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METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis

The regulatory role of N6-methyladenosine (m6A) modification in the onset and progression of cancer has garnered increasing attention in recent years. However, the specific role of m6A modification in pulmonar...

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HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis ...

A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment

The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induce...

Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m 6 A) is the most abundant reversible methylati...

A phenotypic screening approach to target p60AmotL2-expressing invasive cancer cells

Tumor cells have the ability to invade and form small clusters that protrude into adjacent tissues, a phenomenon that is frequently observed at the periphery of a tumor as it expands into healthy tissues. The ...

HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Recently, targeted therapies including PD1 (programmed cell death 1) antibodies have been used in advanced GC patients. Howev...

GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression

Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumo...

RBM10 C761Y mutation induced oncogenic ASPM isoforms and regulated β-catenin signaling in cholangiocarcinoma

Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the altern...

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many ...

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice

Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol ...

Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity

Regulatory B cells (Bregs), a specialized subset of B cells that modulate immune responses and maintain immune tolerance in malignant tumors, have not been extensively investigated in the context of bladder ca...

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration sch...

Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies

Cancer stem cells (CSCs) were first discovered in the 1990s, revealing the mysteries of cancer origin, migration, recurrence and drug-resistance from a new perspective. The expression of pluripotent genes and ...

Tumor suppressor role of the complement inhibitor CSMD1 and its role in TNF-induced neuroinflammation in gliomas

The complement inhibitor CSMD1 acts as a tumor suppressor in various types of solid cancers. Despite its high level of expression in the brain, its function in gliomas, malignant brain tumors originating from ...

A high-content screen of FDA approved drugs to enhance CAR T cell function: ingenol-3-angelate improves B7-H3-CAR T cell activity by upregulating B7-H3 on the target cell surface via PKCα activation

CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-posi...

Liquid biopsy techniques and lung cancer: diagnosis, monitoring and evaluation

Lung cancer stands as the most prevalent form of cancer globally, posing a significant threat to human well-being. Due to the lack of effective and accurate early diagnostic methods, many patients are diagnose...

Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic...

Analysis of the effect of CCR7 on the microenvironment of mouse oral squamous cell carcinoma by single-cell RNA sequencing technology

Studies have shown that CCR7, an important inflammatory factor, can promote the proliferation and metastasis of oral squamous cell carcinoma (OSCC), but its role in the tumor microenvironment (TME) remains unc...

Correction: A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle

The original article was published in Journal of Experimental & Clinical Cancer Research 2024 43 :74

Bispecific aptamer-decorated and light-triggered nanoparticles targeting tumor and stromal cells in breast cancer derived organoids: implications for precision phototherapies

Based on the established role of cancer-stroma cross-talk in tumor growth, progression and chemoresistance, targeting interactions between tumor cells and their stroma provides new therapeutic approaches. Dual...

PELI1: key players in the oncogenic characteristics of pancreatic Cancer

Pancreatic cancer (PC) is a highly malignant gastrointestinal tumor, which is characterized by difficulties in early diagnosis, early metastasis, limited therapeutic response and a grim prognosis. Therefore, i...

Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer

Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive.

CDKL1 potentiates the antitumor efficacy of radioimmunotherapy by binding to transcription factor YBX1 and blocking PD-L1 expression in lung cancer

The evasion of the immune response by tumor cells through programmed death-ligand 1 (PD-L1) has been identified as a factor contributing to resistance to radioimmunotherapy in lung cancer patients. However, th...

Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition

This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in on...

Cross-reactive CD8 + T cell responses to tumor-associated antigens (TAAs) and homologous microbiota-derived antigens (MoAs)

We have recently shown extensive sequence and conformational homology between tumor-associated antigens (TAAs) and antigens derived from microorganisms (MoAs). The present study aimed to assess the breadth of ...

Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001

In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored t...

Anaplastic thyroid cancer spheroids as preclinical models to test therapeutics

Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for ATC spheroid culture is yet to be developed. In this study, we created a...

The localization, origin, and impact of platelets in the tumor microenvironment are tumor type-dependent

How platelets interact with and influence the tumor microenvironment (TME) remains poorly characterized.

Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer

Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells...

Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade

The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients...

Validation of a multiomic model of plasma extracellular vesicle PD-L1 and radiomics for prediction of response to immunotherapy in NSCLC

Immune-checkpoint inhibitors (ICIs) have showed unprecedent efficacy in the treatment of patients with advanced non-small cell lung cancer (NSCLC). However, not all patients manifest clinical benefit due to th...

Correction: RNA-binding protein RPS7 promotes hepatocellular carcinoma progression via LOXL2-dependent activation of ITGB1/FAK/SRC signaling

The original article was published in Journal of Experimental & Clinical Cancer Research 2024 43 :45

C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription

Acute myeloid leukemia (AML) with biallelic ( CEBPA bi ) as well as single mutations located in the bZIP region is associated with a favorable prognosis, but the underlying mechanisms are still unclear. Here, we pro...

Correction: The epigenetic downregulation of LncGHRLOS mediated by RNA m6A methylase ZCCHC4 promotes colorectal cancer tumorigenesis

The original article was published in Journal of Experimental & Clinical Cancer Research 2024 43 :44

Functionally-instructed modifiers of response to ATR inhibition in experimental glioma

The DNA damage response (DDR) is a physiological network preventing malignant transformation, e.g. by halting cell cycle progression upon DNA damage detection and promoting DNA repair. Glioblastoma are incurab...

Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer

While T cell-activating immunotherapies against recurrent head and neck squamous cell carcinoma (HNSCC) have shown impressive results in clinical trials, they are often ineffective in the majority of patients....

TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication

Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) – the most aggressive BC ...

A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle

Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer developm...

The Correction to this article has been published in Journal of Experimental & Clinical Cancer Research 2024 43 :93

TGF-β-activated circRYK drives glioblastoma progression by increasing VLDLR mRNA expression and stability in a ceRNA- and RBP-dependent manner

The TGF-β signalling pathway is intricately associated with the progression of glioblastoma (GBM). The objective of this study was to examine the role of circRNAs in the TGF-β signalling pathway.

S100A9 + CD14 + monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function

The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. Th...

Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer

A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol oxidoreductase, is confirmed to be highly u...

Inhibition of MER proto-oncogene tyrosine kinase by an antisense oligonucleotide enhances treatment efficacy of immunoradiotherapy

The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previou...

KLF7 regulates super-enhancer-driven IGF2BP2 overexpression to promote the progression of head and neck squamous cell carcinoma

Head and neck squamous carcinoma (HNSCC) is known for its high aggressiveness and susceptibility to cervical lymph node metastasis, which greatly contributes to its poor prognosis. During tumorigenesis, many t...

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis

Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failu...

Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway

Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells c...

GMP-manufactured CRISPR/Cas9 technology as an advantageous tool to support cancer immunotherapy

CRISPR/Cas9 system to treat human-related diseases has achieved significant results and, even if its potential application in cancer research is improving, the application of this approach in clinical practice...

Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition

Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analy...

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development an...

IL6-STAT3-C/EBPβ-IL6 positive feedback loop in tumor-associated macrophages promotes the EMT and metastasis of lung adenocarcinoma

Lung cancer is one of the most common tumors in the world, and metastasis is one of the major causes of tumor-related death in lung cancer patients. Tumor-associated macrophages (TAMs) are a major component of...

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia

In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly under...

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IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity

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• Accepted Manuscript April 2 2024

Kelly D. Moynihan , Manu P. Kumar , Hussein Sultan , Danielle C. Pappas , Terrence Park , S. Michael Chin , Paul Bessette , Ruth Y. Lan , Henry C. Nguyen , Nathan D. Mathewson , Irene Ni , Wei Chen , Yonghee Lee , Sindy Liao-Chan , Jessie Chen , Ton N.M. Schumacher , Robert D. Schreiber , Yik A. Yeung , Ivana M. Djuretic; IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity. Cancer Discov 2024; https://doi.org/10.1158/2159-8290.CD-23-1266

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IL-2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, while others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL-2 to CD8+ T cells, which are key anti-tumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, CD8 cis-targeted IL-2 that demonstrates over 500-fold preference for CD8+ T cells over NK and Treg cells, which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL-2’s effects on CD8+ T cells in vitro and induced selective expansion of CD8+ T cells in primates. In mice, an AB248 surrogate demonstrated superior anti-tumor activity and enhanced tolerability as compared to an untargeted IL-2RBy agonist. Efficacy was associated with expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a “better effector” population. These data support the potential utility of AB248 in clinical settings.

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Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review

Sergiusz Łukasiewicz.

1 Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; lp.lzoc@zciweisakulS (S.Ł.); [email protected] (A.S.)

Marcin Czeczelewski

2 Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; [email protected] (M.C.); lp.teno@amrofa (A.F.)

Alicja Forma

3 Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; [email protected]

Robert Sitarz

Andrzej stanisławek.

4 Department of Oncology, Chair of Oncology and Environmental Health, Medical University of Lublin, 20-081 Lublin, Poland

Simple Summary

Breast cancer is the most common cancer among women. It is estimated that 2.3 million new cases of BC are diagnosed globally each year. Based on mRNA gene expression levels, BC can be divided into molecular subtypes that provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. This review addresses the overview on the BC epidemiology, risk factors, classification with an emphasis on molecular types, prognostic biomarkers, as well as possible treatment modalities.

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.

1. Introduction

Being characterized by six major hallmarks, carcinogenesis might occur in every cell, tissue, and organ, leading to the pathological alternations that result in a vast number of cancers. The major mechanisms that enable its progression include evasion of apoptosis, limitless capacity to divide, enhanced angiogenesis, resistance to anti-growth signals and induction of own growth signals, as well as the capacity to metastasize [ 1 ]. Carcinogenesis is a multifactorial process that is primarily stimulated by both—genetic predispositions and environmental causes. The number of cancer-related deaths is disturbingly increasing every year ranking them as one of the major causes of death worldwide. Even though a significant number of cancers do not always need to result in death, they significantly lower the quality of life and require larger costs in general.

Breast cancer is currently one of the most prevalently diagnosed cancers and the 5th cause of cancer-related deaths with an estimated number of 2.3 million new cases worldwide according to the GLOBOCAN 2020 data [ 2 ]. Deaths due to breast cancer are more prevalently reported (an incidence rate approximately 88% higher) in transitioning countries (Melanesia, Western Africa, Micronesia/Polynesia, and the Caribbean) compared to the transitioned ones (Australia/New Zealand, Western Europe, Northern America, and Northern Europe). Several procedures such as preventive behaviors in general as well as screening programs are crucial regarding a possible minimization of breast cancer incidence rate and the implementation of early treatment. Currently, it is the Breast Health Global Initiative (BHGI) that is responsible for the preparation of proper guidelines and the approaches to provide the most sufficient breast cancer control worldwide [ 3 ]. In this review article, we have focused on the female breast cancer specifically since as abovementioned, it currently constitutes the most prevalent cancer amongst females.

2. Breast Cancer Epidemiology

According to the WHO, malignant neoplasms are the greatest worldwide burden for women, estimated at 107.8 million Disability-Adjusted Life Years (DALYs), of which 19.6 million DALYs are due to breast cancer. [ 4 ]. Breast cancer is the most frequently diagnosed cancer in women worldwide with 2.26 million [95% UI, 2.24–2.79 million] new cases in 2020 [ 5 ]. In the United States, breast cancer alone is expected to account for 29% of all new cancers in women [ 6 ]. The 2018 GLOBOCAN data shows that age-standardized incidence rates (ASIR) of breast cancer are strongly and positively associated with the Human Development Index (HDI) [ 7 ]. According to 2020 data, the ASIR was the highest in very high HDI countries (75.6 per 100,000) while it was more than 200% lower in medium and low HDI countries (27.8 per 100,000 and 36.1 per 100,000 respectively) [ 5 ].

Besides being the most common, breast cancer is also the leading cause of cancer death in women worldwide. Globally, breast cancer was responsible for 684,996 deaths [95% UI, 675,493–694,633] at an age-adjusted rate of 13.6/100,000 [ 5 ]. Although incidence rates were the highest in developed regions, the countries in Asia and Africa shared 63% of total deaths in 2020 [ 5 ]. Most women who develop breast cancer in a high-income country will survive; the opposite is true for women in most low-income and many middle-income countries [ 8 ].

