not cancers with an ultrasound.

What is CA 125?

CA 125 is a protein in the blood that can be elevated when ovarian cancers are present. However, it also can be elevated with other conditions, such as menstruation, uterine fibroids and endometriosis, leading to false-positive results. Early detection is the goal of a good screening program, but CA 125 can miss a significant number of early-stage ovarian cancers.

Ultrasounds and CA 125 tests have been evaluated as potential screening tools. Unfortunately, they could not consistently detect ovarian cancer early enough to improve patient outcomes and have a high false-positive result rate, increasing the risk of unnecessary stress, anxiety and surgery.

However, there are some situations in which these tests are used to screen for ovarian cancer, such as in patients with genetic mutations that put them at high risk for cancer and in certain patients previously treated for ovarian cancer.

What are the symptoms of ovarian cancer?

Symptoms of ovarian cancer are often vague and also can occur with several other common conditions.

Common symptoms of ovarian cancer include:

Abdominal bloating
Change in bowel function
Feeling full more quickly when eating
Pelvic pain
Unintentional weight loss

While experiencing one or more of these symptoms is common and does not mean you have ovarian cancer, discussing them with your healthcare team is a good idea. — Brad Nitzsche, M.D. , is an OB-GYN with Mayo Clinic Health System in La Crosse , Wisconsin.

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EMP1 correlated with cancer progression and immune characteristics in pan-cancer and ovarian cancer

Original Article
Published: 14 May 2024
Volume 299 , article number 51 , ( 2024 )

Cite this article

Jun Zhang 1 ,
Jing Yang 1 ,
Xing Li 1 ,
Lin Mao 1 ,
Yan Zhang 1 ,
Yi Liu 2 &
Yindi Bao ORCID: orcid.org/0009-0006-7017-7540 1

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This study examines the prognostic role and immunological relevance of EMP1 (epithelial membrane protein-1) in a pan-cancer analysis, with a focus on ovarian cancer. Utilizing data from TCGA, CCLE, and GTEx databases, we assessed EMP1 mRNA expression and its correlation with tumor progression, prognosis, and immune microenvironment across various cancers. Our results indicate that EMP1 expression is significantly associated with poor prognosis in multiple cancer types, including ovarian, bladder, testicular, pancreatic, breast, brain, and uveal melanoma. Immune-related analyses reveal a positive correlation between EMP1 and immune cell infiltration, particularly neutrophils, macrophages, and dendritic cells, as well as high expression of immune checkpoint such as CD274, HAVCR2, IL10, PDCD1LG2, and TGFB1 in most tumors. In vivo experiments confirm that EMP1 promotes ovarian cancer cell proliferation, metastasis, and invasion. In conclusion, EMP1 emerges as a potential prognostic biomarker and therapeutic target in various cancers, particularly ovarian cancer, due to its influence on tumor progression and immune cell dynamics. Further research is warranted to elucidate the precise mechanisms of EMP1 in cancer biology and to translate these findings into clinical applications.

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The pan-cancer landscape of crosstalk between epithelial-mesenchymal transition and immune evasion relevant to prognosis and immunotherapy response

Prognostic immunologic signatures in epithelial ovarian cancer

Establishment and validation of an immune infiltration predictive model for ovarian cancer

Availability of data and materials.

The RNA-sequencing data and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA) database ( https://portal.gdc.cancer.gov/ ), the Genotype-Tissue Expression (GTEx) ( https://www.gtexportal.org/ ) and the Broad Institute Cancer Cell Line Encyclopedia (CCLE) ( https://sites.broadinstitute.org/ccle/ ). The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to gratefully acknowledge contributions from TCGA, CCLE and GTEx.

This work was supported by funds including the National Key Research and Development Program of China (grant nos. 2018YFC1002804 and 2016YFC1000600), the National Natural Science Foundation of China (grant nos. 81771618, 81971356).

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BY and JZ conceived and designed the research. JZ and XL collected and conducted data under the instruction of BY. JY supervised the study and provided funds. BY, LM, YZ participant in vivo experiments. JZ wrote the initial paper and BY revised the paper. All authors read and approved the final manuscript.

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Correspondence to Yindi Bao .

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Zhang, J., Yang, J., Li, X. et al. EMP1 correlated with cancer progression and immune characteristics in pan-cancer and ovarian cancer. Mol Genet Genomics 299 , 51 (2024). https://doi.org/10.1007/s00438-024-02146-1

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Published: 15 May 2024

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

Giada De Lazzari ORCID: orcid.org/0000-0002-5217-8201 1 ,
Alena Opattova ORCID: orcid.org/0000-0002-4508-6560 1 &
Sabrina Arena ORCID: orcid.org/0000-0002-1318-2494 1 , 2

Journal of Experimental & Clinical Cancer Research volume 43 , Article number: 146 ( 2024 ) Cite this article

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Over the last few decades, the incidence of urogenital cancers has exhibited diverse trends influenced by screening programs and geographical variations. Among women, there has been a consistent or even increased occurrence of endometrial and ovarian cancers; conversely, prostate cancer remains one of the most diagnosed malignancies, with a rise in reported cases, partly due to enhanced and improved screening efforts.

Simultaneously, the landscape of cancer therapeutics has undergone a remarkable evolution, encompassing the introduction of targeted therapies and significant advancements in traditional chemotherapy. Modern targeted treatments aim to selectively address the molecular aberrations driving cancer, minimizing adverse effects on normal cells. However, traditional chemotherapy retains its crucial role, offering a broad-spectrum approach that, despite its wider range of side effects, remains indispensable in the treatment of various cancers, often working synergistically with targeted therapies to enhance overall efficacy.

For urogenital cancers, especially ovarian and prostate cancers, DNA damage response inhibitors, such as PARP inhibitors, have emerged as promising therapeutic avenues. In BRCA -mutated ovarian cancer, PARP inhibitors like olaparib and niraparib have demonstrated efficacy, leading to their approval for specific indications. Similarly, patients with DNA damage response mutations have shown sensitivity to these agents in prostate cancer, heralding a new frontier in disease management. Furthermore, the progression of ovarian and prostate cancer is intricately linked to hormonal regulation. Ovarian cancer development has also been associated with prolonged exposure to estrogen, while testosterone and its metabolite dihydrotestosterone, can fuel the growth of prostate cancer cells. Thus, understanding the interplay between hormones, DNA damage and repair mechanisms can hold promise for exploring novel targeted therapies for ovarian and prostate tumors.

In addition, it is of primary importance the use of preclinical models that mirror as close as possible the biological and genetic features of patients’ tumors in order to effectively translate novel therapeutic findings “from the bench to the bedside”.

In summary, the complex landscape of urogenital cancers underscores the need for innovative approaches. Targeted therapy tailored to DNA repair mechanisms and hormone regulation might offer promising avenues for improving the management and outcomes for patients affected by ovarian and prostate cancers.

In this review, we aimed to explore the complex landscape of urogenital cancers, with a specific focus on the current therapeutic approaches available, particularly for ovarian and prostate cancer. We highlight the pivotal roles played by genomic instability and DNA repair mechanisms in both the development and treatment of these malignancies. We emphasize the crucial impact of mutations in DNA repair genes, which have paved the way for targeted therapeutic interventions. Furthermore, we underscore the intricate interplay between hormonal dysregulation and DNA damage, suggesting potential for new treatment modalities. Finally, we shed light on the importance of advanced models as genetically engineered mouse models, patient-derived xenografts and organoids. These models not only mimic human cancers more accurately, but also serve as indispensable tools in guiding the development of tailored therapies in the frame of a precision medicine approach in the battle against urogenital cancers.

Urogenital cancers: insights from ovarian and prostate tumorigenesis

Urogenital cancers encompass a diverse array of malignancies affecting the urinary and reproductive systems, arising from organs like the kidneys, bladder, prostate, testicles, ovaries, uterus, and related structures [ 1 ]. Each cancer type within this spectrum possesses unique characteristics, risk factors, and treatment approaches [ 2 ]. Therefore, early detection, accurate diagnosis, and timely intervention are crucial for improving outcomes in individuals diagnosed with these cancers [ 1 ]. A fundamental aspect of cancer development lies in the role of DNA repair mechanisms. In healthy cells, DNA repair mechanisms accurately fix genetic damage, preserving genomic stability. However, compromised repair systems lead to the accumulation of DNA damage, resulting in accumulation of mutations and genomic instability, which are key hallmarks of cancer [ 3 , 4 ]. Inherited defects in DNA repair genes, such as BRCA1/2 in breast, ovarian and prostate cancers, significantly increase the risk of tumor development [ 3 ]. Tumors exploiting deficient repair pathways become reliant on alternative mechanisms, driving genomic instability and cancer progression. This understanding of repair deficiency in cancer cells has led to the identification of specific therapeutic targets [ 5 ]. For instance, as demonstrated by González-Martín and colleagues, cancers with impaired homologous recombination (HR) are particularly sensitive to PARP inhibitors (PARPi) and the authors demonstrate the effectiveness of niraparib as specific therapeutic agent against HR in treating patients with ovarian cancer [ 6 ]. Given the critical role of DNA repair pathways in cancer progression, in this review we will delve these mechanisms focusing on two main subtypes of urogenital cancer, ovarian and prostate tumors.

Both these cancers, while distinct in their manifestation and impact on different genders, share common ground in the molecular dysregulation of cellular processes, including DNA repair pathways and common mutation in genes such as BRCA1/2 [ 7 , 8 ].

Ovarian cancer (OC), often termed as the “silent killer,” is the sixth most common cancer and the fifth for mortality in women and it poses unique challenges due to its asymptomatic nature in early stages [ 2 , 9 ]. Globally, the incidence and mortality rates of OC exhibit considerable geographical variability: higher incidence is shown in Northern Europe and the United States and lower in Japan while its mortality has exhibited a notable decrease from 2017 through 2020 [ 2 , 10 ]. The etiology of OC is multifaceted, implicating a range of risk factors. Advanced age emerges as a significant contributor, with the majority of cases diagnosed in postmenopausal women [ 9 , 11 ]. The pathophysiology of OC involves the dysregulation of key cellular processes, including uncontrolled cell proliferation and evasion of apoptosis, often leading to the formation of epithelial tumors [ 12 , 13 ]. Diagnostic strategies for OC encompass protein and imaging diagnostics, along with preoperative assessments, employing methods like different index assays as described in the work of Liberto and colleagues [ 14 ]. As pointed out in this and other works [ 14 , 15 , 16 ] a panel of four marker for OC diagnosis including CA125, CA72-4, CA15-3, and MCSF can help in increasing the sensitivity of the technology. Together with protein markers also imaging diagnostics have evolved; imaging techniques, such as ultrasound and magnetic resonance imaging (MRI), help in visualizing tumors and assessing their extent [ 17 , 18 ]. The complexity of OC is also reflected on treatment modalities since surgical interventions, including hysterectomy and oophorectomy are often employed as first line treatment [ 19 ]. The surgical approach is often reinforced by chemotherapy, with agents like cisplatin, carboplatin and taxanes (e.g. paclitaxel) and targeted therapies such as PARPi in specific genetically altered tumors [ 19 , 20 ]. Preventive strategies and screening programs are integral components of the comprehensive approach to urogenital cancers. Risk-reducing measures, such as prophylactic surgery for individuals with high-risk genetic mutations, offer a preventive option for OC [ 21 , 22 ]. However, challenges persist in developing effective screening methods for OC due to its often asymptomatic nature in early stages [ 21 , 22 ]. Moreover, OC distinctly highlights how genetic and molecular dysregulations in the urogenital tract can lead to malignancy. Genetic mutations, notably in the BRCA1 and BRCA2 genes but also in TP53 , KRAS and PIK3CA , are central to understand this type of tumor since they highlight broader tumorigenic processes across OC [ 23 , 24 ]. In fact, beyond their known role in double-strand DNA break repair pathways and in particular in the regulation of HR, these mutations also have other functions such as being a regulator of oxidative stress and cell cycle progression ( BRCA1 ) or being involved in transcriptional regulation ( BRCA1/2 ) [ 25 , 26 ]. In this context, starting from the main function of these genes, researchers have increasingly emphasized the analysis of the link between their dysregulation and tumorigenesis and consequently the study of homologous recombination repair (HRR) deficiencies which has led to significant therapeutic advancements on urogenital cancers [ 26 , 27 , 28 ]. Moreover, the observed heterogeneity in ovarian tumor cells, including variations in the tumor microenvironment and metabolic pathways, offers a deeper understanding of tumorigenesis. The intricate interactions within the ovarian tumor microenvironment, involving stromal cells, immune evasion mechanisms, and angiogenesis, further elucidate the complexities of tumorigenesis in the urogenital system. This understanding is pivotal in developing targeted therapeutic strategies, as it reveals how cancer cells manipulate their surroundings for survival and growth. Moreover, the metabolic adaptations seen in OC cells provide insights into potential vulnerabilities that could be therapeutically exploited, indicating how metabolic dysregulation in the urogenital tract can contribute to cancer development [ 29 ].

Prostate cancer (PC) is the most common type of solid cancer and the second cause of cancer-related death in men [ 2 ]. The etiology of PC includes different types of risk factors such as age, race, family history, and germline mutations ( BRCA1/2, CHEK2, ATM ) [ 30 ]; in addition, metabolic syndrome, obesity, and smoking have been identified as possible risk factors [ 31 ]. PC is characterized by different stages, from intraepithelial neoplasia and localized PC, to the advanced prostate adenocarcinoma with local invasion. The most advanced stage, metastatic PC (mPC), is characterized by the invasion of other different organs and tissues in the body. For the grading of PC, the Gleason grading system is used [ 32 ]. Early detection is crucial for successfully treating PC. Various screening methods aim to improve cancer detection in its early stages, with the prostate-specific antigen (PSA) test being the most widely promoted and FDA-approved method since 1986. PSA, typically found at low levels in the blood, becomes elevated in the presence of prostatic disease due to disruption in organ microarchitecture [ 33 ]. However, the low specificity of the PSA test necessitates additional measures to reduce unnecessary prostate biopsies, leading to the development of the prostate health index (PHI) blood test. This test combines free and total PSA with the (− 2) pro-PSA isoform (p2PSA) to enhance accuracy [ 34 ]. Recent studies showed Prostate Cancer Antigen 3 (PCA3) as overexpressed in 95% of PC cases, leading to the development of a non-invasive urine PCA3 test for screening [ 35 ]. Usually, the screening starts for 50-year-old men, but for high-risk individuals (germline mutations in BRCA1, BRCA2, ATM, CHEK2 ; family history of PC) the screening should commence as early as age 40 [ 36 ]. Diagnostic strategies for PC include MRI combined with dynamic contrast-enhanced MRI and more specific Prostate-Specific Membrane Antigen (PSMA) positron emission tomography PET/CT [ 37 ].