In 2020 breast cancer mortality-to-incidence ratio (MIR) as a representative indicator of 5-year survival rates [ 9 ] was 0.30 globally [ 5 ]. Taking into consideration the clinical extent of breast cancer, in locations with developed health care (Hong-Kong, Singapore, Turkey) the 5-year survival was 89.6% for localized and 75.4% for regional cancer. In less developed countries (Costa Rica, India, Philippines, Saudi Arabia, Thailand) the survival rates were 76.3% and 47.4% for localized and regional breast cancer respectively [ 10 ].

Breast cancer incidence and death rates have increased over the last three decades. Between 1990 and 2016 breast cancer incidence has more than doubled in 60/102 countries (e.g., Afghanistan, Philippines, Brazil, Argentina), whereas deaths have doubled in 43/102 countries (e.g., Yemen, Paraguay, Libya, Saudi Arabia) [ 11 ]. Current projections indicate that by 2030 the worldwide number of new cases diagnosed reach 2.7 million annually, while the number of deaths 0.87 million [ 12 ]. In low- and medium-income countries, the breast cancer incidence is expected to increase further due to the westernization of lifestyles (e.g., delayed pregnancies, reduced breastfeeding, low age at menarche, lack of physical activity, and poor diet), better cancer registration, and cancer detection [ 13 ].

3. Risk Factors of Breast Cancer

The number of risk factors of breast cancer is significant and includes both modifiable factors and non-modifiable factors ( Table 1 ).

Modifiable and non-modifiable risk factors of breast cancer.

3.1. Non-Modifiable Factors

3.1.1. female sex.

Female sex constitutes one of the major factors associated with an increased risk of breast cancer primarily because of the enhanced hormonal stimulation. Unlike men who present insignificant estrogen levels, women have breast cells which are very vulnerable to hormones (estrogen and progesterone in particular) as well as any disruptions in their balance. Circulating estrogens and androgens are positively associated with an increased risk of breast cancer [ 14 ]. The alternations within the physiological levels of the endogenous levels of sex hormones result in a higher risk of breast cancer in the case of premenopausal and postmenopausal women; these observations were also supported by the Endogenous Hormones and Breast Cancer Collaborative Group [ 15 , 16 , 17 ].

Less than 1% of all breast cancers occur in men. However, breast cancer in men is a rare disease that’s at the time of diagnosis tends to be more advanced than in women. The average age of men at the diagnosis is about 67. The important factors increase a man’s risk of breast cancer are: older age, BRCA2/BRCA1 mutations, increased estrogen levels, Klinefelter syndrome, family history of breast cancer, and radiation exposure [ 18 ].

3.1.2. Older Age

Currently, about 80% of patients with breast cancer are individuals aged >50 while at the same time more than 40% are those more than 65 years old [ 19 , 20 , 21 ]. The risk of developing breast cancer increases as follows—the 1.5% risk at age 40, 3% at age 50, and more than 4% at age 70 [ 22 ]. Interestingly, a relationship between a particular molecular subtype of cancer and a patient’s age was observed –aggressive resistant triple-negative breast cancer subtype is most commonly diagnosed in groups under 40 age, while in patients >70, it is luminal A subtype [ 21 ]. Generally, the occurrence of cancer in older age is not only limited to breast cancer; the accumulation of a vast number of cellular alternations and exposition to potential carcinogens results in an increase of carcinogenesis with time.

3.1.3. Family History

A family history of breast cancer constitutes a major factor significantly associated with an increased risk of breast cancer. Approximately 13–19% of patients diagnosed with breast cancer report a first-degree relative affected by the same condition [ 23 ]. Besides, the risk of breast cancer significantly increases with an increasing number of first-degree relatives affected; the risk might be even higher when the affected relatives are under 50 years old [ 24 , 25 , 26 ]. The incidence rate of breast cancer is significantly higher in all of the patients with a family history despite the age. This association is driven by epigenetic changes as well as environmental factors acting as potential triggers [ 27 ]. A family history of ovarian cancer—especially those characterized by BRCA1 and BRCA2 mutations—might also induce a greater risk of breast cancer [ 28 ].

3.1.4. Genetic Mutations

Several genetic mutations were reported to be highly associated with an increased risk of breast cancer. Two major genes characterized by a high penetrance are BRCA1 (located on chromosome 17) and BRCA2 (located on chromosome 13). They are primarily linked to the increased risk of breast carcinogenesis [ 29 ]. The mutations within the above-mentioned genes are mainly inherited in an autosomal dominant manner, however, sporadic mutations are also commonly reported. Other highly penetrant breast cancer genes include TP53 , CDH1 , PTEN , and STK11 [ 30 , 31 , 32 , 33 , 34 ]. Except for the increased risk of breast cancer, carriers of such mutations are more susceptible to ovarian cancer as well. A significant number of DNA repair genes that can interact with BRCA genes including ATM , PALB2 , BRIP1 , or CHEK2 , were reported to be involved in the induction of breast carcinogenesis; those are however characterized by a lower penetrance (moderate degree) compared to BRCA1 or BRCA2 ( Table 2 ) [ 29 , 35 , 36 , 37 , 38 ]. According to quite recent Polish research, mutations within the XRCC2 gene could also be potentially associated with an increased risk of breast cancer [ 39 ].

Major genes associated with an increased risk of breast cancer occurrence.

3.1.5. Race/Ethnicity

Disparities regarding race and ethnicity remain widely observed among individuals affected by breast cancer; the mechanisms associated with this phenomenon are not yet understood. Generally, the breast cancer incidence rate remains the highest among white non-Hispanic women [ 51 , 52 ]. Contrarily, the mortality rate due to this malignancy is significantly higher among black women; this group is also characterized by the lowest survival rates [ 53 ].

3.1.6. Reproductive History

Numerous studies confirmed a strict relationship between exposure to endogenous hormones—estrogen and progesterone in particular—and excessive risk of breast cancer in females. Therefore, the occurrence of specific events such as pregnancy, breastfeeding, first menstruation, and menopause along with their duration and the concomitant hormonal imbalance, are crucial in terms of a potential induction of the carcinogenic events in the breast microenvironment. The first full-term pregnancy at an early age (especially in the early twenties) along with a subsequently increasing number of births are associated with a reduced risk of breast cancer [ 54 , 55 ]. Besides, the pregnancy itself provides protective effects against potential cancer. However, protection was observed at approximately the 34th pregnancy week and was not confirmed for the pregnancies lasting for 33 weeks or less [ 56 ]. Women with a history of preeclampsia during pregnancy or children born to a preeclamptic pregnancy are at lower risk of developing breast cancer [ 57 ]. No association between the increased breast cancer risk and abortion was stated so far [ 58 ].

The dysregulated hormone levels during preeclampsia including increased progesterone and reduced estrogen levels along with insulin, cortisol, insulin-like growth factor-1, androgens, human chorionic gonadotropin, corticotropin-releasing factor, and IGF-1 binding protein deviating from the physiological ranges, show a protective effect preventing from breast carcinogenesis. The longer duration of the breastfeeding period also reduces the risk of both the ER/PR-positive and -negative cancers [ 59 ]. Early age at menarche is another risk factor of breast cancer; it is possibly also associated with a tumor grade and lymph node involvement [ 60 ]. Besides, the earlier age of the first menstruation could result in an overall poorer prognosis. Contrarily, early menopause despite whether natural or surgical, lowers the breast cancer risk [ 61 ].

3.1.7. Density of Breast Tissue

The density of breast tissue remains inconsistent throughout the lifetime; however, several categories including low-density, high-density, and fatty breasts have been established in clinical practice. Greater density of breasts is observed in females of younger age and lower BMI, who are pregnant or during the breastfeeding period, as well as during the intake of hormonal replacement therapy [ 62 ]. Generally, the greater breast tissue density correlates with the greater breast cancer risk; this trend is observed both in premenopausal and postmenopausal females [ 63 ]. It was proposed that screening of breast tissue density could be a promising, non-invasive, and quick method enabling rational surveillance of females at increased risk of cancer [ 64 ].

3.1.8. History of Breast Cancer and Benign Breast Diseases

Personal history of breast cancer is associated with a greater risk of a renewed cancerous lesions within the breasts [ 65 ]. Besides, a history of any other non-cancerous alternations in breasts such as atypical hyperplasia, carcinoma in situ, or many other proliferative or non-proliferative lesions, also increases the risk significantly [ 66 , 67 , 68 ]. The histologic classification of benign lesions and a family history of breast cancer are two factors that are strongly associated with breast cancer risk [ 66 ].

3.1.9. Previous Radiation Therapy

The risk of secondary malignancies after radiotherapy treatment remains an individual matter that depends on the patient’s characteristics, even though it is a quite frequent phenomenon that arises much clinical concern. Cancer induced by radiation therapy is strictly associated with an individual’s age; patients who receive radiation therapy before the age of 30, are at a greater risk of breast cancer [ 69 ]. The selection of proper radiotherapy technique is crucial in terms of secondary cancer risk—for instance, tangential field IMRT (2F-IMRT) is associated with a significantly lower risk compared to multiple-field IMRT (6F-IMRT) or double partial arcs (VMAT) [ 70 ]. Besides, the family history of breast cancer in patients who receive radiotherapy additionally enhances the risk of cancer occurrence [ 71 ]. However, Bartelink et al. showed that additional radiation (16 Gy) to the tumor bed combined with standard radiotherapy might decrease the risk of local recurrence [ 72 ].

3.2. Modifiable Factors

3.2.1. chosen drugs.

Data from some research indicates that the intake of diethylstilbestrol during pregnancy might be associated with a greater risk of breast cancer in children; this, however, remains inconsistent between studies and requires further evaluation [ 73 , 74 ]. The intake of diethylstilbestrol during pregnancy is associated with an increased risk of breast cancer not only in mothers but also in the offspring [ 75 ]. This relationship is observed despite the expression of neither estrogen nor progesterone receptors and might be associated with every breast cancer histological type. The risk increases with age; women at age of ≥40 years are nearly 1.9 times more susceptible compared to women under 40. Moreover, breast cancer risk increases with greater diethylstilbestrol doses [ 76 ]. Numerous researches indicate that females who use hormonal replacement therapy (HRT) especially longer than 5 or 7 years are also at increased risk of breast cancer [ 77 , 78 ]. Several studies indicated that the intake of chosen antidepressants, mainly paroxetine, tricyclic antidepressants, and selective serotonin reuptake inhibitors might be associated with a greater risk of breast cancer [ 79 , 80 ]. Lawlor et al. showed that similar risk might be achieved due to the prolonged intake of antibiotics; Friedman et al. observed that breast risk is mostly elevated while using tetracyclines [ 81 , 82 ]. Attempts were made to investigate a potential relationship between hypertensive medications, non-steroidal anti-inflammatory drugs, as well as statins, and an elevated risk of breast cancer, however, this data remains highly inconsistent [ 83 , 84 , 85 ].

3.2.2. Physical Activity

Even though the mechanism remains yet undeciphered, regular physical activity is considered to be a protective factor of breast cancer incidence [ 86 , 87 ]. Chen et al. observed that amongst females with a family history of breast cancer, physical activity was associated with a reduced risk of cancer but limited only to the postmenopausal period [ 88 ]. However, physical activity is beneficial not only in females with a family history of breast cancer but also in those without such a history. Contrarily to the above-mentioned study, Thune et al. pointed out more pronounced effects in premenopausal females [ 89 ]. There are several hypotheses aiming to explain the protective role of physical activity in terms of breast cancer incidence; physical activity might prevent cancer by reducing the exposure to the endogenous sex hormones, altering immune system responses or insulin-like growth factor-1 levels [ 88 , 90 , 91 ].