PC is well known by high morphological and genetic heterogeneity [ 38 ]. The main genetic alterations in PC affect androgen receptor (AR), Phosphatidylinositol-3-kinase/ Phosphatase and tensin homolog (PIK3CA–PTEN ), WNT , and genes involved in DNA repair signaling pathways ( BRCA1, BRCA2, ATM, CHEK2 ) [ 39 ].Treatment options for PC depend on the stage of the disease. For localized disease, active surveillance, radical prostatectomy, or ablative radiotherapy are employed. Patients with localized disease show a favourable outcome if the disease is early detected and treated. For the advanced stages, radiotherapy and/or androgen deprivation therapy are used. For the mPC, AR-targeted agents, chemotherapy (taxanes), and radionuclides are used [ 40 ]. As we already mentioned, PC is characterized by the presence of DNA repair mutations, which increases in the metastatic setting of the PC. Therefore, the PARPi olaparib has been approved for use in patients with BRCA2 mutations [ 41 ]. However, after an initial response, PC can progress in developing castration resistance (CRPC), posing ongoing challenges in disease management.

In this first section of this review, we aimed to explore urogenital cancers tumorigenesis which helps our understanding of these particular type of cancers but also provides critical insights into the mechanisms of cancer development. Both tumors share notable similarities for example in DNA damage and repair mechanisms, hormonal regulation and key tumor characteristics. They both frequently exhibit defects in DNA damage repair (DDR) pathways, such as homologous recombination (common mutations in BRCA genes) [ 42 ], and hormone regulation plays a significant role in both, with estrogen receptor signaling influencing OC and androgen receptor pathways being pivotal in PC [ 43 ]. Additionally, both cancers often develop resistance to hormone-based therapies and may respond to PARPi, highlighting shared therapeutic vulnerabilities [ 44 ]. Due to these similarities, from now on this review will be mainly focused on mechanisms of DNA damage and repair and hormonal regulation in the context of OC and PC by evaluating the currently available therapeutic strategies and preclinical available models for both cancers.

Deconvolution of urogenital cancer complexity

Exploring the role of OC and PC in the urogenital tract tumorigenesis lays the groundwork for understanding cancer’s broader complexities. This exploration extends to the fundamental framework of the hallmarks of cancer, delving into genetic instability and synthetic lethality, which are pivotal in comprehending the multifaceted nature of cancer. In this scenario, cancer research underwent a paradigm shift with the introduction of the “Hallmarks of Cancer” by Hanahan and Weinberg in their 2000 publication [ 45 ]. This concept delineates a set of mechanisms acquired by human cells during their transition from normal to neoplastic states, crucial for malignant tumor development [ 45 ]. Initially, Hanahan and Weinberg outlined six biological capabilities acquired during the multistep development of human tumors, such as insensitivity to antigrowth signals, evasion of apoptosis, sustained angiogenesis, limitless replicative potential, tissue invasion and self-sufficiency in growth signals [ 46 ]. Subsequently, this list was expanded to eight hallmarks and two enabling characteristics by incorporating tumor-promoting inflammation, genome instability and mutation and the ability of cancer cells to often undergo changes in their metabolism and to avoid immune system destruction [ 47 ]. Among these hallmarks, “Genome Instability and Mutation” holds a central position, driving the acquisition of other hallmarks.

Genomic instability, defined as an increased susceptibility of a cell's genome to acquire mutations, stems from defects in DNA repair mechanisms, replication errors, exposure to mutagenic agents, or other genetic or environmental factors, leading to high mutation rate and resulting in a heterogeneous tumor population with diverse genetic compositions [ 48 , 49 ].

In the context of OC, one of the most significant implications of genomic instability is the development of resistance both primary and secondary to platinum-based chemotherapy, a cornerstone of its treatment [ 50 , 51 , 52 ]. Primary resistance occurs when cancer cells exhibit intrinsic resistance to therapeutic agents, while secondary (acquired) resistance develops over time, likely due to adaptation to treatment selection pressure [ 50 , 53 ] For instance, alterations in the BRCA1/2 genes, which are crucial for HRR, are common in OC and can confer initial sensitivity to platinum-based therapies. During treatment, the occurrence of reversion mutations in these genes can restore lost repair function, leading to drug resistance [ 51 , 54 ]. Furthermore, other recent studies have identified additional genetic alterations that contribute to platinum resistance in OC, such as mutations in RAD51C and RAD51D , which further complicate the treatment landscape [ 55 , 56 ]. Additionally, the high degree of genomic instability in OC can correlate with tumor heterogeneity, as demonstrated by Bashashati and colleagues [ 57 ], revealing distinct genetic profiles among tumor subclones that may respond differently to the therapy In line with this, researchers start to explored the implications of intratumor heterogeneity in OC prognosis, emphasizing the need for personalized treatment approaches [ 58 ]. Liquid biopsy technologies offer dynamic and precise monitoring of these genetic variations, aiding in the assessment of treatment response and disease progression [ 58 , 59 , 60 ]. The genomic instability of both OC and PC has also opened new avenues for targeted therapy. PARPi, for example, exploit the concept of synthetic lethality in cancer cells deficient in HRR as seen in BRCA -mutated OC and PC [ 61 , 62 ]. Recent advancements in this area have shown promising results in the use of PARPi in prolonging progression-free survival especially in patients carrying BRCA mutation and HRD-positive status [ 63 , 64 ]. However, the adaptive capacity of cancer cells due to genomic instability presents an ongoing challenge. This adaptive nature of cancer due to its genomic instability, not only leads to challenges like chemoresistance and tumor heterogeneity, but also paves the way for innovative therapeutic strategies, such as those exploiting synthetic lethality [ 65 ]. In a synthetically lethal relationship, the simultaneous impairment of two genes or pathways leads to cell death, whereas the disruption of either alone is tolerable to the cell. This concept is particularly relevant in cancer cells, which often harbour specific genetic mutations making them susceptible to targeted therapies that exploit their inherent genetic weaknesses [ 65 ]. PC and OC are a prime candidate for therapies based on synthetic lethality; indeed, BRCA mutations impair the HR DNA repair pathway, making the cancer cells more dependent on alternative repair mechanisms [ 66 ]. This dependency creates an opportunity for targeted therapy as we have already discussed. More recent studies have expanded on these findings exploring the broader implications of synthetic lethality focusing especially on the combination therapies that integrate synthetic lethality concepts. Lord and Ashworth investigated the synergistic effects of combining PARPi with other targeted agents, offering novel strategies to overcome resistance mechanisms that OC cells develop in response to monotherapy [ 5 ]. While genomic instability poses significant challenges in the form of chemoresistance and tumor heterogeneity, it also provides opportunities for developing innovative targeted therapy strategies. The latest studies in the field reinforce the potential of synthetic lethality in offering effective, personalized treatment options for OC, catering to its adaptive nature and genetic diversity.

DNA damage: DNA repair mechanisms in ovarian and prostate tumors

As highlighted in the previous section, the ongoing research in genomic instability and synthetic lethality in OC and PC treatment sparks discussion about the intricate interplay among genomic instability, DNA damage, and repair mechanisms. Understanding these mechanisms is pivotal in this context where DDR plays a significant role in disease development and progression. A wealth of literature has been published on this topic and here we aim to provide a concise overview of the key concepts, primarily focusing on urogenital tumors.

DNA damage can be broadly categorized into two groups: single-strand breaks (SSBs) and double-strand breaks (DSBs). SSBs are the most common and are generally less harmful as the complementary DNA strand remains intact, serving as a template for repair. In contrast, DSBs are more critical and can lead to significant genomic instability if not appropriately repaired [ 47 ]. This distinction is crucial in the context of urogenital cancers, where genetic material integrity is paramount for cell function [ 67 ].

Cells have evolved several mechanisms to repair damaged DNA, each tailored to specific types of damage. These includes Nucleotide Excision Repair (NER), which is primarily responsible for repairing bulky DNA lesions caused by UV radiation and certain chemicals; Base Excision Repair (BER) which corrects small, non-helix-distorting base lesions caused by oxidation or methylation. In addition, Mismatch Repair (MMR) corrects errors that occur during DNA replication. Defects in MMR are known to contribute to the development of certain types of cancers, including urogenital cancers [ 47 ]. Finally, HR and Non-Homologous End Joining (NHEJ) are two critical pathways for repairing DSBs. HR is an error-free repair process utilizing a sister chromatid as a template for repair, while NHEJ is an error-prone process directly joining broken end [ 49 ]. These cancers often exhibit inherent defects in DNA repair pathways, particularly in HR [ 68 ]. DNA damage and repair mechanisms are critically linked to the therapeutic potential of DDR inhibitors (DDRi). These inhibitors, such as PARPi, target mechanisms that cancer cells rely on for survival and proliferation exploiting the concept of synthetic lethality [ 46 ]. As discussed in the previous paragraph, BRCA1 and BRCA2 mutations impair HR repair in OC and make OC cells particularly vulnerable to PARPi. By inhibiting PARP enzymes, which play a crucial role in single-strand break repair, these drugs exacerbate DNA damage in cells already compromised in their ability to repair double-strand breaks, leading to cell death. For this reason, this approach is often use therapeutically [ 69 ] and clinical trials with PARPi in OC are extensively reported in different studies [ 70 , 71 , 72 ]. However, the scope of DDRi extends beyond PARPi and BRCA mutations. Recent studies have shown that other DDR pathways and inhibitors are also clinically significant; indeed, we will focus on other DDRi such as ATRi, CHK1i, WEE1i and DNA-PKi. For instance, inhibitors targeting the ATR-CHK1-WEE1 axis, which are key components of the DDR involved in the cell cycle checkpoint regulation, have shown promise in preclinical models of OC [ 73 ]. These inhibitors can enhance the effects of DNA-damaging chemotherapy and radiation therapy, offering a potential combinatorial approach to cancer treatment. For this reason, several clinical trials based on ATR-CHK1-WEE1 axis are further exploring this avenue (Table 1 ) [ 47 ]. Addressing this challenge requires a deeper understanding of resistance mechanisms and the development of next-generation DDR inhibitors able to overcome it [ 74 ]. When developing new DDRi, tailoring treatments based on individual genetic profiles is imperative. As suggested in the work of Foster and colleagues, genomic sequencing can identify specific DNA repair deficiencies in tumors, guiding the selection of appropriate DDR inhibitors [ 75 ]. This precision medicine approach ensures that patients receive the most effective treatment tailored to their unique cancer biology.

Comprehensive molecular characterization of PC has revealed a significant inter-patient genomic heterogeneity and phenotypic diversity. The most prominently altered pathways include androgen signaling (50%), PI3K signaling (40%), the cell cycle (24%), WNT/beta-catenin signaling (19%), RAS pathway (8%) [ 76 , 77 ] along with DDR pathways (27%) [ 78 ]. Recent studies have indicated that germline mutations in DDR genes are associated with a higher risk of developing PC and worse clinical outcomes as well as with aggressive phenotype with increased probability to develop metastasis [ 79 ]. Approximately 10–19% of primary PCs exhibit somatic alterations in DDR genes, with this number increasing to 23–27% in the metastatic setting. Mateo and colleagues showed differences in AR, TP53, RB1 , and PI3K/AKT mutational status between matched hormone-naive and metastatic castration-resistant prostate cancer (mCRPC) biopsies [ 80 ]. Furthermore, multicentric study on a cohort of 150 mCRPC showed increased aberrations of BRCA2, BRCA1 and ATM (19.3%) compared to primary PCs [ 81 ]. Taken together this introduces important prognostic value of DDR mutations. Current studies and clinical trials indicated that alterations in DDR genes also contribute to disease progression and therapy response in PC [ 41 ]. Initially identified mutations in DDR genes were BRCA1 and BRCA2 genes, followed by discoveries of germline or somatic mutations also in other DDR genes e.g.: ATM, CDK12, FANCA, RAD51B, and RAD51C, CHEK2 in PC [ 76 , 82 ] . Inactivating mutations in these tumor suppressor genes increase predisposition to PC. Moreover, loss-of-function mutations of DDR-associated genes leads to a deficiency in error-free HR repair. DSBs are then repaired by alternative repair pathways that are more error-prone, e.g. NHEJ. Consequently, these lead to the genetic instability of the tumor. Despite this, these genes present potential therapeutic targets in PC [ 41 ]. Increasing evidence suggests that other DNA repair pathways, such as a MMR and BER, may play an important role in PC. Approximately 4% of PC tumors and 6% of metastatic PCs (mPC) had alterations in MSH2 and MSH6 , with clinical implications such as resistance to immune checkpoint inhibitors (ICIs) noted in MMR-deficient patients [ 83 ]. Vasquez and colleagues showed that upregulation of BER related genes is associated with poor survival in PC patients, with inhibition of BER by natamycin significantly impaired PC cells proliferation in androgen depleted PC [ 84 ]. As pointed out before, genome instability is one of the important hallmarks of cancer [ 4 ] and DDR is responsible for the maintenance of genome integrity. In PC, cancer cells frequently harbour DDR gene deficiencies, providing a potential avenue for targeting DDR to induce cancer cell death. The PARPi olaparib was initially approved for the treatment of advanced ovarian and breast cancers associated with germline BRCA1 or BRCA2 mutations [ 85 ]. Clinical trials such as the TOPARP have demonstrated high response rates to PARPi in patients with DDR gene defects [ 39 ]. The clinical trial TOPARP-B studied the antitumour activity of olaparib against mCRPC with DDR gene aberrations [ 86 ]. Similar results have been obtained in clinical trials with rucaparib [ 87 ]. Based on these studies PARPi were approved by FDA for PC treatment in 2020 and the importance of these pathways in PC therapy response is also confirmed by the number of clinical trials already performed or currently ongoing [ 88 ]. Additionally, ongoing trials focusing on components like the ATR-CHK1-WEE1 axis suggest potential novel therapeutic options, as single agents or combinations, for PC. Drapela and colleagues showed synergistic effect of CHK1 inhibitor MU380 with gemcitabine in in vitro model of CRPC [ 89 ]. ATR inhibition led to the destabilization of PD-L1 protein in vitro. This indicates potential possibility to use of ATRi in combination with immune checkpoint blockade as a novel therapy option [ 90 ]. Examples of ongoing clinical studies focused on ATR-CHK1-WEE1 are summarized in the table below (Table 2 ).

How could the combination of PARPi and immune checkpoint inhibitors (ICI) affect “cold” tumor treatment?

Immunotherapy has emerged as novel approach in the oncological landscape and among the most promising strategies in this field are immune checkpoint inhibitors (ICIs), which have revolutionized cancer treatment by promoting the body's immune system to recognize and combat tumor cells. In particular, ICIs efficacy has recently seen a relevant improvement in tumors such as ovarian ad prostate ones, that are generally considered as immunologically "cold" due to their low mutation burden and reduced immunogenicity [ 91 , 92 ]. The most involved checkpoints pathways include the programmed cell death protein 1 (PD-1), PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) which modulate T cell function. In the PD-1/PD-L1 pathway, PD-1, a receptor expressed on T cells, binds to PD-L1, which is expressed on tumor cells and some immune cells. This interaction results in the inhibition of T cell activation and proliferation, thereby dampening the immune response against cancer cells. CTLA-4, on the other hand, reduces the activation of T cells, further downregulating the immune response [ 93 , 94 ]. These immune checkpoint pathways have emerged as promising targets for cancer immunotherapy, with the development of monoclonal antibodies against PD-1 (e.g. nivolumab, pembrolizumab), PD-L1 (e.g. avelumab, atezolizumab, durvalumab) and CTLA-4 (e.g. ipilimumab) showing clinical efficacy in the treatment of various cancers [ 93 , 95 ]. By inhibiting checkpoint molecules, ICIs are also beginning to show promise in overcoming the immune resistance often encountered in OC and PC treatment. Recent advancements have aimed to overcome these challenges by combining ICIs with other therapies such as chemotherapy, targeted therapy, and PARPi, which may affect the tumor microenvironment to enhance immune response [ 88 , 96 , 97 ]. In particular, the combination of PARPi and ICIs is being actively explored in clinical trials. In OC the main ICIs approved and used in clinical trials are pembrolizumab, nivolumab and ipilumab and they are used either alone (NCT02674061, NCT01611558 and NCT02728830) or in combination with chemotherapeutic agents such as paclitaxel (NCT03394885 and NCT02440425) and carboplatin (NCT03029598) or with PARPi such as rucaparib (NCT03824704, ARIES study) or niraparib (NCT02657889, TOPACIO study). From these clinical trials of note for their results are the TOPACIO/Keynote-162 study, the MEDIOLA study and the NCT2484404 study [ 98 ]. The TOPACIO study evaluated the combination of pembrolizumab and niraparib in recurrent platinum-resistant epithelial OC patients. The preliminary results of this study appear promising, being 4/8 evaluable OC patients responsive and the other 4 patients achieving SD, highlighting the importance of this combinatorial approach especially for OC and also other tumors with poor response to immunotherapy alone [ 99 ]. The MEDIOLA study evaluated the effect of the combination of olaparib and durvalumab (anti-PD-L1) in PARPi and ICI naïve BRCA mutant OC patients. As preliminary results, the combination has shown a high objective response rate (92%) in germline mutant BRCA patients, while the combination of olaparib, durvalumab and bevacizumab resulted as the best treatment for BRCA wild-type patients [ 100 ]. The results obtained from the MEDIOLA study were also confirmed by the NCT2484404 study in which the combination of olaparib and durvalumab was evaluated in patients with recurrent OC , showing also in this case a good tolerability for this treatment [ 101 ]. The encouraging results observed from this combinatorial treatment approach is fostering the design of novel clinical trial that might improve the response of OC to PD-1/PD-L1 and CTLA-4 inhibitors OC [ 102 ].

In PC, pembrolizumab has been approved only for patients with high microsatellite instability and deficient mismatch repair, which occur in 2–4% of cases [ 103 ]. There are several clinical studies to evaluate the effect of pembrolizumab alone [ 104 , 105 ] and in combination with enzalutamide [ 106 , 107 ] docetaxel [ 108 ] and olaparib [ 105 ] in PC. Initial data showed that only a minor subset of heavily pretreated patients can benefit from pembrolizumab therapy [ 104 ]. For example, in the Keynote 028 study, 23 patients with mCRPC positive for PD-L1 expression were enrolled and received pembrolizumab treatment, only four patients responded positively [ 104 ]. Keynote199 study showed that pembrolizumab as a monotherapy has antitumor activity in the bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy (enzalutamide and abiraterone). This study also showed that 12% of the patients had aberrations in BRCA1/2 or ATM , and 10 (7%) had alterations in 12 or more other HRR genes. None of the six patients who experienced a response with evaluable genomic data had microsatellite instability. Taken together, responders with BRCA1/2 or ATM mutations had a longer response duration than responders without HRR aberrations [ 109 ]. The effect of the combination of olaparib and PD-1 has been published in several types of tumors [ 110 ]. In case of PC results of the combinational treatment with pembrolizumab and olaparib showed limited efficacy. Moreover, the efficacy was independent of HRR status and PD-L1 status [ 111 ]. When in combination, pembrolizumab plus enzalutamide in mCRPC previously treated with abiraterone showed limited antitumor activity. The phase 1b or 2 KEYNOTE-365 trial study included molecularly unselected docetaxel-treated mCRPC patients.

Recent studies indicate that ICIs alone and in combinations have only moderate effects in PC, but accurate predictive biomarkers have yet to be established for PC. Moreover, all the studies were performed on heavily pretreated and molecularly not selected patients. On a base of recent findings about pembrolizumab therapy and HRR [ 109 ], ICIs may be more effective in specific groups of molecularly selected PC patients carrying HRR defects. For example, as we have already mention above, the combination of ATR inhibition and anti-PD-L1 treatment resulted in synergistic, antitumor activity in PC [ 90 ]. This potent combination has already been tested in early-phase clinical trials in advanced malignancies (NCT04266912 and NCT04095273).

Hormonal regulation and its implications for DNA damage and repair

DNA damage in urogenital cancers is often pervasive, resulting from both endogenous metabolic processes and exogenous factors like radiation or chemotherapy [ 112 ]. Internally, DNA damage may arise from errors in DNA replication, reactive oxygen species (ROS) generated during cellular metabolism and natural cellular processes like hormone metabolism, particularly relevant in urogenital cancers [ 113 , 114 ]. While the previous paragraph addressed errors in DNA replication, we now aim to delve into hormonal regulation and its implication for DNA damage and repair in OC and PC, two hormone-regulated malignancies (Fig. 1 ).

Interplay between hormones and DNA Repair in BRCA -deficient cancers. The figure indicates the intersection of hormone therapy with the concept of 'BRCAness' in the context of ovarian (left side) and prostate (right side) cancer. In the nucleus, the DNA carrying BRCA1/2 mutations undergoes damage that can’t be repaired by the homologous recombination-based system. The inhibition of PARP, a key enzyme in the repair of single-strand DNA breaks, leads to synthetic lethality in these mutated cells, resulting in cell death. Modulation of estrogen (E), androgen (A) and progesterone (P) can influence the therapeutic landscape. Once the hormones enter inside the cells, they bind to their respective receptor (R) and might interact with different pathways and translocate to the nucleus to activate transcription of targeted genes. Inhibition of AR and ER blocks receptor translocation and might exert synthetic lethality with DNA damage response inhibitors, while the effect promoted by PR regulation through PR modulators (PRMs) remains still unclear

Hormonal regulation plays a significant role in the pathophysiology of OC. Ovarian hormones, primarily estrogen and progesterone, have been shown to affect cell proliferation, apoptosis, and DNA repair mechanisms [ 115 ]. A list of the main hormonal therapy and the respective clinical trials is presented below (Table 3 ).

Estrogen receptors (ER), primarily ERα and ERβ, are nuclear hormone receptors that mediate the effects of estrogen in target tissues. ERα is commonly associated with proliferative responses, while ERβ is thought to counteract these effects and is often linked with protective roles in cancer [ 116 ]. The mechanism of action of ERs involves the binding of estrogen, which facilitates their dimerization and subsequent binding to estrogen response elements (EREs) in the DNA. This binding initiates transcriptional regulation of various genes involved in cell growth, survival and differentiation [ 116 ]. In OC, the expression and activity of these receptors can significantly influence tumor behavior and patient prognosis. Recent studies, have highlighted the complex role of ERs in OC, demonstrating how ERα and ERβ can differentially regulate gene expression and contribute to cancer progression [ 117 , 118 , 119 ]. The link between ERs and DNA damage and repair mechanisms is an area of growing interest. Estrogen, through ER-mediated signaling, can influence the expression and activity of genes involved in DNA repair pathways, including HR and NHEJ [ 120 , 121 ]. While a considerable amount of literature has explored the relationship between hormonal regulation and DNA repair pathways, only a few studies have delved deeply into this area [ 122 ]. Some of them have shown that estrogen-induced ER activation can modulate the expression of key DNA repair proteins, such as BRCA1 and RAD51 ; this modulation can affect the efficiency of DNA repair mechanisms, influencing the sensitivity of OC cells to DNA-damaging agents [ 123 ]. Moreover, estrogen itself can be a source of DNA damage. Its metabolism can generate ROS and genotoxic metabolites, leading to DNA adducts and mutations and further implicating ER signaling in genomic instability [ 124 ]. Dysregulation of ERs, either through overexpression, mutation, or altered signaling pathways, can have significant implications in cancers, including OC [ 69 ]. Overexpression of ERα has been associated with increased tumor proliferation and poor prognosis. Conversely, loss or reduced expression of ERβ is often observed in OC and is thought to contribute to tumor aggressiveness and resistance to therapy [ 125 ]. Some researchers also highlighted the impact of ER dysregulation on the efficacy of hormonal therapies in BRCA mutant cancers showing that alterations in ER expression or function could lead to resistance to agents like selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) [ 126 , 127 ]. On the other hand, progesterone has been shown to exert a protective effect against the development of OC. Progesterone receptors (PR), existing in two main isoforms PR-A and PR-B, are expressed in ovarian tissue and influence various cellular processes. While PR-B is typically associated with progesterone's classical reproductive actions, PR-A can act as a dominant negative inhibitor of both PR-B and ERs [ 128 ]. Progesterone receptors, which exist in two isoforms, upon binding progesterone, undergo conformational changes, dimerize, and translocate to the nucleus where they bind to progesterone response elements (PREs) in the DNA. This binding initiates the transcription of various genes involved in cell proliferation, differentiation and survival. The mechanism is tightly regulated and is subject to modulation by various co-factors and cellular contexts [ 129 ]. These mechanisms have been explored in different studies in which it was demonstrate that PR signaling can influence tumor behavior and response to therapy [ 129 ]. Currently, different clinical trials are focusing on PR signaling, especially evaluating the therapeutic potential of progesterone receptor modulators (PRMs), a new class of synthetic compounds, such as mifepristone (NCT02014337, NCT02046421). PRMs compete in the binding sites of the PR and can act both as agonist or antagonists respectively by inducing or inhibiting transcriptional activation of the PR making them more clinically relevant [ 130 ]. Of note, interest in studying the relationship between PR signaling and DNA damage and repair mechanisms is increasingly emerging. Progesterone has been shown to impact the expression of genes involved in DNA repair pathways, potentially influencing genomic stability, but the mechanism remains still unknown [ 131 ]. Some work suggests that progesterone-activated PRs may modulate the expression of key DNA repair proteins and influence the cellular response to DNA damage [ 132 ]. This modulation may have critical implications in the context of OC, where DNA repair capacity can significantly affect tumor behavior and treatment response. Dysregulation of PR signaling, either through altered receptor expression, mutations, or changes in ligand availability, can significantly affect OC since the overexpression or constitutive activation of PRs can lead to abnormal stimulation of target genes, contributing to tumorigenesis and progression [ 133 ]. Conversely, loss of PR expression or function has been associated with a more aggressive tumor phenotype and poorer prognosis in OC [ 132 ]. In OC, also AR can play a critical role despite its pivotal role in other malignancies such as PC. In the work by Chung and colleagues, the researchers point out that AR can contribute to tumorigenesis, metastasis and chemoresistance [ 134 ]. Although OC is more traditionally associated with estrogen and progesterone receptors, different other studies have highlighted AR involvement in OC. AR expression has been observed in various subtypes of OC and its activation has been linked to tumor growth and poor prognosis suggesting that targeting AR signaling, especially with AR antagonists such as enzalutamide, might represent a potential therapeutic strategy for OC [ 134 , 135 , 136 ]. In this context, abiraterone, a potent inhibitor of the enzyme CYP17A1, plays a crucial role in androgen biosynthesis and has been explored as a therapeutic agent in AR-driven cancers. The CORAL (Cancer of the OvaRy Abiraterone triaL) study (NCT04476030) was designed to evaluate the clinical activity of abiraterone in epithelial OC and it is the only one currently available in the literature. In this trial a subset of patients derived sustained clinical benefit providing important information regarding the role of AR-mediated signaling inhibition in patients with recurrent, advanced epithelial OC (EOC) [ 137 ]. This trial represents a significant effort to target the AR pathway in OC, potentially offering a new therapeutic avenue for patients with AR-positive tumors.

The intricate relationship between hormonal influences and DNA repair processes in OC offers insights into novel therapeutic strategies, including the use of hormonal therapies for which many clinical trials exist. These therapies aim to modulate or block hormonal effects, particularly those of estrogen [ 132 ]. SERMs, AIs and Gonadotropin hormone-releasing hormone (GnRH) analogs are among the primary classes of hormonal therapies used [ 138 ]. SERMs, such as tamoxifen, function by competitively binding to estrogen receptors, thereby inhibiting estrogen-mediated signaling in cancer cells. In different clinical trials were evaluated the effect of different hormones; for example tamoxifen showing promising results in patients with resistant OC (NCT02728622). Aromatase inhibitors, including drugs like letrozole and anastrozole work by inhibiting the aromatase enzyme responsible for estrogen synthesis. Even in this case some trials assess the effectiveness of letrozole in advanced OC resistant or not to platinum therapy (NCT04720807, NCT04421547), demonstrating its potential. Finally, GnRH analogues, used primarily in premenopausal women, suppress ovarian function, thus reducing estrogen production [ 139 ].

Despite the potential of hormonal therapies, several challenges exist in their clinical application. Recent clinical trials have been instrumental in advancing our understanding of hormonal therapies in OC. As describe above, there are different clinical trials already focusing on SERMs or aromatase inhibitors, but fewer on the use of hormonal therapy in combination with other treatments, such as PARPi or other targeted therapies aiming to enhance efficacy and overcome resistance. As demonstrated in the work by Hao and colleagues, the intricate interplay between non-classical estrogen signaling and HRR deficiency in OC underscores the pivotal role of ERα in this process. In this study they provide evidence that ERα can exert a repressive effect on HRR activity identifying HR as an ERα target, thereby leading to an increased chemosensitivity of OC cells. [ 140 ] This work highlights the potential benefits of hormone replacement therapy in ameliorating the outcomes of OC treatment which can maybe be enhanced by combinatorial treatment with DDRi. Targeting the effects of estrogen and progesterone offers several advantages in the treatment of OC. One of the primary advantages of hormonal therapy is its targeted approach as we described before, since it allows targeting the hormonal key players in the proliferation and survival of OC cells. Compared to traditional chemotherapy, hormonal therapies generally present a more favourable toxicity profile. They are associated with fewer and less severe side effects, making them a more tolerable treatment option for many patients. Finally, hormonal therapies have also shown particular efficacy in certain subtypes of OC, such as estrogen receptor-positive (ER +) or low-grade serous carcinomas [ 141 ]. Despite these advantages, one of the major challenges with hormonal therapy is the development of resistance. Over time, OC cells can adapt to these therapies, altering their receptor expression or activating alternative signaling pathways, but there are only a few review articles in which this type of resistance is investigated and no research works are available [ 118 , 142 ]. Moreover, hormonal therapies are not universally effective across all OC subtypes. For example, high-grade serous OC (HGSOC), the most common and aggressive subtype, often does not effectively respond to hormonal therapy [ 118 ]. In summary, hormonal therapy in OC offers a targeted, less toxic alternative to traditional chemotherapy, with particular efficacy in certain cancer subtypes. However, challenges such as resistance development, limited efficacy in certain subtypes, and side effects cannot be overlooked. Thus, ongoing clinical trials and preclinical research are essential in addressing these challenges, improving therapeutic outcomes, finding alternatives to hormone therapy resistance and advancing personalized medicine approaches in the treatment of OC.