3.2.3. Body Mass Index

According to epidemiological evidence, obesity is associated with a greater probability of breast cancer. This association is mostly intensified in obese post-menopausal females who tend to develop estrogen-receptor-positive breast cancer. Yet, independently to menopausal status, obese women achieve poorer clinical outcomes [ 92 ]. Wang et al. showed that females above 50 years old with greater Body Mass Index (BMI) are at a greater risk of cancer compared to those with low BMI [ 93 ]. Besides, the researchers observed that greater BMI is associated with more aggressive biological features of tumor including a higher percentage of lymph node metastasis and greater size. Obesity might be a reason for greater mortality rates and a higher probability of cancer relapse, especially in premenopausal women [ 94 ]. Increased body fat might enhance the inflammatory state and affects the levels of circulating hormones facilitating pro-carcinogenic events [ 95 ]. Thus, poorer clinical outcomes are primarily observed in females with BMI ≥ 25 kg/m 2 [ 96 ]. Interestingly, postmenopausal women tend to present poorer clinical outcomes despite proper BMI values but namely due to excessive fat volume [ 97 ]. Greater breast cancer risk with regards to BMI also correlates with the concomitant family history of breast cancer [ 98 ].

3.2.4. Alcohol Intake

Numerous evidences confirm that excessive alcohol consumption is a factor that might enhance the risk of malignancies within the gastrointestinal tract; however, it was proved that it is also linked to the risk of breast cancer. Namely, it is not alcohol type but rather the content of alcoholic beverages that mostly affect the risk of cancer. The explanation for this association is the increased levels of estrogens induced by the alcohol intake and thus hormonal imbalance affecting the risk of carcinogenesis within the female organs [ 99 , 100 ]. Besides, alcohol intake often results in excessive fat gain with higher BMI levels, which additionally increases the risk. Other hypotheses include direct and indirect carcinogenic effects of alcohol metabolites and alcohol-related impaired nutrient intake [ 101 ]. Alcohol consumption was observed to increase the risk of estrogen-positive breast cancers in particular [ 102 ]. Consumed before the first pregnancy, it significantly contributes to the induction of morphological alterations of breast tissue, predisposing it to further carcinogenic events [ 103 ].

3.2.5. Smoking

Carcinogens found in tobacco are transported to the breast tissue increasing the plausibility of mutations within oncogenes and suppressor genes ( p53 in particular). Thus, not only active but also passive smoking significantly contributes to the induction of pro-carcinogenic events [ 104 ]. Besides, longer smoking history, as well as smoking before the first full-term pregnancy, are additional risk factors that are additionally pronounced in females with a family history of breast cancer [ 105 , 106 , 107 , 108 ].

3.2.6. Insufficient Vitamin Supplementation

Vitamins exert anticancer properties, which might potentially benefit in the prevention of several malignancies including breast cancer, however, the mechanism is not yet fully understood. Attempts are continually made to analyze the effects of vitamin intake (vitamin C, vitamin E, B-group vitamins, folic acid, multivitamin) on the risk of breast cancer, nevertheless, the data remains inconsistent and not sufficient to compare the results and draw credible data [ 108 ]. In terms of breast cancer, most studies are currently focused on vitamin D supplementation confirming its potentially protective effects [ 109 , 110 , 111 ]. High serum 25-hydroxyvitamin D levels are associated with a lower incidence rate of breast cancer in premenopausal and postmenopausal women [ 110 , 112 ]. Intensified expression of vitamin D receptors was shown to be associated with lower mortality rates due to breast cancer [ 113 ]. Even so, further evaluation is required since data remains inconsistent in this matter [ 108 , 114 ].

3.2.7. Exposure to Artificial Light

Artificial light at night (ALAN) has been recently linked to increased breast cancer risk. The probable causation might be a disrupted melatonin rhythm and subsequent epigenetic alterations [ 115 ]. According to the studies conducted so far, increased exposure to ALAN is associated with a significantly greater risk of breast cancer compared to individuals with lowered ALAN exposure [ 116 ]. Nonetheless, data regarding the excessive usage of LED electronic devices and increased risk of breast cancer is insufficient and requires further evaluation as some results are contradictory [ 116 ].

3.2.8. Intake of Processed Food/Diet

According to the World Health Organization (WHO), highly processed meat was classified as a Group 1 carcinogen that might increase the risk of not only gastrointestinal malignancies but also breast cancer. Similar observations were made in terms of an excessive intake of saturated fats [ 117 ]. Ultra-processed food is rich in sodium, fat, and sugar which subsequently predisposes to obesity recognized as another factor of breast cancer risk [ 118 ]. It was observed that a 10% increase of ultra-processed food in the diet is associated with an 11% greater risk of breast cancer [ 118 ]. Contrarily, a diet high in vegetables, fruits, legumes, whole grains, and lean protein is associated with a lowered risk of breast cancer [ 119 ]. Generally, a diet that includes food containing high amounts of n-3 PUFA, vitamin D, fiber, folate, and phytoestrogen might be beneficial as a prevention of breast cancer [ 120 ]. Besides, lower intake of n-6 PUFA and saturated fat is recommended. Several in vitro and in vivo studies also suggest that specific compounds found in green tea might present anti-cancer effects which has also been studied regarding breast cancer [ 121 ]. Similar properties were observed in case of turmeric-derived curcuminoids as well as sulforaphane (SFN) [ 122 , 123 ].

3.2.9. Exposure to Chemical

Chronic exposure to chemicals can promote breast carcinogenesis by affecting the tumor microenvironment subsequently inducing epigenetic alterations along with the induction of pro-carcinogenic events [ 124 ]. Females chronically exposed to chemicals present significantly greater plausibility of breast cancer which is further positively associated with the duration of the exposure [ 125 ]. The number of chemicals proposed to induce breast carcinogenesis is significant; so far, dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyl (PCB) are mostly investigated in terms of breast cancer since early exposure to those chemicals disrupts the development of mammary glands [ 126 , 127 ]. A potential relationship was also observed in the case of increased exposure to polycyclic aromatic hydrocarbons (PAH), synthetic fibers, organic solvents, oil mist, and insecticides [ 128 ].

3.2.10. Other Drugs

Other drugs that might constitute potential risk factors for breast cancer include antibiotics, antidepressants, statins, antihypertensive medications (e.g., calcium channel blockers, angiotensin II-converting enzyme inhibitors), as well as NSAIDs (including aspirin, ibuprofen) [ 129 , 130 , 131 , 132 , 133 ].

4. Breast Cancer Classification

4.1. histological classification.

Invasive breast cancers (IBC) comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. The World Health Organization (WHO) distinguish at least 18 different histological breast cancer types [ 134 ].

Invasive breast cancer of no special type (NST), formerly known as invasive ductal carcinoma is the most frequent subgroup (40–80%) [ 135 ]. This type is diagnosed by default as a tumor that fails to be classified into one of the histological special types [ 134 ]. About 25% of invasive breast cancers present distinctive growth patterns and cytological features, hence, they are recognized as specific subtypes (e.g., invasive lobular carcinoma, tubular, mucinous A, mucinous B, neuroendocrine) [ 136 ].

Molecular classification independently from histological subtypes, invasive breast cancer can be divided into molecular subtypes based on mRNA gene expression levels. In 2000, Perou et al. on a sample of 38 breast cancers identified 4 molecular subtypes from microarray gene expression data: Luminal, HER2-enriched, Basal-like, and Normal Breast-like [ 137 ]. Further studies allowed to divide the Luminal group into two subgroups (Luminal A and B) [ 138 , 139 ]. The normal breast-like subtype has subsequently been omitted, as it is thought to represent sample contamination by normal mammary glands. In the Cancer Genome Atlas Project (TCGA) over 300 primary tumors were thoroughly profiled (at DNA, RNA, and protein levels) and combined in biological homogenous groups of tumors. The consensus clustering confirmed the distinction of four main breast cancer intrinsic subtypes based on mRNA gene expression levels only (Luminal A, Luminal B, HER2-enriched, and basal-like) [ 140 ]. Additionally, the 5th intrinsic subtype—claudin-low breast cancer was discovered in 2007 in an integrated analysis of human and murine mammary tumors [ 141 ].

In 2009, Parker et al. developed a 50-gene signature for subtype assignment, known as PAM50, that could reliably classify particular breast cancer into the main intrinsic subtypes with 93% accuracy [ 142 ]. PAM50 is now clinically implemented worldwide using the NanoString nCounter ® , which is the basis for the Prosigna ® test. The Prosigna ® combines the PAM50 assay as well as clinical information to assess the risk of distant relapse estimation in postmenopausal women with hormone receptor-positive, node-negative, or node-positive early-stage breast cancer patients, and is a daily-used tool assessing the indication of adjuvant chemotherapy [ 143 , 144 , 145 ].

4.2. Luminal Breast Cancer

Luminal breast cancers are ER-positive tumors that comprise almost 70% of all cases of breast cancers in Western populations [ 146 ]. Most commonly Luminal-like cancers present as IBC of no special subtype, but they may infrequently differentiate into invasive lobular, tubular, invasive cribriform, mucinous, and invasive micropapillary carcinomas [ 147 , 148 ]. Two main biological processes: proliferation-related pathways and luminal-regulated pathways distinguish Luminal-like tumors into Luminal A and B subtypes with different clinical outcomes.

Luminal A tumors are characterized by presence of estrogen-receptor (ER) and/or progesterone-receptor (PR) and absence of HER2. In this subtype the ER transcription factors activate genes, the expression of which is characteristic for luminal epithelium lining the mammary ducts [ 149 , 150 ]. It also presents a low expression of genes related to cell proliferation [ 151 ]. Clinically they are low-grade, slow-growing, and tend to have the best prognosis.

In contrast to subtype A, Luminal B tumors are higher grade and has worse prognosis. They are ER positive and may be PR negative and/or HER2 positive. Additionally, it has high expression of proliferation-related genes (e.g., MKI67 and AURKA) [ 152 , 153 , 154 ]. This subtype has lower expression of genes or proteins typical for luminal epithelium such as the PR [ 150 , 155 ] and FOXA1 [ 146 , 156 ], but not the ER [ 157 ]. ER is similarly expressed in both A and B subtypes and is used to distinguish luminal from non-luminal disease.

4.3. HER2-Enriched Breast Cancer

The HER2-enriched group makes up 10–15% of breast cancers. It is characterized by the high expression of the HER2 with the absence of ER and PR. This subtype mainly expresses proliferation—related genes and proteins (e.g., ERBB2/HER2 and GRB7), rather than luminal and basal gene and protein clusters [ 154 , 156 , 157 ]. Additionally, in the HER2-enriched subtype there is evidence of mutagenesis mediated by APOBEC3B. APOBEC3B is a subclass of APOBEC cytidine deaminases, which induce cytosine mutation biases and is a source of mutation clusters [ 158 , 159 , 160 ].

HER2-enriched cancers grow faster than luminal cancers and used to have the worst prognosis of subtypes before the introduction of HER2-targeted therapies. Importantly, the HER2-enriched subtype is not synonymous with clinically HER2-positive breast cancer because many ER-positive/HER2-positive tumors qualify for the luminal B group. Moreover, about 30% of HER2-enriched tumors are classified as clinically HER2-negative based on immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) methods [ 161 ].

4.4. Basal-Like/Triple-Negative Breast Cancer

The Triple-Negative Breast Cancer (TNBC) is a heterogeneous collection of breast cancers characterized as ER-negative, PR-negative, and HER2-negative. They constitute about 20% of all breast cancers. TNBC is more common among women younger than 40 years of age and African-American women [ 161 ]. The majority (approximately 80%) of breast cancers arising in BRCA1 germline mutation are TNBC, while 11–16% of all TNBC harbor BRCA1 or BRCA2 germline mutations. TNBC tends to be biologically aggressive and is often associated with a worse prognosis [ 162 ]. The most common histology seen in TNBC is infiltrating ductal carcinoma, but it may also present as medullary-like cancers with a prominent lymphocytic infiltrate; metaplastic cancers, which may show squamous or spindle cell differentiation; and rare special type cancers like adenoid cystic carcinoma (AdCC) [ 163 , 164 , 165 ].

The terms basal-like and TNBC have been used interchangeably; however, not all TNBC are of the basal type. On gene expression profiling, TNBCs can be subdivided into six subtypes: basal-like (BL1 and BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR), as well as an unspecified group (UNS) [ 166 , 167 ]. However, the clinical relevance of the subtyping still unclear, and more research is needed to clarify its impact on TNBC treatment decisions [ 168 ].

4.5. Claudin-Low Breast Cancer

Claudin-low (CL) breast cancers are poor prognosis tumors being mostly ER-negative, PR-negative, and HER2-negative. CL tumors account for 7–14% of all invasive breast cancers [ 147 ]. No differences in survival rates were observed between claudin-low tumors and other poor-prognosis subtypes (Luminal B, HER2-enriched, and Basal-like). CL subtype is characterized by the low expression of genes involved in cell-cell adhesion, including claudins 3, 4, and 7, occludin, and E-cadherin. Besides, these tumors show high expression of epithelial-mesenchymal transition (EMT) genes and stem cell-like gene expression patterns [ 169 , 170 ]. Moreover, CL tumors have marked immune and stromal cell infiltration [ 171 ]. Due to their less differentiated state and a preventive effect of the EMT-related transcription factor, ZEB1 CL tumors are often genomically stable [ 172 , 173 ].

4.6. Surrogate Markers Classification

In clinical practice, the key question is the discrimination between patients who will or will not benefit from particular therapies. By using molecular assays, more patients can be spared adjuvant chemotherapy, but these tests are associated with significant costs. Therefore, surrogate subgroups based on pathological morphology and widely available immunohistochemical (IHC) markers are used as a tool for risk stratification and guidance of adjuvant therapy [ 174 ]. A combination of the routine pathological markers ER, PR, and HER2 is used to classify tumors into intrinsic subtypes [ 175 ]. Semiquantitative evaluation of Ki-67 and PR is helpful for further typing of the Luminal subtype [ 176 , 177 ]. Moreover, evaluation of cytokeratin 5/6 and epidermal growth factor receptor is utilized to identify the Basal-like breast cancer among the TNBC [ 178 ].

In St. Gallen’s 2013 guidelines the IHC-based surrogate subtype classification was recommended for clinical decision making [ 179 ]. However, these IHC-based markers are only a surrogate and cannot establish the intrinsic subtype of any given cancer, with discordance rates between IHC-based markers and gene-based assays as high as 30% [ 180 ].

4.7. American Joint Committee on Cancer Classification

The baseline tool to estimate the likely prognosis of patients with breast cancer is the AJCC staging system that includes grading, immunohistochemistry biomarkers, and anatomical advancement of the disease. Since its inception in 1977, the American Joint Committee on Cancer (AJCC) has published an internationally accepted staging system based on anatomic findings: tumor size (T), nodal status (N), and metastases (M). However, gene expression profiling has identified several molecular subtypes of breast cancer [ 181 ]. The eighth edition of the AJCC staging manual (2018), outlines a new prognostic staging system for breast cancer that, in addition to anatomical features, acknowledges biological factors [ 182 ]. These factors—ER, PR, HER2, grade, and multigene assays—are recommended in practice to define prognosis [ 183 , 184 ].

The most widely used histologic grading system of breast cancer is the Elston-Ellis modification [ 185 ] of Scarff-Bloom-Richardson grading system [ 186 ], also known as the Nottingham grading system. The grade of a tumor is determined by assessing morphologic features: (a) formation of tubules, (b) mitotic count, (c) variability, and the size and shape of cellular nuclei. A score between 1 (most favorable) and 3 (least favorable) is assigned for each feature. Grade 1 corresponds to combined scores between 3 and 5, grade 2 corresponds to a combined score of 6 or 7, and grade 3 corresponds to a combined score of 8 or 9.

In addition to grading and biomarkers, the commercially available multigene assays provide additional prognostic information suitable for incorporation in the AJCC 8th edition. The 21-gene assay Oncotype DX ® assessed by reverse transcription-polymerase chain reaction (RT-PCR) was the only assay sufficiently evaluated and included in the staging system. This assay is valuable in the staging of patients with hormone receptor-positive, HER2-negative, node-negative tumors that are <5 cm. Patients with results of the assay (Recurrence Score) less than 11 had excellent disease-free survival at 6.9 years of 98.6% with endocrine therapy alone [ 187 ]. Hence, adjuvant systemic chemotherapy can be safely omitted in patients with a low-risk multigene assay [ 188 ].

The AJCC staging manual includes a pathological and a clinical-stage group. The clinical prognostic stage group should be utilized in all patients on initial evaluation before any systemic therapy. Clinical staging uses the TNM anatomical information, grading, and expression of these three biomarkers. When patients undergo surgical resection of their primary tumor, the post-resection anatomic information coupled with the pretreatment biomarker findings results in the final Pathologic Prognostic Stage Group.

The recent update of breast cancer staging by the biologic markers improved the outcome prediction in comparison to prior staging based only on anatomical features of the disease. The validation studies involving the reassessment of the Surveillance, Epidemiology, and End Results (SEER) database ( n = 209,304, 2010–2014) and the University of Texas MD Anderson Cancer Center database ( n = 3327, years of treatment 2007–2013) according to 8th edition AJCC manual proved the more accurate prognostic information [ 189 , 190 ].

5. Prognostic Biomarkers

5.1. estrogen receptor.

Estrogen receptor (ER) is an important diagnostic determinant since approximately 70–75% of invasive breast carcinomas are characterized by significantly enhanced ER expression [ 191 , 192 ]. Current practice requires the measurement of ER expression on both—primary invasive tumors and recurrent lesions. This procedure is mandatory to provide the selection of those patients who will most benefit from the implementation of the endocrine therapy mainly selective estrogen receptor modulators, pure estrogen receptor downregulators, or third-generation aromatase inhibitors [ 193 ]. Even though the diagnosis of altered expression of ER is particularly relevant in terms of the proper therapy selection, ER expression might also constitute a predictive factor—patients with high ER expression usually present significantly better clinical outcomes [ 194 ]. A relationship was observed between ER expression and the family history of breast cancer which further facilitates the utility of ER expression as a diagnostic biomarker of breast cancer especially in cases of familial risk [ 195 ]. Besides, Konan et al. reported that ERα-36 expression could constitute one of the potential targets of PR-positive cancers and a prognostic marker at the same time [ 196 ].

5.2. Progesterone Receptor

PR is highly expressed (>50%) in patients with ER-positive while quite rarely in those with ER-negative breast cancer [ 197 ]. PR expression is regulated by ER therefore, physiological values of PR inform about the functional ER pathway [ 197 ]. However, both ER and PR are abundantly expressed in breast cancer cells and both are considered as diagnostic and prognostic biomarkers of breast cancer (especially ER-positive ones) [ 198 ]. Greater PR expression is positively associated with the overall survival, time to recurrence, and time to either treatment failure or progression while lowered PR levels are usually related to a more aggressive course of the disease as well as poorer recurrence and prognosis [ 199 ]. Thus, favorable management of breast cancer patients highly depends on the assessment of PR expression. Nevertheless, the predictive value of PR expression still remains controversial [ 200 ].

5.3. Human Epidermal Growth Factor Receptor 2

The expression of human epidermal growth factor receptor 2 (HER2) accounts for approximately 15–25% of breast cancers and its status is primarily relevant in the choice of proper management with breast cancer patients; HER2 overexpression is one of the earliest events during breast carcinogenesis [ 201 ]. Besides, HER2 increases the detection rate of metastatic or recurrent breast cancers from 50% to even more than 80% [ 202 ]. Serum HER2 levels are considered to be a promising real-time marker of tumor presence or recurrence [ 203 ]. HER2 amplification leads to further overactivation of the pro-oncogenic signaling pathways leading to uncontrolled growth of cancer cells which corresponds with poorer clinical outcomes in the case of HER2-positive cancers [ 204 ]. Overexpression of HER2 also correlates with a significantly shorter disease-free period [ 205 ] as well as histologic type, pathologic state of cancer, and a number of axillary nodes with metastatic cancerous cells [ 205 ].

5.4. Antigen Ki-67

The Ki-67 protein is a cellular marker of proliferation and the Ki-67 proliferation index is an excellent marker to provide information about the proliferation of cancerous cells particularly in the case of breast cancer. The proliferative activities determined by Ki-67 reflect the aggressiveness of cancer along with the response to treatment and recurrence time [ 206 ]. Thus, Ki-67 is crucial in terms of the choice of the proper treatment therapy and the potential follow-ups due to recurrence. Though, due to several limitations of the analytical validity of Ki-67 immunohistochemistry, Ki-67 expression levels should be considered benevolently in terms of definite treatment decisions. Ki-67 might be considered as a potential prognostic factor as well; according to a meta-analysis of 68 studies involving 12,155 patients, the overexpression of Ki-67 is associated with poorer clinical outcomes of patients [ 207 ]. High expression of Ki-67 also reflects poorer survival rates of breast cancer patients [ 208 ]. There are speculations whether Ki-67 could be considered as a potential predictive marker, however, such data is still limited and contradictory.

Mib1 (antibody against Ki-67) proliferation index remains a reliable diagnostic biomarker of breast cancer, similarly to Ki-67. A decrease in both Mib1 and Ki-67 expression levels is associated with a good response of breast cancer patients to preoperative treatment [ 209 ]. Mib1 levels are significantly greater in patients with concomitant p53 mutations [ 210 ]. Mib1 assessment might be especially useful in cases of biopsy specimens small in size, inappropriate for neither mitotic index nor S-phase fraction evaluation [ 211 ].

5.6. E-Cadherin

E-cadherin is a critical protein in the epithelial-mesenchymal transition (EMT); loss of its expression leads to the gradual transformation into mesenchymal phenotype which is further associated with increased risk of metastasis. The utility of E-cadherin as a breast biomarker is yet questionable, however, some research indicated that its expression is potentially associated with several breast cancer characteristics such as tumor size, TNM stage, or lymph node status [ 212 ]. Low or even total loss of E-cadherin expression might be potentially useful in the determination of histologic subtype of breast cancer [ 213 , 214 ]. E-cadherin levels do not seem to be promising in terms of patients’ survival rates assessment, however, there are some reports indicating that higher levels of E-cadherin were associated with shorter survival rates in patients with invasive breast carcinoma [ 213 , 215 ]. Lowered E-cadherin expression is positively associated with lymph node metastasis [ 216 ].

5.7. Circulating Circular RNA

Circulating circular RNAs (circRNAs) belong to the group of non-coding RNA and were quite recently shown to be crucial in terms of several hallmarks of breast carcinogenesis including apoptosis, enhanced proliferation, or increased metastatic potential [ 217 ]. One of the most comprehensively described circRNAs, mostly specific to breast cancer include circFBXW7—which was proposed as a potential diagnostic biomarker as well as therapeutic tool for patients with triple-negative breast cancer (TNBC), as well as hsa_circ_0072309 which is abundantly expressed in breast cancer patients and usually associated with poorer survival rates [ 218 ]. Has_circ_0001785 is considered to be promising as a diagnostic biomarker of breast cancer [ 219 ]. The number of circRNAs dysregulated during breast carcinogenesis is significant; their expression might be either upregulated (e.g., has_circ_103110, circDENND4C) or downregulated (e.g., has_circ_006054, circ-Foxo3) [ 220 ]. Besides, specific circRNAs have been reported in different types of breast cancer such as TNBC, HER2-positive, and ER-positive [ 221 ]. Recently it was showed that an interaction between circRNAs and micro-RNA—namely in the form of Cx43/has_circ_0077755/miR-182 post-transcriptional axis, might predict breast cancer initiation as well as further prognosis. Cx43 is transmembrane protein responsible for epithelial homeostasis that mediates junction intercellular communication and its loss dysregulates post-transcriptional axes in breast cancer initiation [ 222 ].

Loss-of-function mutations in the TP53 (P53) gene have been found in numerous cancer types including osteosarcomas, leukemia, brain tumors, adrenocortical carcinomas, and breast cancers [ 223 , 224 ]. P53 protein is essential for normal cellular homeostasis and genome maintenance by mediating cellular stress responses including cell cycle arrest, apoptosis, DNA repair, and cellular senescence [ 225 ]. The silencing mutation of the P53 gene is evident at an early stage of cancer progression. In breast cancer, the prevalence of TP53 mutations is present in approximately 80% of patients with the TNBC and 10% of patients with Luminal A disease [ 226 ].