In PC, the AR is a member of the steroid hormone receptor family. AR signaling plays a fundamental role in physiological prostate development and function as well as in male morphologic development and configuration of the central neurons system [ 143 ]. The AR gene, located on the X chromosome, encodes 110 kDa protein composed of conserved DNA-binding domain and androgen-binding domain and a less conserved N-terminal transactivation domain [ 144 ]. AR influences transcription of androgen responsive genes. Recent findings showed the role of AR in PC growth and progression. In PC, AR can regulate cell proliferation, apoptosis, migration, invasion and cell differentiation [ 145 ]. Some studies also showed prognostic value of AR determined by immunohistochemistry, but the results are inconsistent and need to be verified [ 146 ]. PC development is dependent on androgens and androgen deprivation therapy (ADT) introduces an important therapeutic opportunity. ADT such as long-acting GnRH agonists (goserelin, histrelin, leuprolide, and triptorelin) or GnRH antagonists (degarelix), second-generation nonsteroidal AR antagonists (enzalutamide, apalutamide, and darolutamide) and the androgen biosynthesis inhibitor abiraterone are the first line therapy for patients with metastatic disease [ 147 ]. A list of the main hormonal therapy and the respective clinical trials is presented below (Table 4 ).

In 1% of primary PC cases, mutations and amplifications of the AR are observed, with this rate increasing to approximately 60% in metastatic tumors [ 148 ]. These mutations predominantly occur in the androgen-building domain of AR, resulting in antiandrogens (e.g. bicalutamide, hydroxyflutamide, enzalutamide, and apalutamide) functioning as AR agonists. This enables cancer progression and contributes to PC resistance to androgen deprivation therapy. Cai and colleagues showed that the T878A mutation has been associated with resistance to abiraterone in a xenograft PC model [ 149 ]. Moreover, mutant AR has been identified in circulating cell-free DNA [ 150 ]. Splicing variants of AR have also been detected in PCs, with AR-V7 splice variant also detected at the protein level [ 151 ]. AR-V7 is frequently detected in CRPC (around 75% of cases) [ 152 ]. Armstrong and collaborators in the prospective multicentric study (The PROPHECY Study) showed that AR-V7 detected in the blood of mCRPC was associated with shorter PFS and OS after abiraterone or enzalutamide treatment [ 153 ] On the other hand, in circulating tumor cells (CTCs) from AR-V7-positive PC, taxanes are more effective, while in AR-V7-negative PC, the effect is comparable [ 154 ]. In recent years, there is emerging evidence that AR signaling and the DDR pathways are related. Goodwin and collaborators showed that DNA damage induces AR activity, and active AR induces cell survival after DNA damage, indicating reciprocal regulation between AR and DDR. The study also revealed the impact of AR on the expression of DNA repair genes, identifying DNA PKcs as a key target of AR after DNA damage [ 155 ]. Furthermore, combining ADT with radiotherapy has been standard care approach for PC. RNAseq and Chipseq analysis on the xenograft model of castration-resistant PC LNCaP-AR, treated by enzalutamide, revealed downregulation of DNA repair genes. Further analysis defined 32 direct targets for AR, including RAD51C, MRE11A, CHEK1, LIG3 . AR signaling promotes double-strand DNA break repair and regulates the transcriptional program of DNA repair genes that promotes PC radio-resistance both in vitro and in vivo [ 156 ]. Previous studies showed that AR deprivation therapy enhances the effect of ionizing radiation by impairing NHEJ. However, AR signaling can also regulate HR genes. Asim and colleagues investigated the functional link between AR and HR, demonstrating decreased numbers of ionizing radiation-induced RAD51 foci in isogenic cells with low AR expression. Additionally, AR is required for effective ATM signaling mediated by MRE11. AR directly regulates HR activity, and androgen inhibition activates PARP signaling. Therefore, inhibition of AR is synthetically lethal with PARP inhibition in PC [ 157 ]. Furthermore, in PC, HR genes are frequently mutated, especially in mCRPC setting, offering potent therapeutic opportunities. The androgen inhibitor enzalutamide can suppress the expression of the HR genes, causing HR deficiency and BRCAness. This explains why enzalutamide and olaparib combination is effective in mCRPC patients and proves that also pharmaceutically induced BRCAness may expand the clinical use of PARPi [ 158 ]. A recent study showed that AR recruitment can be blocked by antineoplastic antibiotic mithramycin (MTM). MTM treatment caused the downregulation of AR target genes, including DDR genes. The study of Wang et al. discovered that MTM impaired DDR and enhanced effectiveness of the ionizing radiation and radiomimetic agent bleomycin [ 159 ]. Combining PARPi with AR inhibitors presents a powerful treatment option, as evidenced by several ongoing clinical studies. A phase 3 study is currently evaluating the PARPi niraparib in combination with apalutamide or abiraterone acetate plus prednisone in mCRPC [ 160 ]. Additionally, ongoing clinical studies are investigating combinations of enzalutamide with nanoparticle-based drugs [ 161 ] and I-131–1095 radiotherapy [ 162 ]. There is an increasing evidence about the role of progesterone and estrogen in the PC [ 163 ]. Recent findings indicated the potential oncogenic effects of progesterone in PC, with elevated progesterone levels associated with poor clinical outcomes in both castration-resistant and hormone-sensitive PC patients (HSPC). An increase in progesterone levels in the plasma of CRPC and HSPC patients was associated with poor clinical outcomes. Progesterone can activate canonical and non-canonical AR target genes, and inhibition of 3b-hydroxysteroid dehydrogenase 1 (3bHSD1) can suppress the oncogenic effects of progesterone [ 164 ]. Prostate tissues express both ERα and ERβ [ 165 ] and PC development depends also on estrogen signaling. Estrogen can increase the occurrence of androgen-induced PC [ 166 ]. Ricke and colleagues showed on a mice model that prostates from ERβ-knockout (βERKO) mice underwent carcinogenesis and the prostates from ER alpha-knockout mice remained free of disease [ 167 ]. Taking together ERβ is a tumor suppressor, and its inhibition leads to the prostate hyperplasia and tumor development. Therefore anti-estrogens and SERMS may reduce the risk of PC development in cases with high levels of ERβ [ 168 ]. ERα is also associated with the invasion and migration of PC cells [ 169 ]. Lombardi and colleagues demonstrated that PC3 cells express ERα and ERβ, with activation of ERβ influencing the expression of β-catenin and promoting proliferation of PC3 cells. Treatment with PKF 118–310, a drug that disrupts the β-catenin/TCF/LEF (T-cell-specific transcription factor/lymphoid enhancer-binding factor) complex, blocked the effect of ER-β [ 170 ].

Preclinical models for studying DNA damage and repair triggered by chemo-, targeted- and hormonal- agents

Thus far, we have recognized the significance of investigating DNA damage and repair alongside hormonal regulation in urogenital cancers, particularly in tumors like OC and PC. To dig deeper into these mechanisms, comprehensive studies necessitate various preclinical models. These range from traditional methods like cell culture and animal models to computational simulations and ex vivo models. Additionally, advanced translational platforms such as organoids, microfluidics, and organ-on-a-chip systems are invaluable tools in elucidating these intricate processes (Fig. 2 ).

Innovative therapeutic strategies and models in ovarian and prostate cancer: from bench to bedside. The figure encapsulates the multifaceted approach to cancer research and treatment, specifically for ovarian and prostate cancer. On the left side, two primary therapeutic targets for these tumors are indicated: the DNA damage response (DDR) pathway, which can be inhibited by DDR inhibitors and hormone therapy, which involves the modulation of androgens, estrogens and progesterone levels. On the right side, the available research models for studying these targets are indicated basing on their complexity: on the top part 2D in vitro models, on the middle part more complex 3D ex vivo models, such as organoids, microfluidic systems, and organ-on-a-chip technologies, on the bottom part animal models including genetically engineered mouse (GEMMs) and patient-derived xenograft (PDX) models

Investigating chemotherapy response using in vitro cell line studies

In vitro models, particularly cell line models, offer a simplified and controlled setting to study cancer biology, drug responses and genetic manipulations. We have extensively discussed how DDR pathways, particularly those involving HR and NHEJ, as well as hormonal regulation are often compromised especially in OC and PC. In this section we will delve into the main in-vitro models outlined in the literature, categorizing them based on the type of treatment and the development of resistance: chemotherapy, targeted therapy and hormone-based therapy both for ovary and prostate tumors.

In vitro chemotherapy-based studies

Despite advancements in research that introduce new therapeutic options, chemotherapy remains one of the primary treatments for OC and PC. Unfortunately, after the initial response, patients often develop resistance, highlighting the need for in vitro models to elucidate the mechanisms associated with these processes.

Cancer cell lines have been extensively utilized to investigate mechanisms of resistance to therapy, particularly in response to chemotherapy, which poses a significant challenge in treating OC and PC. To explore potential novel therapeutic strategies to overcome resistance, researchers have developed several cellular models with acquired resistance. By continuous exposure of cancer cell lines to the drug, researchers can observe the emergence of resistance and possibly identify the molecular changes that occur [ 49 , 171 , 172 ]. Consequently, several studies have focused on understanding the effects of chemotherapy alone or in combination with other treatments to elucidate the underlying mechanisms [ 74 ]. For instance, Bicaku and colleagues analyzed the response to carboplatin, cisplatin, and paclitaxel in OC survival. They treated 36 OC cell lines with these drugs, quantified IC50 levels and performed pre-treatment gene expression analyses correlating it with the IC50 levels biological pathway analysis. Results showed that cell line sensitivity to carboplatin, cisplatin, paclitaxel and their combination was associated with the expression of 77, 68, 64, and 25 biological pathways, respectively. From these results the study identified the Transcription/CREB pathway as one to be noted and that was associated with OC overall survival and cell line platinum sensitivity [ 74 ]. Similarly, Blanc-Durand and colleagues developed an assay to study HR in a chemotherapy treatment context. Their study found that HR deficiency, identified through a RAD51 functional assay, was associated with higher response rates to neoadjuvant platinum chemotherapy and longer progression-free survival in OC [ 173 ]. Another study by Acland et al. aimed to identify molecular features specific to chemoresistance in OC using carboplatin-resistant OVCAR5 and CaOV3 cell line models. The results of this study revealed enhanced migratory and invasive potential in the chemoresistant lines compared to the parental ones. Moreover, through mass spectrometry analysis they found distinct metabolic and signaling perturbations in chemoresistant lines, including dysregulation in cytokine and type 1 interferon signaling. This shared feature between cell lines and patient-derived primary cells indicates a common molecular aspect of chemoresistance, providing insights for future research on molecular mechanisms of chemoresistance and related phenotypes [ 46 ].

In PC, cell lines with acquired resistance to taxanes were developed by cultivation with increasing concentration of the drug [ 174 ]. Lima and colleagues identified multiple mechanisms associated with docetaxel resistance such as ABCB1, an ATP-binding cassette transporter overexpression, moreover increased expression of the genes associated with androgen signaling, cell survival, and overexpression of non-coding RNAs [ 175 ]. ABCB1 overexpression was also identified as a main player of cabazitaxel cross resistance with docetaxel [ 176 ]. Furthermore, DNA-PKc, a crucial component of the DDR, was found to promote taxane resistance in mCRPC [ 177 ]. According published evidence there are several mechanisms contributed in docetaxel resistance development as P-glycoprotein which was overexpressed in cell lines resistant to docetaxel (DU-145R and 22Rv1R). Inhibition of P-glycoprotein with elacridar (a P-glycoprotein inhibitor) reversed the presence of resistant phenotype [ 178 ]. Mumenthaler and colleagues used a pharmacological inhibitor targeting the Pim kinase (SGI-1776), to evaluate the effect of Pim kinase activity on PC cell survival and resistance. They exploited a paclitaxel-resistant 22Rv1 cell line, showing that inhibition of Pim kinase activity sensitized taxane chemoresistant cells to apoptosis, indicating its potential as a therapeutic target in overcoming docetaxel resistance [ 179 ].

In vitro targeted therapy-based studies

HR alterations are prevalent in both OC and PC, presenting potential and novel therapeutic targets for both diseases. However, to improve therapy response and advance personalized medicine, there is a critical need to develop accurate in vitro models.

For OC, A2780, OVCAR-3 and SKOV-3 cell lines are among the most frequently utilized to investigate the effects of targeted therapy, given their well-established profiles regarding BRCA1/2 mutations and other DDR-related genes [ 180 ]. For instance, numerous studies have employed these OC cell lines to elucidate the role of PARPi and/or ATM/ATR kinases in DNA repair processes [ 181 ]. Biegala and colleagues sought to understand olaparib resistance in OC and enhance its efficacy by investigating the cellular mechanisms of resistance. A key finding of their work was the development of an olaparib-resistant OC cell line (PEO1-OR) from BRCA2 mutated PEO1 cells. The study revealed that PEO1-OR cells acquired resistance through BRCA2 secondary mutations, upregulating HR repair-promoting factors and PARP1. Additionally, olaparib-resistant cells exhibited reduced sensitivity to ATR/CHK1 inhibitors, suggesting that combination therapy might resensitize them to PARPi, offering a potential strategy to overcome acquired resistance to PARPi in OC [ 182 ]. In another study, Fleury and colleagues investigated the sensitivity of HGSOC cell lines to PARPi, specifically olaparib. While PARPi sensitivity is commonly linked to HR deficiency, this study reveals a more complex scenario by demonstrating that downregulation of genes in the NER and MMR pathways also increases PARPi response. The highest sensitivity was observed when HR deficiency was concurrent with downregulation of either NER or MMR pathways, proposing a novel model for predicting PARPi sensitivity in patients [ 183 ].

In PC, LNCaP and C4-2B resistant to olaparib also exhibited resistance to other clinically relevant PARPi (rucaparib, niraparib, talazoparib). These olaparib-resistant cell lines accumulated DNA damage compared to parental cells, suggesting potential mechanisms underlying resistance [ 184 ]. On a base of current treatment strategies, it is clinically relevant to study cross resistance between current PC therapies i.e. (taxanes) and olaparib. There is increasing evidence that cells with acquired chemoresistance to docetaxel report cross-resistance to olaparib. DU-145 with acquired resistance to docetaxel showed ABCB1 overexpression-mediated cross-resistance to olaparib [ 184 ]. Schaaf and colleagues obtained similar results regarding cross-resistance between taxanes and olaparib; in addition, they show that cells resistant to docetaxel retain sensitivity to enzalutamide and vice versa [ 185 ].

In vitro hormone therapy-based studies

Given the significance of hormonal regulation in OC and PC, the following section will focus on the in vitro models that elucidate the mechanism of action, therapy response and chemoresistance of therapies targeted to hormonal regulation.