There have been many studies showing the prognostic role of p53 loss-of-function mutation in breast cancer [ 227 , 228 ]. However, the missense mutations may alters p53 properties causing not only a loss of wild-type function, but also acquisition novel activities-gain of function [ 229 ]. The IHC status of p53 has been proposed as a specific prognostic factor in TNBC, and a feature that divides TNBC into 2 distinct subgroups: a p53-negative normal breast-like TN subgroup, and a p53-positive basal-like subgroup with worse overall survival [ 230 , 231 , 232 ]. However, there is not enough evidence to utilize p53 gene mutational status or immunohistochemically measured protein for determining standardized prognosis in patients with breast cancer [ 233 ].

5.9. MicroRNA

MicroRNAs (miRNA) are a major class of endogenous non-coding RNA molecules (19–25 nucleotides) that have regulatory roles in multiple pathways [ 234 ]. Some miRNAs are related to the development, progression, and response of the tumor to therapy [ 235 ]. Several studies have investigated abnormally expressed miRNAs as biomarkers in breast cancer tissue samples. According to meta-analysis by Adhami et al. two miRNAs (miRNA-21 and miRNA-210) were upregulated consistently and six miRNAs (miRNA-145, miRNA-139-5p, miRNA-195, miRNA-99a, miRNA-497, and miRNA-205) were downregulated consistently in at least three studies [ 236 ].

The miRNA-21 overexpression was observed in TNBC tissues and was associated with enhanced invasion and proliferation of TNBC cells as well as downregulation of the PTEN expression [ 237 ]. Similarly, the high expression of miRNA-210 is related to tumor proliferation, invasion, and poor survival rates in breast cancer patients [ 238 , 239 ].

The miRNA-145 is an anti-cancer agent having the property of inhibiting migration and proliferation of breast cancer cells via regulating the TGF-β1 expression [ 240 ]. However, the miRNA-145 is downregulated in both plasma and tumors of breast cancer patients [ 241 ]. Similarly, miRNA-139-5p and miRNA-195 have tumor suppressor activity in various cancers [ 242 , 243 ].

Nevertheless, further clinical researches focusing on these miRNAs are needed to utilize them as reproducible, disease-specific markers that have a high level of specificity and sensitivity.

5.10. Tumor-Associated Macrophages

Macrophages are known for their immunomodulatory effects and they can be divided according to their phenotypes into M1- or M2-like states [ 244 , 245 ]. M1 macrophages secrete IL-12 and tumor necrosis factor with antimicrobial and antitumor effects. M2 macrophages produce cytokines, including IL-10, IL-1 receptor antagonist type II, and IL-1 decoy receptor. Therefore, macrophages with M1-like phenotype have been linked to good disease course while M2-like phenotype has been associated with adverse outcome, potentially through immunosuppression and the promotion of angiogenesis and tumor cell proliferation and invasion [ 246 , 247 ]. In literature, tumor-associated macrophages (TAMs) are associated with M2 macrophages which promote tumor growth and metastasis.

For breast cancer, studies have shown that the density of TAMs is related to hormone receptor status, stage, histologic grade, lymph node metastasis, and vascular invasion [ 248 , 249 , 250 , 251 ]. According to meta-analysis conducted by Zhao et al. high density of TAMs was related to overall survival disease-free survival [ 252 ].

Conversely, M1 polarized macrophages are linked to favorable prognoses in various cancers [ 253 , 254 , 255 ]. In breast cancer, the high density of M1-like macrophages predicted improved survival in patients with HER2+ phenotype and may be a potential prognostic marker [ 256 ].

However, further studies are needed to clarify the influence of macrophages on breast cancer biology as well as investigate the role of their intratumoral distribution and surface marker selection.

5.11. Inflammation-Based Models

The host inflammatory and immune responses in the tumor and its microenvironment are critical components in cancer development and progression [ 257 ]. The tumor-induced systemic inflammatory response leads to alterations of peripheral blood white blood cells [ 258 ]. Therefore, the relationship between peripheral blood inflammatory cells may serve as an accessible and early method of predicting patient prognosis. Recent studies have reported the predictive role of the inflammatory cell ratios: neutrophil-to-lymphocyte ratio, the lymphocyte-to-monocyte ratio, and the platelet-to-lymphocyte ratio for prognosis in different cancers [ 258 , 259 , 260 , 261 ].

5.11.1. The Neutrophil-to-Lymphocyte Ratio (NLR)

In an extensive study on 27,031 cancer patients, Proctor et al. analyzed the prognostic value of NLR and found a significant relationship between NLR and survival in various cancers including breast cancer [ 262 ]. There are pieces of evidence of the role of lymphocytes in breast cancer immunosurveillance [ 263 , 264 ]. Opposingly neutrophils suppress the cytolytic activity of lymphocytes, leading to enhanced angiogenesis and tumor growth and progression [ 265 ].

Azab et al. first reported that NLR before chemotherapy was an independent factor for long-term mortality and related it to age and tumor size in breast cancer [ 266 ]. In a recent meta-analysis by Guo et al., performed on 17,079 individuals, the high NLR level was associated with both poor overall survival as well as disease-free survival for breast cancer patients. Moreover, it was reported that association between NLR and overall survival was stronger in TNBC patients than in HER2-positive ones [ 267 ].

5.11.2. Lymphocyte-to-Monocyte Ratio

The association of the lymphocyte-to-monocyte ratio (LMR) with patients’ prognosis has been reported for several cancers [ 268 , 269 ]. As lymphocytes have an antitumor activity by inducing cytotoxic cell death and inhibiting tumor proliferation [ 270 ], the monocytes are involved in tumorigenesis, including differentiation into TAMs [ 246 , 247 , 271 ]. In the tumor microenvironment, cytokines, and free radicals that are secreted by monocytes and macrophages are associated with angiogenesis, tumor cell invasion, and metastasis [ 271 ].

A meta-analysis investigating the prognostic effect of LMR showed that low LMR levels are associated with shorter overall survival outcomes in Asian populations, TNBC patients, and patients with non-metastatic and mixed stages [ 272 ]. Moreover, high LMR levels are associated with favorable disease-free survival of breast cancer patients under neoadjuvant chemotherapy [ 273 ].

5.11.3. Platelet-to-Lymphocyte Ratio (PLR)

A high platelet count has been associated with poor prognosis in several types of cancers [ 274 , 275 , 276 ]. Platelets contain both pro-inflammatory molecules and cytokines (P-selectin, CD40L, and interleukin (IL)-1, IL-3, and IL-6) and many anti-inflammatory cytokines. Tumor angiogenesis and growth may be stimulated by the secretion of platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-beta, and platelet factor 4 [ 277 , 278 , 279 ].

A meta-analysis study investigated the prognostic importance of PLR by analyzing 5542 breast cancer patients. High PLR level was associated with poor prognosis (overall survival and disease-free survival), yet, its prognostic value was not determined for molecular subtypes of breast cancer. Nevertheless, an association was found between PLR and clinicopathological features of the tumor, including stage, lymph node metastasis, and distant metastasis [ 280 ]. In the aforementioned meta-analysis, there was a difference in the incidence of high levels of PLR between HER2 statuses [ 280 ], while other studies found a difference between hormone ER or PR statuses [ 281 , 282 ].

6. Treatment Strategies

6.1. surgery.

There are two major types of surgical procedures enabling the removal of breast cancerous tissues and those include (1) breast-conserving surgery (BCS) and (2) mastectomy. BCS—also called partial/segmental mastectomy, lumpectomy, wide local excision, or quadrantectomy—enables the removal of the cancerous tissue with simultaneous preservation of intact breast tissue often combined with plastic surgery technics called oncoplasty. Mastectomy is a complete removal of the breast and is often associated with immediately breast reconstruction. The removal of affected lymph nodes involves sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND). Even though BCS seems to be highly more beneficial for patients, those who were treated with this technique often show a tendency for a further need for a complete mastectomy [ 283 ]. However, usage of BCS is mostly related to significantly better cosmetic outcomes, lowered psychological burden of a patient, as well as reduced number of postoperative complications [ 284 ]. Guidelines of the European Society for Medical Oncology (ESMO) for patients with early breast cancer make the choice of therapy dependent to tumor size, feasibility of surgery, clinical phenotype, and patient’s willingness to preserve the breast [ 285 ].

6.2. Chemotherapy

Chemotherapy is a systemic treatment of BC and might be either neoadjuvant or adjuvant. Choosing the most appropriate one is individualized according to the characteristics of the breast tumor; chemotherapy might also be used in the secondary breast cancer. Neoadjuvant chemotherapy is used for locally advanced BC, inflammatory breast cancers, for downstaging large tumors to allow BCS or in small tumors with worse prognostics molecular subtypes (HER2 or TNBC) which can help to identify prognostics and predictive factors of response and can be provided intravenously or orally. Currently, treatment includes a simultaneous application of schemes 2–3 of the following drugs—carboplatin, cyclophosphamide, 5-fluorouracil/capecitabine, taxanes (paclitaxel, docetaxel), and anthracyclines (doxorubicin, epirubicin). The choice of the proper drug is of major importance since different molecular breast cancer subtypes respond differently to preoperative chemotherapy [ 286 ]. Preoperative chemotherapy is comparably effective to postoperative chemotherapy [ 287 ].

Even though chemotherapy is considered to be effective, its usage very often leads to several side effects including hair loss, nausea/vomiting, diarrhea, mouth sores, fatigue, increased susceptibility to infections, bone marrow supression, combined with leucopenia, anaemia, easier bruising or bleeding; other less frequent side effects include cardiomyopathy, neuropathy, hand-foot syndrome, impaired mental functions. In younger women, disruptions of the menstrual cycle and fertility issues might also appear. Special form of chemotherapy is electrochemotherapy which can be used in patients with breast cancer that has spread to the skin, however, it is still quite uncommon and not available in most clinics.

6.3. Radiation Therapy

Radiotherapy is local treatment of BC, typically provided after surgery and/or chemotherapy. It is performed to ensure that all of the cancerous cells remain destroyed, minimizing the possibility of breast cancer recurrence. Further, radiation therapy is favorable in the case of metastatic or unresectable breast cancer [ 288 ]. Choice of the type of radiation therapy depends on previous type of surgery or specific clinical situation; most common techniques include breast radiotherapy (always applied after BC), chest-wall radiotherapy (usually after mastectomy), and ‘breast boost’ (a boost of high-dose radiotherapy to the place of tumor bed as a complement of breast radiotherapy after BCS). Regarding breast radiotherapy specifically, several types are distinguished including

• (1) intraoperative radiation therapy (IORT)
• (2) 3D-conformal radiotherapy (3D-CRT)
• (3) intensity-modulated radiotherapy (IMRT)
• (4) brachytherapy—which refers to internal radiation in contrast to other above-mentioned techniques.

Irritation and darkening of the skin exposed to radiation, fatigue, and lymphoedema are one of the most common side effects of radiation therapy applied in breast cancer patients. Nonetheless, radiation therapy is significantly associated with the improvement of the overall survival rates of patients and lowered risk of recurrence [ 289 ].

6.4. Endocrinal (Hormonal) Therapy

Endocrinal therapy might be used either as a neoadjuvant or adjuvant therapy in patients with Luminal–molecular subtype of BC; it is effective in cases of breast cancer recurrence or metastasis. Since the expression of ERs, a very frequent phenomenon in breast cancer patients, its blockage via hormonal therapy is commonly used as one of the potential treatment modalities. Endocrinal therapy aims to lower the estrogen levels or prevents breast cancer cells to be stimulated by estrogen. Drugs that block ERs include selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene) and selective estrogen receptor degraders (SERDs) (fulvestrant) while treatments that aim to lower the estrogen levels include aromatase inhibitors (AIs) (letrozole, anastrazole, exemestane) [ 290 , 291 ]. In the case of pre-menopausal women, ovarian suppression induced by oophorectomy, luteinizing hormone-releasing hormone analogs, or several chemotherapy drugs, are also effective in lowering estrogen levels [ 292 ]. However, approximately 50% of hormonoreceptor-positive breast cancer become progressively resistant to hormonal therapy during such treatment [ 293 ]. Endocrinal therapy combined with chemotherapy is associated with the reduction of mortality rates amongst breast cancer patients [ 294 ].

6.5. Biological Therapy

Biological therapy (targeted therapy) can be provided at every stage of breast therapy– before surgery as neoadjuvant therapy or after surgery as adjuvant therapy. Biological therapy is quite common in HER2-positive breast cancer patients; major drugs include trastuzumab, pertuzumab, trastuzumab deruxtecan, lapatinib, and neratinib [ 295 , 296 , 297 , 298 , 299 ]. Further, the efficacy of angiogenesis inhibitors such as a recombinant humanized monoclonal anti-VEGF antibody (rhuMAb VEGF) or bevacizumab are continuously investigated [ 300 ].

In the case of Luminal, HER2-negative breast cancer, pre-menopausal women more often receive everolimus -TOR inhibitor with exemestane while postmenopausal women often receive CDK 4–6 inhibitor palbociclib or ribociclib simultaneously, combined with hormonal therapy [ 301 , 302 , 303 ]. Two penultimate drugs along with abemaciclib and everolimus can also be used in HER2-negative and estrogen-positive breast cancer [ 304 , 305 ]. Atezolizumab is approved in triple-negative breast cancer, while denosumab is approved in case of metastasis to the bones [ 306 , 307 , 308 ].

7. Conclusions

In this review, we aimed to summarize and update the current knowledge about breast cancer with an emphasis on its current epidemiology, risk factors, classification, prognostic biomarkers, and available treatment strategies. Since both the morbidity and mortality rates of breast cancer have significantly increased over the past decades, it is an urgent need to provide the most effective prevention taking into account that modifiable risk factors might be crucial in providing the reduction of breast cancer incidents. So far, mammography and sonography is the most common screening test enabling quite an early detection of breast cancer. The continuous search for prognostic biomarkers and targets for the potential biological therapies has significantly contributed to the improvement of management and clinical outcomes of breast cancer patients.

Author Contributions

Conceptualization, A.F., R.S. and A.S.; critical review of literature, S.Ł., M.C., A.F., J.B., R.S., A.S.; writing—original draft preparation, M.C., A.F.; writing—review and editing, S.Ł., M.C., A.F., J.B., R.S., A.S.; supervision, R.S. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Article Contents

Developing interventions to address health-related social needs among patients with cancer: aligning with the nasem 5as framework, evidence base for health-related social needs interventions among patients with cancer, practical recommendations for health-related social needs intervention trials among patients with cancer, considerations for collaboration with community partners on health-related social needs interventions, future research agenda for interventions to address health-related social needs among patients with cancer, data availability, author contributions, conflicts of interest, acknowledgements.

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Interventions addressing health-related social needs among patients with cancer

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Evan M Graboyes, Simon C Lee, Stacy Tessler Lindau, Alyce S Adams, Brenda A Adjei, Mary Brown, Gelareh Sadigh, Andrea Incudine, Ruth C Carlos, Scott D Ramsey, Rick Bangs, Interventions addressing health-related social needs among patients with cancer, JNCI: Journal of the National Cancer Institute , Volume 116, Issue 4, April 2024, Pages 497–505, https://doi.org/10.1093/jnci/djad269

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Health-related social needs are prevalent among cancer patients; associated with substantial negative health consequences; and drive pervasive inequities in cancer incidence, severity, treatment choices and decisions, and outcomes. To address the lack of clinical trial evidence to guide health-related social needs interventions among cancer patients, the National Cancer Institute Cancer Care Delivery Research Steering Committee convened experts to participate in a clinical trials planning meeting with the goal of designing studies to screen for and address health-related social needs among cancer patients.

In this commentary, we discuss the rationale for, and challenges of, designing and testing health-related social needs interventions in alignment with the National Academy of Sciences, Engineering, and Medicine 5As framework. Evidence for food, housing, utilities, interpersonal safety, and transportation health-related social needs interventions is analyzed. Evidence regarding health-related social needs and delivery of health-related social needs interventions differs in maturity and applicability to cancer context, with transportation problems having the most maturity and interpersonal safety the least. We offer practical recommendations for health-related social needs interventions among cancer patients and the caregivers, families, and friends who support their health-related social needs. Cross-cutting (ie, health-related social needs agnostic) recommendations include leveraging navigation (eg, people, technology) to identify, refer, and deliver health-related social needs interventions; addressing health-related social needs through multilevel interventions; and recognizing that health-related social needs are states, not traits, that fluctuate over time. Health-related social needs–specific interventions are recommended, and pros and cons of addressing more than one health-related social needs concurrently are characterized. Considerations for collaborating with community partners are highlighted. The need for careful planning, strong partners, and funding is stressed. Finally, we outline a future research agenda to address evidence gaps.

Tamara (pseudonym) is a mother aged 43 years with stage III cervical cancer who has 2 children. Tamara is the only person in the family with a car and usually drives herself to medical appointments. She missed her first cycle of chemotherapy and some of her radiation therapy because she had to take her son to his job. Tamara does not have health insurance and stopped paying rent to try to cover the out-of-pocket expenses for her chemotherapy and radiation therapy. When she got behind on rent and was going to be evicted, Tamara decided to stop treatment. When she later was able to return to her cancer team, restaging scans showed that her cervical cancer had metastasized widely.

Health-related social needs are adverse social determinants of health for which the person indicates a desire for support ( 1 , 2 ). Health-related social needs, which include conditions like food insecurity, transportation problems, and housing instability, are a critical issue for patients with cancer ( 3 , 4 ). It is estimated that approximately 25%-60% of patients with cancer experience food insecurity, 20% suffer from housing instability, and 15% struggle with transportation for cancer care ( 5-9 ). By impairing access, utilization, and timely delivery of quality oncology care, health-related social needs contribute to adverse cancer outcomes ( 3 , 4 , 9 ). The relationship between health-related social needs and delaying or postponing seeking medical care, missed medical care, treatment nonadherence, treatment delays, and interruptions is well documented ( 10-13 ). For patients with cancer, health-related social needs are also associated with worse health-related quality of life ( 14 ) and may contribute to higher rates of recurrence and worse survival ( 15-17 ). In addition, health-related social needs contribute to observed inequities in cancer incidence, severity, access to care, and outcomes ( 3 , 4 ).

Identifying and addressing health-related social needs within cancer care delivery are necessary to achieve optimal health outcomes and reduce pervasive inequities ( 3 , 18 ). Leading organizations such as the National Cancer Institute (NCI); American Society of Clinical Oncology; American Cancer Society; the National Cancer Policy Forum; and National Academies of Sciences, Engineering, and Medicine (NASEM) have emphasized the importance of identifying and addressing health-related social needs among patients with cancer ( 3 , 4 , 19-21 ). Although recent advances have improved our understanding of the role that health-related social needs play in health disparities, rigorous clinical trials evaluating approaches to address health-related social needs among patients with cancer are needed ( 22 ).

To address this gap, the NCI Cancer Care Delivery Research Steering Committee convened a clinical trials planning meeting on addressing health-related social needs. The primary goal of the meeting was “to create consensus on the design of a multi-practice, multi-intervention prospective controlled study aimed at screening for and addressing HRSNs [health-related social needs] among patients with newly diagnosed cancer.” ( 23 ) The clinical trials planning meeting focused on trial design for deployment within the NCI Community Oncology Research Program (NCORP). NCORP is a national network that provides infrastructure for therapeutic, screening and prevention, care delivery, and supportive care oncology clinical trials. NCORP consists of 7 research bases and 46 community sites of which 14 are designated as minority/underserved community sites ( 24 ). Within the clinical trials planning meeting, the intervention group focused specifically on 1) identifying interventions addressing health-related social needs related to food insecurity, transportation problems, housing instability, utility help needs, and interpersonal safety among patients with cancer and 2) evaluating the potential of the interventions to improve clinical and health-related quality-of-life outcomes within community-based oncology care practice settings. The interventions group was composed of a multidisciplinary team of stakeholders including patients, NCORP-affiliated clinicians and researchers (from academic minority/underserved and community oncology sites), NCORP-affiliated administrators and staff, NCI staff, and community-based content experts. The interventions group divided into 5 teams, each tasked with reviewing evidence for 1 of the 5 health-related social needs identified above.

This commentary provides a framework for considering interventions to address common health-related social needs for patients with cancer and an overview of interventions that have been developed and used in practice. It also discusses key areas of controversy and emerging thought and outlines a future agenda for intervention design options addressing health-related social needs among patients with cancer.

The NASEM, in its landmark publication Integrating Social Care into the Delivery of Health Care , proposed 5 health-care activities (the 5As) that enable health systems to enhance the integration of health-related social needs care into the delivery of health care: Awareness, Adjustment, Assistance, Alignment, and Advocacy ( Table 1 ) ( 25 ). The 5As provide a framework for conceptualizing how health-related social needs interventions fit into a broader plan of health system action in this area. Attention to health-related social needs for patients with cancer and their social unit (eg, caregiver, family, friends) is essential for addressing baseline social conditions that can impede treatment planning and initiation; accommodating the time demands and costs of cancer care including time away from work and parenting responsibilities to coordinate and participate in care; and ensuring adequate nutrition, stable housing, and interpersonal safety for the patients and their social unit throughout the cancer care continuum. For patients and families to benefit and recover fully from cancer treatment, their basic material and social needs must be met throughout the course of care.

The National Academy of Sciences, Engineering, and Medicine 5As framework for conceptualizing health-care system activities that strengthen social care integration ( 25 )

For Awareness, there is important variability in how point-of-care screening and assessment of health-related social needs among patients with cancer occur in clinical practice ( 26 ). This variability reflects, in part, the lack of validated health-related social needs screening measures for patients with cancer. As a result, some cancer centers use assessments validated in noncancer populations, whereas others use institution-specific tools that have not undergone validity testing in any population ( 26 ). Important sources of health-related social needs screening variability also relate to screening via single domain assessments [eg, 2-item Hunger Vital Sign ( 27 ) for food insecurity] or multidomain measures [eg, Accountable Health Communities Health-Related Social Needs Screening Tool ( 28 )]. In addition, differences in practice exist for the method of collecting the information, with some practices using direct patient self-report (eg, asynchronously via the electronic health record prior to the clinical encounter), while others conduct point-of-care screening with in-person assessment(s) (eg, by a nurse, medical assistant, social worker) ( 29 ). In some settings, assistance is provided universally without screening (eg, everyone receives community resource information) ( 30 ). Finally, there is important variability in who to screen (no one, everyone, high-risk groups), when to screen (upon cancer diagnosis, serially), why to screen (assess individual or population risk, estimate potential demand, guide targeted interventions), how to assess patient need and preference after a positive screen, and how to link patients with a need and preference to the appropriate intervention (eg, assistance, adjustment).

Most interventions fall in the 5As category of Assistance (ie, the process of connecting patients to relevant resources to address their health-related social needs). These resources may come from within the 4 walls of the cancer care setting or from community-based organizations. For patients with cancer, assistance provided by the oncology team might include provision of transportation vouchers or waiving cancer center parking fees for patients receiving weekly chemotherapy infusions. Two major types of Assistance have been implemented in cancer care to address health-related social needs: 1) co-located supportive oncology services ( 10 , 12 ) and 2) community-based support services (typically not cancer specific). Colocated or clinically subsidized supportive oncology services include provision of transportation to the clinical site for daily radiation therapy, on-site food pantries, and psychosocial support from on-site navigators or social workers. Community-based assistance interventions address health-related social needs by linking patients to existing community-based resources outside the clinical cancer care setting. Examples of linkage-based interventions include referrals to a community-based food pantry, coordinating rides from the American Cancer Society Road to Recovery program for daily radiation therapy, and referral to community-based social workers for counseling or other psychosocial support.

Another intervention category is Adjustment: alterations in health-care delivery to accommodate identified needs. Although considerations related to techquity remain, examples of adjustment include switching an in-person follow-up visit to a telemedicine encounter for a patient lacking transportation or finding a radiation oncology provider closer to home to minimize travel burden for daily radiation. Challenges to studying adjustment in care delivery include difficulties with standardizing adjustment interventions (eg, dose, intensity, frequency), abstracting adjustment decisions from narrative information in the electronic health record, and its widespread prevalence in modern patient-centered care delivery paradigms (and resultant challenge for designing true control conditions).