In OC, the majority of the studies is focused on estrogen-based therapy. For instance, Chao and colleagues investigated estrogen impact on OC cell growth and survival, focusing on alterations in cell-cycle regulatory proteins. They treated ovarian adenocarcinoma cell lines, OC-117-VGH (estrogen receptor-deficient) and OVCAR3 (estrogen receptor-positive), with different estrogen concentrations and observed differential effects on cell-cycle regulatory proteins. While there were no significant changes in cyclin D1 and E expression, p16/INK4a and p27/KIP1 expression was higher in OC-117-VGH than in OVCAR3. This suggests that estrogen-mediated inhibitory effects on OC might be mediated through different pathways in ER-positive and ER-negative cell lines [ 139 ]. Similarly, Li and colleagues explored estrogen role in EOC proliferation. They found that estrogen stimulation increased OC cell proliferation and invasion, with higher expression of transient receptor potential channel C3 (TRPC3) observed in OC tissue compared to normal tissue, suggesting TRPC3 as a potential therapeutic target [ 186 ]. In the study by Lima and colleagues, the impact of sex hormones on ADAMTS 1 and 4 expression in OC cells was evaluated. Progesterone was found to significantly increase ADAMTS protein and mRNA levels, particularly in ES-2 cells, with this effect reversed by the progesterone receptor antagonist RU486. This study concluded that progesterone, through its receptor, modulates ADAMTS 1 and 4 levels in OC cell lines, thereby influencing cancer features [ 187 ]. Additionally, Pedernera and colleagues assessed the effect of sexual steroids, including progesterone, on cell survival in primary cultures of ovarian carcinoma. From the analysis of samples from 35 patients with various subtypes of epithelial OC, they found a significant reduction in cell survival after progesterone treatment, particularly in endometrioid ovarian carcinoma. This effect was notably pronounced in cells positive for PR, suggesting a crucial role for progesterone and its receptor in reducing the progression of endometrioid ovarian carcinoma [ 188 ]. Furthermore, Limaye and colleagues evaluated the effectiveness of AR inhibition in managing HGSOC with recurrent cases. This study focused on a patient with HGSOC who experienced multiple relapses, but achieved excellent disease control through AR inhibition by using bicalutamide. The results of this study support the potential of targeting AR signaling in the treatment of OC, especially in patients with recurrent disease after initial treatments [ 189 ].

Androgen deprivation therapies are crucial for inhibiting PC progression. It is known that enzalutamide treatment decreases the expression of HR associated genes. Therapeutical approach where enzalutamide is followed by the olaparib showed significantly increased PC cell apoptosis [ 158 ]. Long-term culture in the presence of enzalutamide generated four genetically distinct enzalutamide-resistant AR-positive and AR-pathway dependent PC cell lines (CWR-R1, LAPC-4, LNCaP, VCaP). The transcriptomic characterization revealed deregulation in AR-associated and non-associated genes e.g. TMEFF2 (Transmembrane protein with EGF-like and two follistatin-like domains-2), β-catenin ( CTNNB1 ) pathways, MT2A (Metallothionein 2A) [ 190 ]. Additionally, studies by Liu and colleagues and Xu and colleagues demonstrated cross-resistance between enzalutamide and abiraterone in enzalutamide-resistant cells, with AR-V7 splicing variant identified as responsible for resistance to abiraterone. Inhibition of AR-V7 by niclosamide and enhancement of enzalutamide treatment by a novel HSP70 allosteric inhibitor, JG98, showed potential therapeutic benefits [ 191 , 192 ]. Moreover, enzalutamide resistant cells remain sensitive to olaparib [ 193 ], which provides interesting therapeutical option for therapy resistant patients. On the other hand, van Soest and colleagues published abiraterone and enzalutamide cross-resistance with taxanes. Notably, docetaxel and cabazitaxel inhibit AR translocation to the nucleus [ 194 ].

The role of DNA repair in enzalutamide treatment response was proved by study Zhang and colleagues. In this study they used CRISP/Cas9 knockout (GeCKO) library to identify the DNA-damaging agent idarubicin responsible to overcame abiraterone and enzalutamide resistance in PC in vitro. Idarubicin can fight enzalutamide and abiraterone resistance by inhibition of XPA expression [ 195 ]. In addition to in vitro models, also in silico models are employed in biological research. These computational models are based on algorithms and simulations to analyze biological data and predict outcomes starting from molecular simulations to whole-genome analyses. They are particularly useful to analyze large datasets, such as genomic sequences, and to identify patterns, mutations, gene expression changes, response to certain treatments and they can even support personalized medicine by predicting the most effective treatment strategies based on individual patients’ genetic profiles [ 196 ].

In vivo mouse models: from GEMMs to PDXs

Animal models serve as crucial systems for studying cancer mechanisms, with genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) offering significant insights into tumor growth, metastasis, and therapeutic responses in an in vivo context. In the first case, GEMMs, featuring specific mutations in DDR genes, provide insights into the role of these genes in cancer development and progression. In the context of OC, different reviews focused their attention on these models highlighting their advantages in managing specific gene mutations and consequently being helpful in understanding the efficacy of a treatment especially for targeted therapies potentially leading to better clinical outcomes [ 197 , 198 , 199 ]. For example, Shi and colleagues demonstrate that the inactivation of multiple genes like PTEN, TRP53, and RB1 in the ovarian surface epithelium of mice led to the development of type I low-grade OC, further emphasizing the utility of GEMMs in modelling the disease and its progression [ 200 ].

When studying PC, there are numerous GEMMs based on different genomic alterations relevant for PC and expressing different stages of the disease progression (for reviews see [ 201 ] and [ 202 ]). Ding and colleagues reported GEMMs by targeting PTEN and TP53 to develop model with metastatic PC and genomic instability [ 203 ]. Downregulation of CHK1 , which correlates with ERG expression in PTEN ± mice model, promoted high-grade prostatic intraepithelial neoplasia into invasive carcinoma [ 204 ].

On the other hand, PDXs generated by engrafting fresh human tumor fragments into immunodeficient mice, reflect patients' tissue histological and genetic characteristics [ 205 ]. The success rate of establishing PDXs depends on mouse origin and cancer tissue type, with higher rates observed in advanced or metastatic tumors. Indeed, the growth of PDX from primary tumors is around 2–10% while for advanced or metastatic tumors it is around 25–30% [ 206 ]. These models have been widely used in different tumors, for example animal models were used to study the effect of BRCA1/2 mutations in OC [ 207 ].

In OC research, PDX models are established by transplanting fresh patient tumor tissues into mice, often at orthotopic sites, to mimic the tumor's original environment and preserve its heterogeneity and genetic landscape [ 208 ]. PDXs have been instrumental in assessing the efficacy of PARPi in OC: Chen and colleagues in 2022 were able not only to replicate in PDX the results of clinical trials such as NOVA (NCT01847274), PRIMA (NCT02655016), and SOLO I, suggesting the utility of these models in mimicking clinical responses, but they predict also PARPi efficacy better than BRCA mutational status or platinum sensitivity. Key findings include high KRAS expression correlating with PARPi sensitivity, AKT1 enrichment indicating resistance, and low CA125 levels as potential PARPi efficacy indicators [ 209 ]. Additionally, Serra and colleagues investigated WEE1 and ATR inhibitors' efficacy in overcoming PARPi resistance in breast and ovarian cancers. Using patient-derived xeno-implant models, the study found that WEE1i response was associated with replication stress markers like STK11/RB1 and phospho-RPA, while ATRi response was associated to ATM mutations. The results suggest that targeting the replication stress response, particularly by WEE1i, can be an effective strategy to overcome PARPi resistance, even in tumors without homologous recombination repair deficiency. This approach provides important results and is under active testing in clinical trials [ 210 ].

In PC, there are several fundamental collection of PDX models like the MURAL collection [ 211 ] and the MD Anderson Prostate Cancer Patient-derived Xenograft Series (MDA PCa PDX) [ 212 ]. PDX models have demonstrated the antitumor activity of cabazitaxel in docetaxel- and enzalutamide-resistant tumors [ 177 ]. Therapy resistance is one of the biggest obstacles in PC therapy. Karkampouna et al. proposed a novel therapeutic strategy using multikinase inhibitors as ponatinib, sunitinib and sorafenib to overcome resistance to main PC therapies based on an androgen-dependent PCa PDX model [ 213 ].

Thus, differently from cell line models, PDX offers a platform for personalized medicine able also to recapitulate tumor heterogenity, crucial in studying the varied responses of different tumor cells to DNA damage and the efficacy of repair mechanisms. As far as PDXs present more advantages compare to cell lines, they also present several limitations: the establishment of PDX models is time-consuming, costly and resource-intensive since the growth rate of human tumors in mice can be slow, and not all patient samples successfully engraft and it requires specialized facilities [ 214 ]. Moreover, while PDX models maintain many aspects of the original tumor microenvironment, the immune component is significantly altered due to the immunodeficient nature of the host mice and this limitation can affect the study of immunological aspects of DDR. In addition, the use of animals in research brings ethical considerations and requires strict adherence to regulatory guidelines. Finally, while PDXs are valuable for preclinical studies, translating findings from these models to clinical outcomes can be challenging.

While animal models (syngeneic models) are widely used for the study of PARPi or other targeted therapies, we acknowledge that only few studies testing ICI in OC and PC are available, and even less works if considering possible combinatorial treatment with other drugs. Grabosch and colleagues assessed in vivo the response to anti-PD-L1 antibody and cisplatin either as single agents or in combination in EOC. The present study revealed that anti-PD-L1 targeted immunotherapy, when administered alone, exhibits remarkable efficacy against most aggressive models, even if this effect is tumor-dependent. It is important to note that cisplatin alone has the ability to modulate the immune microenvironment. Nevertheless, the combination of cisplatin with immune therapy appeared as the key for increasing mice survival rates in models of aggressive tumors and recurrent disease [ 215 ]. Also in the more recent work by Meng and colleagues, syngeneic mouse models were used to evaluate the therapeutic response of anti-PD-L1 therapy in OC, confirming how the effect of immunotherapy alone is limited, while the possible combination with PARPi such as niraparib, can improve the outcome [ 216 ]. Similarly to OC, for PC only few studies can be found [ 217 ]. Czernin and colleagues studied the synergistic effect of 225 Ac-PSMA617 and anti-PD-1 antibody on a model of C57BL/6-mice bearing syngeneic RM1-PGLS tumors. The results of the study demonstrate synergic antitumor effect of PSMA RNT plus PD-1 blockade [ 217 ]. Eximond and colleagues tested also the triple combination anti-CTLA-4 + anti-PD-1 + RT in the model of syngeneic CRPC mouse. Their study showed that two ICIs in combination with RT had a stronger effect in comparison with monotherapy [ 218 ]. In general ICI therapy has only a moderate effect in PC. But there is an evidence that ADT might sensitize tumors to the checkpoint blockade by enhancing CD8 T cell function in mice model. Study on mouse implanted with PD-1 resistant tumors showed that enzalutamide is able to sensitize these mice to anti-PD-L1 antibody therapy by direct effect of androgen deprivation on immune cells in the tumor [ 219 ].

Overall these works suggest that combinatorial strategies for ICI, including both chemotherapy or targeted therapies, should be taken into considerations both for OC and PC to increase ICI effect.

Patient-derived 3D models: organoids, microfluidics and organ-on-a-chip

While previous models have contributed significantly to our understanding of ovarian and PCs, they fall short in fully capturing the complexity of human tumor microenvironment. To bridge this gap, translational models like organoids, microfluidics, and organ-on-a-chip systems have emerged as pivotal tools in cancer research. These models represent a significant milestone, particularly microfluidics and organ-on-a-chip systems, which integrate living human cells within a micro-engineered environment, simulating the physiology and mechanics of human organs. In details, microfluidics involves the manipulation of fluids at a microscale in channels with dimensions of tens to hundreds of micrometres, allowing precise control of the cellular microenvironment and facilitating the study of cellular responses under various physiological conditions [ 220 ]. Organ-on-a-chip systems, an extension of microfluidic technology, integrate cell cultures in a micro-engineered environment to mimic the structure and function of human organs. These systems can replicate key aspects of an organ’s microarchitecture and biomechanical properties, providing a more physiologically relevant model for studying disease processes [ 221 ]. The use of the microfluidic models has been instrumental in studying OCs, replicating tumor microenvironment and providing insights into tumor invasion and drug testing [ 222 ]. Despite their advantages, these systems are not without limitations. First, the design and fabrication of microfluidic and organ-on-a-chip systems can be complex and costly; they are optimized for small-scale experiments and the translation to clinical applications is challenging and not immediate. Finally, these systems often involve intricate techniques and precise control of experimental conditions [ 223 ].

OC and PC research has been hampered by the lack of suitable in vitro model systems. The most noteworthy translational model is the organoid one, as a self-organizing three-dimensional cell cultures generated from isolated pluripotent stem cells or progenitor cells of a patient’s tumor or non-tumor tissue [ 224 ]. Organoids closely mimic the architecture, functionality and genetic landscape of the original tissue, bridging the gap between traditional in vitro models and in vivo studies, becoming an indispensable tool in both basic research and clinical applications [ 225 ]. The genesis of organoid technology is largely attributed to the pioneering work of Hans Clevers, who has opened new avenues in studying a wide array of organs. Clevers and his team first demonstrated the potential of organoids in modeling the gut, showing that a single Lgr5 + stem cell from the adult mouse intestine could grow into a self-organizing structure that recapitulates the intestinal epithelium in vitro [ 226 ]. This revolutionary work illuminated the path for organoid research across various organ systems including the brain, gut, liver, prostate and ovaries [ 227 ], providing moreover new models for drug testing and for understanding disease mechanisms at a cellular level.

Focusing in particular on OC, due to the high degree of heterogeneity, organoid establishment and maintenance in culture was not easy. In this context, the literature is plenty of studies focusing on their establishment and different protocols were published and are still improving [ 228 , 229 , 230 ]. Moreover, there are also many works in which these organoids provide a means to investigate the unique tumor microenvironment of OC, including the study of tumor initiation, progression, metastasis and drug resistance [ 231 ]. One of the first relevant study in this field is the one from Kopper and colleagues in which OC organoids have been used to model different subtypes of the disease, including HGSOC being thus crucial in studying subtype-specific characteristics and responses to treatment [ 232 ]. The primary objective of their research was to establish a diverse panel of OC organoids that accurately reflect the various subtypes of OC, including HGSOC, which is the most common and aggressive form of the disease. These organoids were developed from tumor samples of patients with different OC subtypes, ensuring that the models encompassed a wide range of genetic and histological variations seen in actual patient tumors. A critical aspect of their study was the successful maintenance of the histopathological and genetic characteristics of the original tumors in the organoids demonstrating that they retained key features of OC, including specific genetic mutations, gene expression profiles, and histological structures, making them highly representative of the in vivo condition. The second main point of this work is that ovarian organoids were also employed to evaluate responses to various chemotherapeutic agents and targeted therapies showing that organoids' responses to these treatments mirrored clinical outcomes, demonstrating their potential as predictive models for personalized medicine. In other studies, organoids have been employed in high-throughput drug screening to identify potential therapeutics for OC. Nanki and colleagues developed expandable OC organoids and, after demonstrating their ability to model various subtypes of OC and to reflect the heterogeneity of the disease, employed them for drug sensitivity and resistance testing [ 233 ]. Of note, in this work they successful developed organoids in less than 3 weeks, capturing the characteristics of different histological cancer subtypes and replicating the primary tumors' mutational landscape. Furthermore, one organoid with a BRCA1 pathogenic variant, showed higher sensitivity olaparib and platinum drugs and an organoid derived from clear cell OC exhibited resistance to conventional drugs, including platinum drugs, paclitaxel, and olaparib [ 233 ]. The potential of organoids in the evaluation of the molecular mechanism underlying OC was also demonstrated in the work from Wang and collaborators, where RNA sequencing of cisplatin-resistant and -sensitive OC organoids revealed higher FBN1 expression in resistant samples. From further investigations they found that FBN1 's is involved in energy stress, angiogenesis, and chemoresistance and thanks to these results, they were able to identify the FBN1/VEGFR2/STAT2 signaling axis as a key mediator in these processes, suggesting potential therapeutic strategies targeting FBN1 combined with antiangiogenic drugs for OC treatment [ 234 ]. Overall, these works suggest that organoids can accurately mirror the biology of the tumor of origin and can be exploited for high-throughput drug screening, identifying potential therapeutics and elucidating drug resistance mechanisms [ 225 , 232 ].