Because the underlying causes of health-related social needs reflect adverse social conditions upstream from the oncology clinic, addressing health-related social needs at a population level requires actions such as alignment and advocacy. Health systems can address health-related social needs through alignment activities to map, organize with, and invest in community social care assets. Indeed, the success of linking patients with health-related social needs to assistance requires that health systems understand the strengths, limitations, and dynamic nature of their community partner ecosystem where referrals are made. In addition to mapping, alignment can also include active investment by the health-care system in social care organizations to build capacity and strengthen relationships. Finally, advocacy is critical to addressing health-related social needs among patients with cancer at the population level. Providing a transportation voucher in clinic, while alleviating a transportation barrier for an individual patient, does not target the root cause of the problem. At a population level, advocacy by health systems has the potential to change the upstream adverse social conditions (eg, inequitable housing policy, inequitable transportation systems) that give rise to health-related social needs for which downstream interventions are needed.

Robust evidence supports the association of social needs with health, and several social care intervention studies have included—even if they have not focused exclusively on—people with cancer. However, studies showing how the health-care sector can effectively intervene to address health-related social needs are nascent, especially in cancer-specific contexts, and vary with respect to rigor and applicability to cancer context ( 22 , 26 , 31 ). In addition, studies are also lacking that evaluate the effectiveness of interventions already in widespread use in oncology clinical care (eg, Adjustment) in different contexts and what it takes to de-implement a health-related social need intervention if it were found to lack effectiveness. Relatively speaking, evidence on health-related social needs interventions addressing food insecurity and transportation challenges among patients with cancer is the most mature. For example, a scoping review of food insecurity and related factors among cancer survivors found evidence to support the effectiveness of patient navigation and social worker–related interventions for improving the quality of cancer care and quality of life ( 32 ). The evidence for interventions to address food insecurity among patients with cancer included findings from a randomized clinical trial that compared 1) hospital cancer clinic–based food pantry, 2) food voucher plus pantry, and 3) home grocery delivery plus pantry among 117 food-insecure patients with cancer ( 33 ). In this preliminary study, food voucher plus pantry was the most effective intervention at improving treatment completion (94.6%), exceeding the prespecified 90% threshold for further study ( 33 ).

To supplement limited published evidence for effective health-related social needs interventions among patients with cancer, findings from interventions conducted with other populations, some including oncology and nononcology patients (but providing no cancer subgroup analysis) and others not indicating participants’ cancer status, were considered ( 34 , 35 ). For example, a meta-analysis described the evidence base for interventions for nonemergent medical transportation in contexts that were not oncology specific, concluding that interventions such as van rides, bus or taxi vouchers, and ride-sharing services were associated with a lower likelihood of missed appointments ( 36 ).

General recommendations

Table 2 shows general (ie, health-related social needs agnostic) recommendations regarding health-related social needs interventions for people with cancer and their support units. First, reflecting that health-related social needs can be stigmatizing conditions ( 7 ), intervention design should minimize unintended negative consequences that lead to further discrimination or marginalization of people with health-related social needs. Future clinical trials assessing health-related social needs screening and interventions should engage deeply with the patient community to understand preferences for health-related social needs assessment as well as considerations related to privacy and confidentiality. Second, health-related social needs identified via screening (thereby creating clinician awareness) in a clinical trial should receive some form of intervention for legal (eg, interpersonal safety) and/or ethical (eg, food insecurity) considerations. Third, evaluation of social care interventions should align with a reasonable target given features of the clinical setting, like readiness for change and capacity for social care delivery. For example, in a cancer care setting that has no social care practice, a proximal implementation objective like acceptability or feasibility may be appropriate. In other settings, receipt of referral coordination may be more attainable than receipt of the actual support service or resolution of the health-related social need. Referral to services can be accomplished by deploying clinical staff, technology, and vendors to identify, refer, and deliver the health-related social needs intervention. Fourth, to address the multilevel determinants of health-related social needs, interventions should consider components across multiple levels (eg, patient, social unit, provider). Fifth, intervention design should recognize that health-related social needs are states, not traits, that may change across the cancer continuum. Intervention design should reflect the dynamic nature of social needs. These key considerations are critical for scalability and sustainability of social care interventions in the cancer care context.

Key general recommendations regarding health-related social needs interventions among patients with cancer and associated domains according to the National Academies of Sciences, Engineering, and Medicine 5As framework

Research recommendations for specific interventions

Whole-person interventions.

Health-related social needs commonly co-occur, especially in the context of a costly medical diagnosis like cancer. Whole-person interventions that concurrently address co-occurring health-related social needs and other self-care needs should be considered for patients with cancer ( 26 , 37 ). When compared with interventions that target a single health-related social need, interventions targeting multiple health-related social needs concurrently could potentially 1) enhance intervention effectiveness and efficiency, 2) prevent dilution of intervention effects on a downstream outcome (eg, treatment completion) from failure to address a co-occurring health-related social need, and 3) ameliorate potential moral and ethical concerns from failing to address an identified social need ( 7 , 38 ). Although studies examining the effects of single vs multiple health-related social needs interventions are lacking, the potential effectiveness of bundling interventions will depend, at least in part, on the state of the evidence for each intervention in a putative bundle.

CommunityRx, an electronic health record–integrated, universally delivered social care intervention, is perhaps the most evidence-based whole-person intervention to date. Trials in mixed (ie, nononcology and oncology) populations demonstrated that it was feasible and acceptable ( 30 ), associated with lower hospitalization and emergency department utilization, and improved confidence and knowledge about finding resources but did not improve mental or physical health-related quality of life ( 39 , 40 ).

In addition to whole-person interventions, specific issues could be considered when developing interventions to evaluate individual health-related social needs ( Table 3 ).

Recommendations regarding health-related social needs interventions among patients with cancer and associated domains within the National Academies of Sciences, Engineering, and Medicine 5As framework

Food insecurity

First, although not applicable to all people with cancer or their social units, the Supplemental Nutrition Assistance Program and the Special Supplemental Nutrition Program for Women, Infants, and Children are well-studied interventions shown to mitigate food insecurity. Efforts (on-site or via referral to a community organization) to ensure public benefit enrollment of eligible people with cancer and their social units could be considered in implementing food security interventions in the cancer care setting. In addition, interventions could consider including home food delivery service and grocery voucher programs ( 12 ). Last, given the length of ambulatory visits for cancer care and the high cost of food in most clinical settings, food insecurity interventions could consider on-site emergency food support such as a colocated food pantry, snack and nutrition cart, or voucher to on-site vendors ( 41 ).

Transportation problems

Transportation is a direct and immediate cost for the patient and social unit for accessing cancer screening and early detection, diagnosis, treatment, and follow-up and can quickly generate substantial unplanned out-of-pocket expenses. Transportation problems among the cancer-affected population are diverse and include lack of access to a vehicle or public transportation; lack of safe transportation; inability to pay for gas, parking, public transit, or temporary lodging near specialty centers; and physical limitations to traveling long distances because of illness ( 10 ). Accordingly, health-related social needs interventions addressing transportation problems should ideally be 1) tailored to the diverse ways in which transportation may affect the ability to access cancer care, 2) calibrated to the patient and social unit (eg, patient health status, availability of informal caregiver), and 3) consider relevant contextual geographic factors (eg, travel distance, rurality). Health-related social needs interventions such as direct reimbursement or vouchers for travel (including gas, tolls, and parking), public transportation, hotel subsidies, and links to community resources that address transportation problems for patients with cancer (eg, American Cancer Society Road to Recovery) are widely used in clinical practice for patients with cancer and could be considered as components of interventions addressing transportation problems ( 29 ). These programs can be funded and sustained through partnerships with nonprofits, philanthropy, grants, operational funds, and reimbursement from insurance ( 29 ). Rideshare-based approaches, which are associated with improved cancer treatment completion, decreased appointment no-show rates, enhanced patient satisfaction, and net revenue generation for the health system, could be explored as a health-related social need intervention for patients with cancer in the appropriate contexts ( 42 , 43 ). However, important potential limitations for rideshare-based interventions among patients with cancer include 1) variable coverage, particularly in rural areas; 2) liability issues regarding transport safety and/or medical appropriateness for discharge to a vehicle; and 3) uncertain applicability of Anti-Kickback and Stark laws.

Housing and utilities instability

Interventions to address housing and utilities instability focus on community and policy-oriented strategies that can be achieved via alignment and advocacy interventions ( 44-47 ). In many cases, housing interventions could be wrapped under broader interventions addressing financial insecurity. Given that lack of stable shelter presents a major and immediate threat to health and safety of people affected by cancer, effective housing and utility-specific interventions likely require financial counseling, social work, emergency legal intervention, and provision of emergency or short-term subsidy for hotel or rental assistance.

Interpersonal safety

Interpersonal safety is prevalent especially among women, underreported in health-related social risk assessment screening (compared with estimates from other sources) ( 48 ) and may be triggered by loss of employment or other vulnerability resulting from cancer diagnosis. Interventions to screen for and address interpersonal safety have generally focused on specific populations based on vulnerability (eg, elders, pregnant women) rather than disease-specific populations ( 49 , 50 ). Important considerations relevant to screening and intervention for interpersonal safety include whether to assess (vs routinely providing cancer patients with interpersonal safety resource information), how to conduct assessments in a manner that facilitates self-disclosure while maintaining privacy ( 51 ), and ensuring the capability to promptly refer people with safety needs to appropriate resources ( 52 ).

For clinic or health system–based interventions addressing health-related social needs among patients undergoing cancer treatment, meaningful and deep collaboration with strong community partners should be developed. These relationships should be dynamic, bidirectional, and sustained. The community partner ecosystem for social care will vary by geography and, like health-related social needs, is dynamic. Availability of resources and access (eg, time, location, eligibility criteria) changes over time. Engagement with community resource organizations, increasingly via resource referral platform technologies, could help ensure high-quality resource information to address health-related social needs. Resource referrals may be to supportive services inside the 4 walls of the health-care system, to the local community, or to national organizations with remote delivery of services.

For interventions involving community-based organizations, the quality of referrals will likely depend on partner engagement. Although many social support organizations likely serve people affected by cancer, they may be unaware that this is the case (eg, food pantries do not routinely assess patron’s health conditions). A strong ecosystem for cancer patient referral would involve outreach to, and education for, key support organizations about cancer-specific referrals. Community organizations wishing to receive cancer patient referrals would ideally communicate their capacity, eligibility criteria, and other expectations for delivering support to this patient population. On one hand, closed-loop resource referral interventions, created through partnerships between referring health-care systems and community-based support organizations using shared technology platforms, could generate useful data to evaluate and optimize the effectiveness of integrating social with medical care for cancer. On the other hand, closed-loop referrals may create administrative burden for community-based organization and be a deterrent for patients who want resource information but are not ready to share their needs. Both present state and future plans landscape analyses at the institution, site, and practice levels may be required and should reflect staff and capacity; availability, accessibility, and scope of services provided by community partners; screening mechanisms; and other considerations. An important concern will be developing workflow processes that minimize risk of patient stigma and response burden (eg, eligibility documentation) as well as burden on clinical staff.

Figure 1 highlights critical knowledge gaps to be addressed in future research. First, the relationship of financial toxicity to the development of incident health-related social needs and exacerbation of preexisting health-related social needs among patients with cancer remains unknown and understudied ( 53 , 54 ). Factors influencing financial toxicity include direct medical costs and nonmedical costs from health-related social needs like transportation, temporary housing, and incremental food along with lost wages; child, elder, and special needs costs; and other collateral expenses. Short of governmental support for coverage of cancer care costs, research and innovation are needed to identify sustainable business models for cancer support organizations focused on alleviating financial toxicity and health-related social needs.

Key knowledge gaps about health-related social need interventions among patients with cancer and proposed research agenda.