It is well known that cells with stem-like potential represent a potential source to create patient-derived organoids (PDOs); in the case of PC, mainly basal cells, that show high proliferation and self-renewal and CD133 and CD44 phenotype compared to luminal cells, contribute to organoid establishment [ 235 ]. In the first PDO models, only basal cells reconstitute a prostate gland. In 2014 Karthaus and colleagues described the development of an R-spondin1-based culture method. This method admits a long-term propagation of murine and human prostate epithelium consisting of fully differentiated CK5 + basal and CK8 + luminal cells [ 236 ]. These protocols allowed cultured PDOs from prostate tissues, but they did not recapitulate AR signaling, which is essential for prostate development and also for PC progression and therapy. By adding Epidermal Growth Factor (EGF), Noggin, and R-spondin 1 to the growth medium, Drost and colleagues were able to generate long term growing organoids that functionally recapitulate AR signaling [ 237 ].

In general, successful generation of PDOs cultures struggles with many pitfalls. Organoid cultures from PC biopsies have variable growth rates caused probably by the high heterogeneity of the disease [ 238 ]. PC PDOs also show low efficiency in their establishment (15–20%) [ 239 ]. Servant and collaborators generated organoids from 81 PC patient samples. The success rate was around 44% for tissues from metastatic prostatectomy and around 28% for tissues from transurethral resection of the prostate [ 240 ]. In the study of Puca and colleagues, organoids from metastatic tissue of 25 PC patients were generated with a success rate of only 16% and the organoids were classified as neuroendocrine PC [ 241 ]. There is a strong evidence that PC organoids grow at different rates depending on the tissue of origin and clinico-pathological features of the patients’ tissue [ 240 ]. Because of their slow growth and low success rate, there is a need to optimize the protocol for generation of PDOs. Gao and colleagues established in 2014 for the first time the long term fully characterized cultured PC organoid platform derived from advanced and metastatic PC tissues, which recapitulates molecular diversity of PC and showed TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss as well as mutations in DNA repair pathway. These PDOs showed common features for advanced PC such as TP53 and RB loss, AR signaling, while mirroring the tumor of origin both at the genetic and phenotypic levels [ 242 ].

In conclusion, the versatility of organoids extends beyond disease modeling to regenerative medicine. Organoids offer a promising avenue for tissue regeneration and personalized medicine, including the potential for organ transplantation and the development of patient-specific treatment plans. Their ability to mimic patient-specific disease phenotypes makes them ideal for precision medicine applications, revolutionizing our ability to model human diseases and test therapeutic interventions with unprecedented precision and relevance.

Conclusions and perspectives

In this review, we emphasize the significance of genomic instability, DNA damage and repair mechanisms, synthetic lethality, and hormonal regulation in OC and PC as well as the importance to use precise in vivo and in vitro models to study these signaling pathways. Understanding these factors is essential for improving diagnosis, treatment and outcomes in patients with urogenital cancers. One key aspect we delves into is the hormonal regulation and its implication for urogenital cancers treatment and resistance especially in the context of DNA damage and repair due to its significant impact on both the development and progression of these hormonal-related diseases. Since hormones such as estrogen, progesterone and androgens play important roles in urogenital function and pathology, their dysregulation can lead to enhanced proliferation of cancer cells and contribute to carcinogenesis. Thus, it is imperative to understand the interplay between hormonal pathways and DNA damage repair mechanisms in the context of OC and PC. Deciphering the role of hormones could facilitate the development of personalized medicine by identifying novel tailored treatments that might effectively circumvent the onset of resistance based on each patient's distinct cancer profile.

In this review we also discuss two of the main challenges for cancer therapy: therapy response and chemoresistance development, both involving DDR. Advances in understanding DDR mechanisms have led to the development of targeted therapies, such as PARPi, and to foster the design of novel therapeutic approaches to overcome acquired resistance. This focus on DNA damage and repair mechanisms is crucial for advancing research in precision medicine and understanding individual variations in DDR pathways in urogenital cancers could help adapting therapies to specific genetic profiles and optimizing therapeutic outcomes. In addition to this point, we have also emphasised the role of ICIs both in OC and PC, especially showing how their effect can be increased when in combination with other agents like ATR inhibitors, which could yield synergistic antitumor effects in patients with limited response to conventional therapies. Thus, further exploration and optimization of combination therapies could extend the benefits of ICIs to a broader patient population.

Lastly, we highlight the importance of utilizing advanced models to study these mechanisms, as they provide important insights into molecular pathways. Animal models and 3D ex vivo models have provided significant advancements in the field of OC and PC research. Starting from animal models, we highlighted how GEMMS and PDXs play pivotal roles in cancer research by providing in vivo systems that closely mirror human tumor biology allowing researchers to study the molecular and cellular mechanisms of cancer and following tumor progression and drug response. Transitioning to 3D technologies, we highlight microfluidics and organ-on-a-chip, which replicate structure and function while enabling fluid manipulation, providing a physiologically relevant model for disease processes. In this context, we wanted to shed light especially on the organoids, which have emerged as a critical bridge between in vitro and in vivo studies. Organoids can mimic the architecture and genetic landscape of the source tissue, enabling the study of disease mechanisms, drug responses and tumor evolution with a level of precision and relevance that was previously unattainable. In OC, organoids effectively tackle disease heterogeneity, modeling different subtypes, like HGSOC and facilitating studies on tumor characteristics and treatment responses. Diverse platforms of OC organoids that retain the genetic and histopathological features of the original tumors have been created, making them suitable for personalized medicine approaches, being used for drug sensitivity testing and elucidating molecular mechanisms underlying cancer. Also PC research has benefited from organoid technology, utilizing basal cells with stem-like potential to establish PC organoids, that mimic AR signaling—a key factor in PC progression. Despite the low establishment efficiency and variable growth rates, significant strides have been made in fully characterizing cultured prostate organoids. Thus, these systems offer detailed insights into tumor biology and are instrumental for therapeutic efficacy and toxicity assessments. In the quest for new cancer treatments, organoids serve as a powerful tool, allowing for more personalized therapy development and reducing reliance on animal testing, thereby expediting translation from bench to bedside. Nonetheless, challenges regarding complexity, cost, and scalability for clinical applications persist and are in constant development and improvement.

By integrating advanced technologies and more reliable models, we might advance our understanding on the interplay between response to DNA damage and hormonal regulation in urogenital cancers and develop more effective and personalized therapeutic options. Overall, the integration of multidisciplinary approaches will be essential for addressing the challenges posed by these complex diseases to improve patient care in the era of personalized medicine.

Availability of data and materials

Not applicable.

Abbreviations

3b-hydroxysteroid Dehydrogenase 1

Aromatase Inhibitor

Androgen Deprivation Therapies

Androgen Receptor

Androgen Receptor splice variant-7

Base Excision Repair

Castration Resistance Prostate cancer

Circulating Tumor Cells

Cytotoxic T-lymphocyte-associated protein 4

DNA Damage Response

DNA Damage Response Inhibitor

Deoxyribonucleic Acid

Double strand Breaks

Epidermal Growth Factor

Estrogen Receptor

Estrogen Response Elements

Genetically engineered mouse models

Gonadotropin hormone-Releasing Hormone

High-Grade Serous Ovarian Cancer

Hormone Sensitive Prostate cancer

Homologous Recombination

Homologous Recombination Repair

Metastatic Castration Resistant Prostate cancer

Metastatic Prostate cancer

Mismatch Repair

Magnetic Resonance Imaging

Mithramycin

Non-Homologous End Joining

Nucleotide Excision Repair

Ovarian cancer
Prostate cancer

Poly-ADP Ribose Polymerase

Poly-ADP Ribose Polymerase inhibitor

Prostate cancer Antigen-3

Programmed cell death protein 1

Programmed cell death-ligand 1

Patient-derived xenografts

Patient Derived Organoids

Positron Emisssion Tomography

Prostate Health Index

Prostate Specif Antigen

Prostate Specific Membrane Antigen

Progesterone Receptor

Progesterone Response Elements

Progesterone Receptor Modulators

Reactive Oxygen Species

Selective Estrogen receptor modulators

Single strand Breaks

Transient receptor potential channel C3

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This manuscript neither is under consideration for publication elsewhere nor had been published previously.

This work is supported by FPRC 5 × 1000 MIUR 2018 INSIDE and FPRC 5 × 1000 Ministero della Salute 2021 EmaGen to S. Arena; Ricerca Locale 2022 and 2023 (premialità pubblicazioni) from Department of Oncology, University of Torino to S.Arena; Italian Ministry of Health, Ricerca Corrente 2024 to S.Arena; A.Opattova was supported by Fondazione Umberto Veronesi.

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Giada De Lazzari, Alena Opattova & Sabrina Arena

Department of Oncology, University of Torino, Strada Provinciale 142, Km 3.95, Candiolo, TO, ZIP 10060, Italy

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GDL, AO and SA discussed and developed the concept; GDL and AO developed figures and tables; GDL, AO and SA wrote the manuscript; SA coordinated the effort and critically revised the manuscript. All authors read and approved the final manuscript.

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De Lazzari, G., Opattova, A. & Arena, S. Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients. J Exp Clin Cancer Res 43 , 146 (2024). https://doi.org/10.1186/s13046-024-03065-0

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Page 1 of 33

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Increasing the Number of Women with Ovarian Cancer Who Are Treated by a Gynecologic Oncologist
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Treatment of Ovarian Cancer

Treatment for ovarian cancer usually involves a combination of surgery and chemotherapy.

If your doctor says that you have ovarian, fallopian tube, or primary peritoneal cancer, ask to be referred to a gynecologic oncologist.

If your doctor says that you have ovarian, fallopian tube, or primary peritoneal cancer, ask to be referred to a gynecologic oncologist—a doctor who has been trained to treat gynecologic cancers, including ovarian cancer. This doctor will work with you to create a treatment plan.

Treatment options

Surgery: An operation in which doctors cut out the cancer.
Chemotherapy: Use of special medicines to shrink or kill the cancer. The drugs can be pills you take or medicines given in your veins, or sometimes both.
Targeted therapy: Use of drugs to block the growth and spread of cancer cells. The drugs can be pills you take or medicines given in your veins. You will get tests to see if targeted therapy is right for your cancer type before this treatment is used.

Visit the National Cancer Institute for more information about ovarian cancer treatment. This site can also help you find health care services.

Which treatment is right for me?

Talk to your cancer doctor about the treatment options available for your type and stage of cancer. Your doctor can explain the risks and benefits of each treatment and their side effects. Side effects are how your body reacts to drugs or other treatments.

Sometimes people get an opinion from more than one cancer doctor. This is called a "second opinion." Getting a second opinion may help you choose the treatment that is right for you.

Clinical trials

Clinical trials use new treatment options to see if they are safe and effective. If you have cancer, you may want to take part. Visit the sites listed below for more information.

NIH Clinical Research Trials and You (National Institutes of Health)
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Complementary and alternative medicine are medicines and health practices that are not standard cancer treatments. Complementary medicine is used in addition to standard treatments. Alternative medicine is used instead of standard treatments. Acupuncture and supplements like vitamins and herbs are some examples.

Many kinds of complementary and alternative medicine have not been tested scientifically and may not be safe. Talk to your doctor about the risks and benefits before you start any kind of complementary or alternative medicine.

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From steel engineering to ovarian tumor research

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Ashutash Kumar stands with arms folded in the lab

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Ashutosh Kumar is a classically trained materials engineer. Having grown up with a passion for making things, he has explored steel design and studied stress fractures in alloys.

Throughout Kumar’s education, however, he was also drawn to biology and medicine. When he was accepted into an undergraduate metallurgical engineering and materials science program at Indian Institute of Technology (IIT) Bombay, the native of Jamshedpur was very excited — and “a little dissatisfied, since I couldn’t do biology anymore.”

Now a PhD candidate and a MathWorks Fellow in MIT’s Department of Materials Science and Engineering, and a researcher for the Koch Institute, Kumar can merge his wide-ranging interests. He studies the effect of certain bacteria that have been observed encouraging the spread of ovarian cancer and possibly reducing the effectiveness of chemotherapy and immunotherapy.

“Some microbes have an affinity toward infecting ovarian cancer cells, which can lead to changes in the cellular structure and reprogramming cells to survive in stressful conditions,” Kumar says. “This means that cells can migrate to different sites and may have a mechanism to develop chemoresistance. This opens an avenue to develop therapies to see if we can start to undo some of these changes.”

Kumar’s research combines microbiology, bioengineering, artificial intelligence, big data, and materials science. Using microbiome sequencing and AI, he aims to define microbiome changes that may correlate with poor patient outcomes. Ultimately, his goal is to engineer bacteriophage viruses to reprogram bacteria to work therapeutically.

Kumar started inching toward work in the health sciences just months into earning his bachelor's degree at IIT Bombay.

“I realized engineering is so flexible that its applications extend to any field,” he says, adding that he started working with biomaterials “to respect both my degree program and my interests."

“I loved it so much that I decided to go to graduate school,” he adds.

Starting his PhD program at MIT, he says, “was a fantastic opportunity to switch gears and work on more interdisciplinary or ‘MIT-type’ work.”

Kumar says he and Angela Belcher, the James Mason Crafts Professor of biological engineering, materials science and of the Koch Institute of Integrative Cancer Research, began discussing the impact of the microbiome on ovarian cancer when he first arrived at MIT.

“I shared my enthusiasm about human health and biology, and we started brainstorming,” he says. “We realized that there’s an unmet need to understand a lot of gynecological cancers. Ovarian cancer is an aggressive cancer, which is usually diagnosed when it’s too late and has already spread.”

In 2022, Kumar was awarded a MathWorks Fellowship. The fellowships are awarded to School of Engineering graduate students, preferably those who use MATLAB or Simulink — which were developed by the mathematical computer software company MathWorks — in their research. The philanthropic support fueled Kumar’s full transition into health science research.

“The work we are doing now was initially not funded by traditional sources, and the MathWorks Fellowship gave us the flexibility to pursue this field,” Kumar says. “It provided me with opportunities to learn new skills and ask questions about this topic. MathWorks gave me a chance to explore my interests and helped me navigate from being a steel engineer to a cancer scientist.”

Kumar’s work on the relationship between bacteria and ovarian cancer started with studying which bacteria are incorporated into tumors in mouse models.

“We started looking closely at changes in cell structure and how those changes impact cancer progression,” he says, adding that MATLAB image processing helps him and his collaborators track tumor metastasis.

The research team also uses RNA sequencing and MATLAB algorithms to construct a taxonomy of the bacteria.

“Once we have identified the microbiome composition,” Kumar says, “we want to see how the microbiome changes as cancer progresses and identify changes in, let’s say, patients who develop chemoresistance.”

He says recent findings that ovarian cancer may originate in the fallopian tubes are promising because detecting cancer-related biomarkers or lesions before cancer spreads to the ovaries could lead to better prognoses.

As he pursues his research, Kumar says he is extremely thankful to Belcher “for believing in me to work on this project.

“She trusted me and my passion for making an impact on human health — even though I come from a materials engineering background — and supported me throughout. It was her passion to take on new challenges that made it possible for me to work on this idea. She has been an amazing mentor and motivated me to continue moving forward.”

For her part, Belcher is equally enthralled.

“It has been amazing to work with Ashutosh on this ovarian cancer microbiome project," she says. "He has been so passionate and dedicated to looking for less-conventional approaches to solve this debilitating disease. His innovations around looking for very early changes in the microenvironment of this disease could be critical in interception and prevention of ovarian cancer. We started this project with very little preliminary data, so his MathWorks fellowship was critical in the initiation of the project.”

Kumar, who has been very active in student government and community-building activities, believes it is very important for students to feel included and at home at their institutions so they can develop in ways outside of academics. He says that his own involvement helps him take time off from work.

“Science can never stop, and there will always be something to do,” he says, explaining that he deliberately schedules time off and that social engagement helps him to experience downtime. “Engaging with community members through events on campus or at the dorm helps set a mental boundary with work.”

Regarding his unusual route through materials science to cancer research, Kumar regards it as something that occurred organically.

“I have observed that life is very dynamic,” he says. “What we think we might do versus what we end up doing is never consistent. Five years back, I had no idea I would be at MIT working with such excellent scientific mentors around me.”

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Published: 17 June 2022

Clinical Studies

Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma

Robert L. Hollis ORCID: orcid.org/0000-0002-1390-3298 1 ,
Ian Croy 1 ,
Michael Churchman 1 ,
Clare Bartos 1 ,
Tzyvia Rye 1 ,
Charlie Gourley 1 &
C. Simon Herrington ORCID: orcid.org/0000-0001-9177-8165 1

British Journal of Cancer volume 127 , pages 1034–1042 ( 2022 ) Cite this article

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Ovarian cancer

Ovarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention.

We curated the largest pathologically confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival and comparison against high-grade serous ovarian carcinoma (HGSOC).

Eighty-two OCS patients were identified; overall survival was poor (median 12.7 months). In all, 79% demonstrated epithelial components of high-grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with endometrioid carcinomatous components. Earlier stage, complete resection and platinum-containing adjuvant chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older ( P < 0.0001), more likely to be FIGO stage I ( P = 0.025), demonstrated lower chemotherapy response rate ( P = 0.001) and had significantly poorer survival ( P < 0.0001).

OCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Histological subclassification does not identify patient subgroups with distinct survival. Aggressive adjuvant chemotherapy should be considered for all cases, including those with early-stage disease.

Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning

Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones

Breast cancer

Ovarian carcinosarcoma (OCS)—previously also known as mixed malignant Müllerian tumour—is an uncommon, highly aggressive cancer of the female genital tract [ 1 ]. Unlike more common ovarian cancers, OCS is biphasic, comprising malignant epithelial (carcinomatous) and malignant mesenchymal (sarcomatous) populations.

While it was originally thought that OCS may represent collisions of separate carcinomas and sarcomas [ 2 , 3 ], molecular studies have revealed a clonal relationship between these two malignant cell populations [ 4 ], pointing to a shared malignant ancestor cell. Much of our understanding of OCS is inferred from uterine carcinosarcoma (UCS), a more common cancer in women [ 5 ]. However, it is well recognised that cancers presenting on the ovary bear stark clinical and molecular differences compared to those of the uterus that demonstrate similar histology [ 6 , 7 , 8 , 9 , 10 ]. Indeed, limited available data suggest differences in the molecular landscape of OCS compared to UCS, though the number of comprehensively characterised OCS samples to date is extremely low [ 4 , 11 ].

OCS are highly heterogeneous, defined by the presence of both high-grade carcinomatous and high-grade sarcomatous cell populations [ 12 ]. Carcinomatous elements may be of any ovarian high-grade carcinoma type (high-grade serous (HGS), endometrioid, clear cell, mucinous). The sarcomatous compartment may be classified as homologous—demonstrating either non-specific appearance or differentiation native to the female genital tract—or heterologous, showing differentiation physiologically foreign to the adnexa [ 1 , 12 ]. The most common heterologous sarcomatous elements are chondroid (chondrosarcoma) and rhabdoid differentiation (rhabdomyosarcoma), with other heterologous elements noted only in rare cases (angiosarcoma, osteosarcoma and liposarcoma; <5% of cases) [ 1 , 12 ].

Despite its aggressive behaviour [ 13 , 14 ], OCS has received relatively little research attention to date. A limited number of studies have characterised an appreciable number of OCS patients in detail [ 15 , 16 , 17 , 18 , 19 , 20 ]. However, these studies have focussed on describing patient outcome and typically have not performed contemporary pathology review to confirm OCS diagnosis; moreover, these studies have not described the histopathological characteristics of cases in detail.

Currently, detailed histopathological classification of the carcinomatous and sarcomatous elements is not routinely performed in OCS diagnosis. Little is therefore known about the relationship between different histopathological features of OCS or whether these features are related to distinct clinical characteristics of OCS patients. We sought to robustly curate a large cohort of OCS cases, performing detailed clinical and histopathological characterisation to improve our understanding of this highly aggressive tumour type.

Cohort identification and clinical annotation

All ovarian cancer cases with a documented diagnosis of carcinosarcoma up to 31 December 2020 were identified from the Edinburgh Ovarian Cancer Database (Fig. 1 ), wherein the details of diagnosis, treatment and outcome of all ovarian cancer patients treated at the Edinburgh Cancer Centre are entered prospectively as part of routine care [ 21 ]. Baseline clinicopathological characteristics, treatment and outcome data were extracted. Overall survival (OS) was calculated from the date of pathologically confirmed diagnosis. Progression-free survival (PFS) was calculated as the time from pathologically confirmed diagnosis to recurrence/progression (Supplementary Methods Section 1 ). Response to first-line adjuvant chemotherapy was evaluated using available radiological data (Supplementary Methods Section 1 ).

IHC immunohistochemistry, H&E haematoxylin and eosin.

Ethical approval for the study was obtained from the Lothian NRS Human Annotated Bioresource (reference 15/ES/0094-SR1330) and the South East Scotland Cancer Information Research Governance Committee (reference CG/DF/E164-CIR21171). All participants gave written informed consent or had consent waived by the ethics committee due to the retrospective nature of the study.

Pathology review

Of the 126 identified cases, archival formalin-fixed paraffin-embedded (FFPE) material was available for 98 cases. Pathology review was performed by an expert gynaecological pathologist (CSH) using haematoxylin–eosin (H&E)-stained slides from every available FFPE block. Available uterine samples were examined to confirm non-uterine origin (median 3 uterine blocks per case in the study cohort). A confirmatory observer (RLH) was present for all review.

Cases without a clear malignant high-grade carcinomatous or sarcomatous component on H&E review were excluded (minimum 5% sarcomatous and 5% carcinomatous component required to be considered carcinosarcoma) (Fig. 1 ). Immunohistochemistry (IHC) for cytokeratins and vimentin were used to confirm the presence of both carcinomatous and sarcomatous compartments [ 1 ] (Supplementary Methods Section 2 ); cases without IHC-confirmed carcinoma and sarcoma were excluded (Fig. 1 ).

Presence of endometriosis, squamous differentiation and serous tubal intraepithelial carcinoma (STIC) were documented as part of pathology review. The relative prevalence of carcinomatous and sarcomatous compartments across all available samples was documented (carcinoma-dominant: >70% carcinoma, sarcoma-dominant: >70% sarcoma, all others: mixed). Presence of carcinomatous and sarcomatous compartments in metastases (omentum and distant sites) was recorded during review (carcinoma only, sarcoma only or mixed carcinosarcoma).

Classification of carcinomatous and sarcomatous elements

The histotype of the carcinomatous compartment was determined by H&E review with IHC for WT1 and p53 in every case (Supplementary Methods Section 2 ) [ 22 ]. WT1 positivity was defined as positive tumour nuclei in carcinomatous cells. p53 staining was classified as aberrant-positive (aberrant diffuse nuclear positivity), aberrant-null (diffusely negative nuclei with confirmed adjacent positive stromal staining) or wild type (variable nuclear positivity) [ 23 ].

Heterologous sarcomatous elements were identified from the H&E-stained slides. Suspected chondrosarcoma and rhabdomyosarcoma were confirmed using IHC for S100 (chondrosarcoma: nuclear S100-positive) and desmin/myogenin (rhabdomyosarcoma: nuclear desmin/myogenin-positive) (Supplementary Methods Section 2 ) [ 24 ]. Liposarcoma was identified by the presence of adipocytes with malignant nuclei and was distinguished specifically from benign adipose tissue infiltrated by carcinosarcoma.

High-grade serous ovarian carcinoma (HGSOC) comparator cohort

A cohort of 362 otherwise unselected patients with a confirmed diagnosis of HGSOC following contemporary pathology review was used as a comparator cohort (Supplementary Methods Section 3 ) [ 25 ]. Characteristics of this cohort are summarised in Supplementary Table S1 .

Statistical analysis

All statistical analyses were performed using R version 4.1.0 (R Foundation for Statistical Computing). Comparisons of frequency were made using the chi-squared and Fisher’s exact test, as appropriate. Continuous data were compared using the Mann–Whitney U -test. Survival analyses were performed using Cox proportional hazards regression models, presented as hazard ratios (HRs) and respective 95% confidence intervals (95% CIs). All tests were two-sided; P < 0.05 was considered statistically significant.

Statistical power

The statistical power of survival analyses were estimated using the powerSurvEpi R package. Power to detect a difference (HR = 0.50) between two OCS populations within the study cohort (50:50 split) was 83.7% (using the study cohort survival event rate of 95.1%). Power to detect a survival difference (HR = 0.50) against the HGSOC comparator cohort ( N = 362, event rate 90.1%) was 99.0%.

Patient characteristics

Of the 126 patients identified with a documented diagnosis of OCS, 82 were included in the study cohort ( n = 32 no tumour material available for pathology review, n = 5 no sarcoma identified on H&E review, n = 2 no carcinoma identified on H&E review, n = 3 possible uterine origin, n = 2 no confirmed cytokeratin-positive carcinoma) (Fig. 1 ). Baseline characteristics of the study cohort are summarised in Table 1 .

The majority of cases were International Federation of Gynecology and Obstetrics (FIGO) stage III at diagnosis (51, 64.6% of evaluable cases; n = 3 non-evaluable) (Table 1 ). In all, 9 (11.4%), 8 (10.1%) and 11 (13.9%) cases were FIGO stages I, II and IV. Median age at diagnosis was 69 years (range 47–83). Four cases (4.9%) underwent neoadjuvant chemotherapy.

Median PFS was 9.6 months (95% CI 7.5–10.7). Median OS was 12.7 months (95% CI 9.2–17.1). For FIGO stage III/IV cases, the median OS was 11.9 months (95% CI 9.0–15.9).

Histopathological characteristics of OCS

The majority of OCS harboured an epithelial component of HGS type (all confirmed WT1 positive) ( n = 65, 79.3%) (Figs. 2 and 3 ); the remaining 17 cases (20.7%) were of endometrioid type (all confirmed WT1 negative). The vast majority of epithelial components had aberrant p53 expression patterns (wild-type pattern in 3 cases, 4.4% of evaluable carcinomatous components) (Fig. 3 ). The majority of cases did not demonstrate a dominance of either the sarcomatous of carcinomatous population (67.5%, 54 of the 80 evaluable cases); 16 (20.0%) were carcinoma-dominant (>70% malignant cells of epithelial type); 10 (12.5%) were sarcoma-dominant (>70% malignant cells of mesenchymal type) (Fig. 3 ).

a , b WT1-positive epithelial component of high-grade serous type. c , d WT1-negative epithelial component of endometrioid type. e , f OCS demonstrating S100-positive malignant cartilage. g , h OCS with myogenin-positive rhabdomyoblasts. i OCS demonstrating liposarcoma (confirmed cytokeratin-negative) adjacent to endometrioid epithelial component. j OCS demonstrating squamous differentiation. Scale bar represents 100 µm.

STIC serous tubal intraepithelial carcinoma, FIGO International Federation of Gynecology and Obstetrics, NE non-evaluable, FT fallopian tube, RD residual disease, NA not available. For epithelial p53 staining, 8 NE for cytoplasmic p53 staining, and 6 NE for other reasons (significant artefacts due to sample age or fixation, null tumour staining without corresponding stromal positivity or other uninterpretable staining patterns).

Heterologous sarcomatous elements were identified in 42 cases (51.2%). The most common heterologous element was chondrosarcoma (31.7% of cases: 23 chondrosarcoma only, 3 chondrosarcoma plus rhabdomyosarcoma); rhabdomyosarcoma was also common (20.7% of cases; 14 rhabdomyosarcoma only, 3 chondrosarcoma plus rhabdomyosarcoma) (Fig. 3 ). Chondrosarcoma was significantly over-represented in OCS with endometrioid epithelial components (9 of 17, 52.9% in endometrioid versus 17 of 65 in HGS, 26.2%; P = 0.044), with only one case demonstrating rhabdomyosarcoma (with concurrent chondrosarcoma) (Fig. 3 ). By contrast, rhabdomyosarcoma was common in OCS with HGS epithelial components (16 of 65 cases, 24.6%). Two OCS (2.4%) demonstrated liposarcoma: both had epithelial components of endometrioid type ( P = 0.041 for over-representation).

Endometriosis was identified in four cases, all of which had carcinomatous components of endometrioid type (Fig. 3 ); two were FIGO stage I and two were FIGO stage III. STIC lesions were identified in eight cases, all of which had HGS epithelial components; four were FIGO stage III, two were stage I, one was stage IV, and one was unknown stage. Squamous differentiation was common in OCS with endometrioid carcinomatous components (35.3%, 6 of 17) but was also identified in four OCS with epithelial components of HGS type (6.2%, 4 of 65, including 1 case with an identified STIC).

The majority of cases with evaluable metastatic sites demonstrated metastases comprising only the carcinomatous population (75.0%, 27 of 36), with a minority showing mixed carcinosarcoma (22.2%, 8 of 36); metastasis of pure sarcomatous population was rare (2.8%, 1 of 36) (Fig. 3 ).

Features associated with patient survival

OCS patients demonstrated similarly poor survival regardless of histological classification by carcinomatous (endometrioid versus HGS) or sarcomatous compartments (homologous versus heterologous) (Fig. 4a ).

a Overall survival (OS) by histological subgrouping. Labelled hazard ratio (HR) represents comparison of high-grade serous (HGS) epithelial with homologous sarcoma (HGS-homologous) versus endometrioid (endo) epithelial with heterologous sarcoma (endo-heterologous); P = 0.380. b OS by residual disease (RD) status following debulking surgery; P = 0.001. c OS by stage at diagnosis. Labelled HR represents comparison of stage I/II versus stage III; P = 0.015. d OS by age at diagnosis; P = 0.538. Patients grouped according to median age at diagnosis across the cohort (69 years). e OS by first-line treatment regime. Labelled HR represents comparison of platinum–taxane versus surgery only; P < 0.001. Additionally, HR for other platinum regimens (26 single-agent platinum, 2 other platinum combinations) versus surgery only is 0.34, 95% CI 0.19–0.61, P < 0.001. f Forest plot of multivariable overall survival analysis, stratified by diagnosis period. Chemo chemotherapy, macro macroscopic, NVRD no visible residual disease.

Achievement of no visible residual disease (NVRD) after surgical debulking was associated with significantly prolonged OS (HR = 0.45, 95% CI 0.28–0.72) (Fig. 4b ). Patients with stage I/II disease at diagnosis had significantly longer OS compared to stage III cases (HR = 0.48, 95% CI 0.27–0.87) (Fig. 4c ). Age at diagnosis did not have a significant impact on survival (Fig. 4d ). Survival time was longest in patients who received platinum–taxane chemotherapy, but this was comparable to those receiving single-agent platinum or other platinum combinations (Fig. 4e ).

Multivariable analysis identified residual disease (RD) status, first-line treatment regime and stage as independently associated with survival (Fig. 4f ).

Comparison of OCS and HGS ovarian carcinoma

OCS patients were significantly older at diagnosis versus a comparator cohort of 362 unselected pathologically confirmed HGSOC patients (median 69 versus 61 years, P < 0.0001) (Fig. 5a ). A significantly greater proportion of OCS patients were diagnosed at FIGO stage I (2.7-fold enrichment; 11.4%, 9 of the 79 evaluable OCS cases versus 4.3%, 15 of the 351 evaluable HGSOC cases; P = 0.025) (Fig. 5b ). The frequency of FIGO stage I cases was similar between OCS with endometrioid and HGS carcinomatous components (11.8 and 11.3%, respectively). Differences in stage and age at diagnosis between OCS and HGSOC remained significant in a sensitivity analysis including only OCS with carcinomatous components of HGS type ( P = 0.033 and P < 0.0001, respectively).

a Age at diagnosis. b FIGO stage at diagnosis; labelled P value represents comparison of the frequency of stage I cases. c Response to first-line chemotherapy; labelled P value represents comparison of overall response rate (complete response [CR] plus partial response [PR] versus stable disease [SD] plus progression disease [PD]). d Overall survival; labelled HR represents multivariable analysis of tumour type (HGSOC versus OCS; P < 0.0001), age at diagnosis and stage at diagnosis, stratified by residual disease status.

Response rate to first-line adjuvant chemotherapy was significantly lower in OCS compared to HGSOC (42.1%, 8 of the 19 evaluable OCS versus 79.8%, 99 of the 124 evaluable HGSOC, P = 0.001) (Fig. 5c ). Multivariable analysis identified significantly shorter survival time for OCS patients compared to HGSOC (multivariable HR for HGSOC versus OCS 0.31, 95% CI 0.23–0.40, P < 0.0001) (Fig. 5d ). The difference in survival remained significant in a sensitivity analysis including only OCS who received platinum-containing chemotherapy (multivariable HR 0.42, P < 0.0001).

OCS are rare, biphasic malignancies that have received relatively little research attention to date. Although OCS is defined specifically as a biphasic tumour composed of high-grade epithelial and mesenchymal components, the histopathological characteristics of OCS are highly heterogeneous. Here we present a large OCS cohort with detailed clinical annotation and histopathological characterisation. To our knowledge, this is the largest pathologically confirmed OCS cohort reported to date.

Most OCS cases demonstrated HGS epithelial components; however, OCS with endometrioid carcinomatous components also represented a major population (around 20% of cases). Smaller studies have shown that the epithelial component is typically of HGS type, with other types representing only a minority of cases [ 1 ]. In UCS, both serous-like and endometrioid-like UCS have been reported [ 26 ]. Most OCS cases did not demonstrate a dominant malignant cell population, with only 20 and 12.5% of cases demonstrating >70% carcinomatous and >70% sarcomatous populations. The observation that the majority of metastases were of pure carcinomatous populations is in line with data demonstrating that most metastases from UCS are carcinomatous [ 26 ].

Around half of OCS cases demonstrated heterologous sarcomatous elements. Overall, both chondrosarcoma and rhabdomyosarcoma were common, identified in 31.7 and 20.7% of cases, respectively. This is in contrast to UCS, where rhabdomyosarcoma is the most frequent heterologous element (approximately 20% of cases), with only around 10% of cases demonstrating chondrosarcoma [ 27 ]. We observed a strong preference for chondrosarcoma over rhabdomyosarcoma in OCS with endometrioid epithelial components (rhabdomyosarcoma identified in only one case, co-occurring with chondrosarcoma). Liposarcoma was rare, consistent with its low frequency in UCS (<5%) [ 27 ], and was only observed in OCS demonstrating endometrioid epithelial components within our cohort. While squamous differentiation is typically an indicator of endometrioid carcinoma, and we show squamous differentiation in some OCS harbouring an endometrioid epithelial component, we also identified squamous differentiation in OCS cases with HGS carcinomatous compartments, indicating that squamous differentiation is not a specific feature of endometrioid tumours in this context. We identified endometriosis and STIC lesions in OCS with endometrioid and HGS carcinomatous components, respectively. This is consistent with the notion that OCS likely represent metaplastic carcinomas, and with endometriosis and STIC lesions being common precursor lesions of endometrioid and HGS ovarian carcinoma, respectively [ 28 ]. OCS may therefore arise through the same pathway as HGS (from the fallopian tube, via STIC) or endometrioid ovarian carcinoma (from endometriosis). While the histology of the carcinomatous component is not associated with differential survival outcome, it is plausible that these features may be associated with distinct molecular profiles, such as the likelihood of harbouring BRCA1 / 2 mutation, which in turn may determine efficacy of targeted agents including poly ADP ribose polymerase (PARP) inhibitors. Endometriosis and STIC lesions were identified in the context of both early (FIGO I/II) and advanced stage (FIGO III/IV) cases.

We demonstrate extremely poor survival in OCS patients, with high risk of relapse and death across patients of all stages, ages and first-line management strategies. The median overall survival time across the study cohort was 12.7 months. Earlier stage at diagnosis (FIGO I/II), undergoing platinum-containing adjuvant chemotherapy, and achievement of NVRD at debulking surgery were all associated with significantly prolonged survival upon multivariable analysis; however, mortality rate was still high in these patient groups. These findings are in line with the importance of optimal debulking across ovarian carcinoma types [ 21 ] and are in agreement with previous data suggesting improved survival in OCS with low RD volume [ 16 , 17 , 18 ]. Previous reports of smaller case numbers have suggested that presence of heterologous elements may be an indicator of poorer prognosis in OCS [ 29 , 30 ], though other investigators have reported no significant association [ 31 , 32 ]. Histological subclassification of patients based on the carcinomatous and sarcomatous elements did not identify patient groups with differential survival outcome in our cohort. These data suggest that subgrouping patients by histological features is not a useful tool for risk stratification and highlight that specific histological features, such as the presence of heterologous sarcomatous elements, are not markers of more aggressive disease.

These data highlight the urgent need for improved treatment strategies for OCS patients. Some studies have investigated the potential role of ifosfamide in OCS management; ifosfamide–paclitaxel chemotherapy appears inferior to platinum–taxane regimens [ 33 ], while the relative efficacy of platinum–ifosfamide versus platinum–taxane remains controversial [ 1 , 34 , 35 ]. Moreover, ifosfamide-containing regimens may be less well tolerated [ 34 , 36 ]. The rarity of OCS has impeded progress of OCS-specific clinical trials, with OCS frequently included as a minor population alongside UCS. The GOG261 study of paclitaxel/ifosfamide versus carboplatin/paclitaxel demonstrated non-inferiority of the carboplatin–paclitaxel regime in a mixed cohort of UCS and OCS [ 36 ], though the majority of cases were UCS (>80%).

Progress toward discovery of effective molecularly targeted agents for OCS has been hindered by lack of molecular characterisation in this tumour type, and this has impeded inclusion of OCS in clinical trials based on specific molecular defects, agnostic to disease site (BASKET trials). Comprehensive molecular profiling to identify potentially actionable disease biology in OCS therefore represents an immediate research priority; specifically, genomic, transcriptomic and proteomic characterisation of OCS cases has the potential to highlight disease biology already targeted by molecular therapeutics in other disease settings. Repurposing of drugs already in use for other cancer types represents a strategy that may facilitate rapid translation of candidate agents into early phase trials. International collaboration will be required to initiate disease-specific trials of OCS with sufficient power to inform future practice. Targeting of EGFR [ 37 , 38 ], HER2 [ 37 , 38 ], PDGFR [ 39 , 40 ] and immunosuppressive molecules [ 41 ] have been suggested as potential strategies from molecular studies of gynaecological carcinosarcomas; however, data are limited and the vast majority of data are derived from UCS, rather than OCS. Molecular therapies routinely used for management of ovarian carcinoma may be of potential use in OCS; bevacizumab has demonstrated greatest efficacy in highest-risk ovarian carcinoma cases [ 42 ], and may therefore be expected to benefit OCS patients, who are high risk by nature. Similarly, a minority of OCS are thought to harbour homologous recombination repair pathway defects [ 11 ], and may therefore be sensitive to PARP inhibition [ 43 ]. Data regarding clinical efficacy of anti-angiogenic agents and PARP inhibitors in OCS are extremely limited. A phase II trial of the anti-angiogenic agent aflibercept demonstrated disappointing activity in recurrent gynaecological carcinosarcoma [ 44 ]; however, this study included only three OCS cases.

While OCS were originally considered separate to epithelial ovarian cancer, it is now believed that OCS represent metaplastic carcinomas [ 3 ]. This has led many to consider OCS as variants of HGSOC [ 45 ]: both are commonly diagnosed at advanced stage, together representing the most aggressive ovarian cancer types, and the majority of OCS harbour carcinomatous components of HGS type. However, we demonstrate that OCS are around three times more likely to be diagnosed at FIGO stage I, are significantly older at diagnosis (median 69 years), show significantly greater levels of intrinsic chemoresistance (response rate around 40%) and demonstrate significantly shorter survival compared to an unselected HGSOC population (multivariable HR for HGSOC 0.31). Moreover, a significant proportion of OCS have an epithelial component of endometrioid type. These data suggest that consideration of OCS as variants of HGSOC is a substantial over-simplification and that OCS in fact represent a distinct high-risk ovarian cancer type with unique clinical behaviour and histopathological characteristics. For forthcoming trials where OCS may be included alongside high-grade endometrioid and HGS ovarian carcinoma, appropriate stratification is recommended.

Major strengths of this work include contemporary pathology review of a large cohort of cases ( n = 82), exclusion of cases with uterine origin and the use of IHC to confirm presence of both carcinomatous and sarcomatous populations, to confirm the histotype of the carcinomatous elements and to confirm the presence of chondrosarcoma and rhabdomyosarcoma. The majority of OCS studies have reported only a small number of cases (typically fewer than 30) [ 1 ] with limited pathological assessment. The detailed clinical annotation and mature outcome data (event rate >90%) available for our cases—prospectively collected as part of routine care—is another major strength, alongside the use of a pathologically confirmed HGSOC comparator cohort. Limitations include the retrospective nature of the study and the extensive study period, with guidelines for ovarian cancer management evolving over this time. However, a long study period was essential for curating a sufficient number of cases for meaningful analysis, which has represented a significant obstacle in previous studies.

OCS represents an extremely aggressive form of ovarian cancer, with distinct clinical behaviour compared to HGSOC. OCS patients are poorly served by currently available treatment options, and new therapeutics strategies—which have been hindered by lack of research attention and the relative rarity of OCS—are urgently required to improve patient outcomes. Absence of RD following debulking surgery and earlier stage at diagnosis are markers of improved survival; however, risk of recurrence and mortality is high across all patient populations. While OCS are histopathologically heterogeneous, significant relationships exist between phenotypes of the carcinomatous and sarcomatous compartments. Histological subclassification does not identify patient subgroups with distinct survival.

Data availability

We are happy to provide relevant data upon reasonable request, subject to compliance with the relevant ethical framework.

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Acknowledgements

We thank the patients who contributed to this study and the Edinburgh Ovarian Cancer Database from which the clinical data reported here were retrieved. This work was supported by a Tenovus Scotland Grant awarded to RLH (E19-11), and by the Nicola Murray Foundation. CB is supported by funding from Cancer Research UK. Sample collection was supported by Cancer Research UK Experimental Cancer Medicine Centre funding.

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Robert L. Hollis, Ian Croy, Michael Churchman, Clare Bartos, Tzyvia Rye, Charlie Gourley & C. Simon Herrington

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RLH: conceptualisation, formal analysis, investigation, methodology, visualisation, funding acquisition, writing—original draft. IC: investigation, writing—review and editing. MC: data curation, project administration, writing—review and editing. TR: data curation, investigation, writing—review and editing. CB: data curation, writing—review and editing. CG: resources, writing—review and editing CSH: investigation, methodology, writing—review and editing.

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Correspondence to Robert L. Hollis .

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RLH: consultancy fees from GSK outside the scope of this work. IC: none. MC: none. TR: none. CB: none. CG: CG: grants from AstraZeneca, MSD, BMS, Clovis, Novartis, BerGenBio, Medannexin and Artios; personal fees from AstraZeneca, MSD, GSK, Tesaro, Clovis, Roche, Foundation One, Chugai, Takeda, Sierra Oncology, Takeda and Cor2Ed outside the submitted work; patents PCT/US2012/040805 issued, PCT/GB2013/053202 pending, 1409479.1 pending, 1409476.7 pending and 1409478.3 pending. CSH: none.

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Ethical approval for the study was obtained from the Lothian NRS Human Annotated Bioresource (reference 15/ES/0094-SR1330). All participants gave written informed consent or had consent waived by the ethics committee due to the retrospective nature of the study. The study was performed in accordance with the Declaration of Helsinki.

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Hollis, R.L., Croy, I., Churchman, M. et al. Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma. Br J Cancer 127 , 1034–1042 (2022). https://doi.org/10.1038/s41416-022-01874-8

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Received : 01 February 2022

Revised : 18 May 2022

Accepted : 30 May 2022

Published : 17 June 2022

Issue Date : 05 October 2022

DOI : https://doi.org/10.1038/s41416-022-01874-8

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ORIGINAL RESEARCH article

Introduction

Materials and methods

Mutation filtering and annotation

Statistical analysis

Participant characteristics

Characteristics of all mutations

Characteristics of deleterious mutations

Characteristics of BRCA1/2 gene mutations

Mutations associated with family history

Mutations associated with age of diagnosis

Mutations associated with native place

Data availability statement

Ethics statement

Author contributions

Acknowledgments

Conflict of interest

Publisher’s note

Supplementary material

Abbreviations

A closer look at ovarian cancer screening

How common is ovarian cancer?

What tests can help detect ovarian cancer?

What is CA 125?

What are the symptoms of ovarian cancer?

Common symptoms of ovarian cancer include:

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