Second, the design of health-related social needs interventions for patients with cancer to properly reflect intensity, frequency, timing, and type of intervention, as well as adaptation for local context, remains unknown. Features of intervention delivery in relation to the trajectory of cancer care warrant consideration, but given the dynamic nature of health-related social needs in relation to cancer care, longitudinal intervention and assessment of impact are needed. In addition, because of the lack of evidence related to the time course for health-related social needs, research should address considerations related to optimal timing for intervention delivery vs opportunistic delivery approaches (eg, anytime, every time). In the context of the 5As framework from NASEM, health-related social needs intervention studies have focused heavily on assessment-driven assistance. However, the framework—and the theory behind it—suggest a potential role for multi-A interventions (eg, data generated via assessment can be aggregated and used for alignment and advocacy activities). Future research can test the effectiveness and implementation of multi–health-related social needs and multi-A interventions.

Third, concurrent with studies evaluating the effectiveness of health-related social needs–based interventions among patients with cancer, research should evaluate implementation determinants and identify strategies to facilitate implementation across diverse care delivery settings. Important differences are likely to exist, varying by geographic location in the United States, rurality, patient catchment areas, practice type, and practice size. Such factors may impact administrative capacity, resources, and expertise necessary to develop, implement, and sustain context-appropriate interventions to address health-related social needs among patients with cancer.

Fourth, the characteristics of the health-related social needs intervention portfolio among patients with cancer should be diversified. A recent landscape analysis of the NCI health-related social needs portfolio showed that ongoing NCI-funded research consisted primarily of observational studies, heavily focused on patients with breast cancer, and primarily delivering assistance-based intervention ( 18 ). The research to date has primarily addressed transportation as an individual patient-level health-related social need ( 18 ). A robust health-related social needs research portfolio comprising a wide variety of study designs (including rigorous clinical trials) that test health-related social needs interventions in varied cancer care delivery settings and across different cancer types will be necessary to address critical gaps in knowledge and improve access, outcomes, and equity among patients with cancer. The NCI’s National Clinical Trials Network and NCORP are particularly well suited to achieve key strategic goals of the current NCI National Cancer Plan: 1) to deliver optimal care and 2) eliminate inequities ( 55 ).

Integration of social care with medical care is increasingly recognized as necessary to address and ultimately promote equity in access, quality, cost, and outcomes among patients with cancer. Recent scientific advances are improving our understanding of how to intervene on health-related social needs among patients with cancer, but the evidence remains weak. A prioritized and sequenced research agenda, informed by best available evidence, can close this gap. An evaluative framework should be developed that comprehends the relationship of health-related social needs screening to health-related social needs intervention delivery, builds on the NASEM 5As framework, considers differences in health-related social needs–specific vs whole-person intervention–based approaches, and addresses how cancer care systems productively engage with community partners. Mitigating health-related social needs through intervention and related studies should be a priority of our cancer care system and will likely serve to improve health equity and outcomes among patients with cancer.

No new data were generated for or analyzed in this commentary.

Evan Graboyes, MD, MPH (Conceptualization; Writing—original draft; Writing—review & editing), Simon Lee, PhD, MPH (Conceptualization; Supervision; Writing—original draft; Writing—review & editing), Stacy Lindau, MD, MAPP (Conceptualization; Writing—original draft; Writing—review & editing), Alyce Adams, PhD (Conceptualization; Writing—original draft; Writing—review & editing), Brenda Adjei, EdD, MPA (Conceptualization; Writing—original draft; Writing—review & editing), Mary Brown, MSW, LSIW-S (Conceptualization; Writing—original draft; Writing—review & editing), Gelareh Sadigh, MD (Conceptualization; Writing—original draft; Writing—review & editing), Andrea Incudine, MPH (Conceptualization; Writing—original draft; Writing—review & editing), Ruth Carlos, MD, MS (Conceptualization; Writing—review & editing), Scott Ramsey, MD, PhD (Conceptualization; Writing—review & editing), and Rick Bangs, MBA, PMP (Conceptualization; Supervision; Writing—original draft; Writing—review & editing).

EMG’s effort was supported by K08 CA237858, R01 CA282165, U10 CA180868 and the American College of Surgeons/Triologic Society. STL’s effort was supported by The University of Chicago Medicine NCI Comprehensive Cancer Center Program Pilot Project Grant, U01 DK137262, R01 DK127961, R01 AG064949, R01 HL150909, P30 CA014599 and philanthropic support from the University of Chicago Comprehensive Cancer Center. GS’s effort was supported by R01 CA262312 and R01 CA272680.

EMG reports receiving research support from Castle Biosciences, honorarium from Castle Biosciences, and personal fees from the National Cancer Institute, all outside of the submitted work. STL reports being the founder and owner of NowPow, LLC, which was acquired by Unite USA Inc in 2021, and is currently an unpaid advisor to and holds stock in Unite USA Inc; receiving royalties of less than $100 per year in 2019, 2020 from UpToDate, Inc; and owning equity in Glenbervie Health, LLC along with her husband. The University of Chicago has filed patents (pending) for the Bionic Breast Project, a project led by STL. All other authors have no conflicts of interest.

The Clinical Trials Planning Meeting was supported by the National Cancer Institute (NCI) Coordinating Center for Clinical Trials and was developed under the leadership of the NCI Division of Cancer Control and Population Sciences and the NCI Cancer Care Delivery Research Steering Committee.

The funders had no role in the writing of the manuscript or the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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How can I plan what to eat or drink when I have diabetes?

How can physical activity help manage my diabetes, what can i do to reach or maintain a healthy weight, should i quit smoking, how can i take care of my mental health, clinical trials for healthy living with diabetes.

Healthy living is a way to manage diabetes . To have a healthy lifestyle, take steps now to plan healthy meals and snacks, do physical activities, get enough sleep, and quit smoking or using tobacco products.

Healthy living may help keep your body’s blood pressure , cholesterol , and blood glucose level, also called blood sugar level, in the range your primary health care professional recommends. Your primary health care professional may be a doctor, a physician assistant, or a nurse practitioner. Healthy living may also help prevent or delay health problems  from diabetes that can affect your heart, kidneys, eyes, brain, and other parts of your body.

Making lifestyle changes can be hard, but starting with small changes and building from there may benefit your health. You may want to get help from family, loved ones, friends, and other trusted people in your community. You can also get information from your health care professionals.

What you choose to eat, how much you eat, and when you eat are parts of a meal plan. Having healthy foods and drinks can help keep your blood glucose, blood pressure, and cholesterol levels in the ranges your health care professional recommends. If you have overweight or obesity, a healthy meal plan—along with regular physical activity, getting enough sleep, and other healthy behaviors—may help you reach and maintain a healthy weight. In some cases, health care professionals may also recommend diabetes medicines that may help you lose weight, or weight-loss surgery, also called metabolic and bariatric surgery.

Choose healthy foods and drinks

There is no right or wrong way to choose healthy foods and drinks that may help manage your diabetes. Healthy meal plans for people who have diabetes may include

• dairy or plant-based dairy products
• nonstarchy vegetables
• protein foods
• whole grains

Try to choose foods that include nutrients such as vitamins, calcium , fiber , and healthy fats . Also try to choose drinks with little or no added sugar , such as tap or bottled water, low-fat or non-fat milk, and unsweetened tea, coffee, or sparkling water.

Try to plan meals and snacks that have fewer

• foods high in saturated fat
• foods high in sodium, a mineral found in salt
• sugary foods , such as cookies and cakes, and sweet drinks, such as soda, juice, flavored coffee, and sports drinks

Your body turns carbohydrates , or carbs, from food into glucose, which can raise your blood glucose level. Some fruits, beans, and starchy vegetables—such as potatoes and corn—have more carbs than other foods. Keep carbs in mind when planning your meals.

You should also limit how much alcohol you drink. If you take insulin  or certain diabetes medicines , drinking alcohol can make your blood glucose level drop too low, which is called hypoglycemia . If you do drink alcohol, be sure to eat food when you drink and remember to check your blood glucose level after drinking. Talk with your health care team about your alcohol-drinking habits.

Find the best times to eat or drink

Talk with your health care professional or health care team about when you should eat or drink. The best time to have meals and snacks may depend on

• what medicines you take for diabetes
• what your level of physical activity or your work schedule is
• whether you have other health conditions or diseases

Ask your health care team if you should eat before, during, or after physical activity. Some diabetes medicines, such as sulfonylureas  or insulin, may make your blood glucose level drop too low during exercise or if you skip or delay a meal.

Plan how much to eat or drink

You may worry that having diabetes means giving up foods and drinks you enjoy. The good news is you can still have your favorite foods and drinks, but you might need to have them in smaller portions  or enjoy them less often.

For people who have diabetes, carb counting and the plate method are two common ways to plan how much to eat or drink. Talk with your health care professional or health care team to find a method that works for you.

Carb counting

Carbohydrate counting , or carb counting, means planning and keeping track of the amount of carbs you eat and drink in each meal or snack. Not all people with diabetes need to count carbs. However, if you take insulin, counting carbs can help you know how much insulin to take.

Plate method

The plate method helps you control portion sizes  without counting and measuring. This method divides a 9-inch plate into the following three sections to help you choose the types and amounts of foods to eat for each meal.

• Nonstarchy vegetables—such as leafy greens, peppers, carrots, or green beans—should make up half of your plate.
• Carb foods that are high in fiber—such as brown rice, whole grains, beans, or fruits—should make up one-quarter of your plate.
• Protein foods—such as lean meats, fish, dairy, or tofu or other soy products—should make up one quarter of your plate.

If you are not taking insulin, you may not need to count carbs when using the plate method.

Work with your health care team to create a meal plan that works for you. You may want to have a diabetes educator  or a registered dietitian  on your team. A registered dietitian can provide medical nutrition therapy , which includes counseling to help you create and follow a meal plan. Your health care team may be able to recommend other resources, such as a healthy lifestyle coach, to help you with making changes. Ask your health care team or your insurance company if your benefits include medical nutrition therapy or other diabetes care resources.

Talk with your health care professional before taking dietary supplements

There is no clear proof that specific foods, herbs, spices, or dietary supplements —such as vitamins or minerals—can help manage diabetes. Your health care professional may ask you to take vitamins or minerals if you can’t get enough from foods. Talk with your health care professional before you take any supplements, because some may cause side effects or affect how well your diabetes medicines work.

Research shows that regular physical activity helps people manage their diabetes and stay healthy. Benefits of physical activity may include

• lower blood glucose, blood pressure, and cholesterol levels
• better heart health
• healthier weight
• better mood and sleep
• better balance and memory

Talk with your health care professional before starting a new physical activity or changing how much physical activity you do. They may suggest types of activities based on your ability, schedule, meal plan, interests, and diabetes medicines. Your health care professional may also tell you the best times of day to be active or what to do if your blood glucose level goes out of the range recommended for you.

Do different types of physical activity

People with diabetes can be active, even if they take insulin or use technology such as insulin pumps .

Try to do different kinds of activities . While being more active may have more health benefits, any physical activity is better than none. Start slowly with activities you enjoy. You may be able to change your level of effort and try other activities over time. Having a friend or family member join you may help you stick to your routine.

The physical activities you do may need to be different if you are age 65 or older , are pregnant , or have a disability or health condition . Physical activities may also need to be different for children and teens . Ask your health care professional or health care team about activities that are safe for you.

Aerobic activities

Aerobic activities make you breathe harder and make your heart beat faster. You can try walking, dancing, wheelchair rolling, or swimming. Most adults should try to get at least 150 minutes of moderate-intensity physical activity each week. Aim to do 30 minutes a day on most days of the week. You don’t have to do all 30 minutes at one time. You can break up physical activity into small amounts during your day and still get the benefit. 1

Strength training or resistance training

Strength training or resistance training may make your muscles and bones stronger. You can try lifting weights or doing other exercises such as wall pushups or arm raises. Try to do this kind of training two times a week. 1

Balance and stretching activities

Balance and stretching activities may help you move better and have stronger muscles and bones. You may want to try standing on one leg or stretching your legs when sitting on the floor. Try to do these kinds of activities two or three times a week. 1

Some activities that need balance may be unsafe for people with nerve damage or vision problems caused by diabetes. Ask your health care professional or health care team about activities that are safe for you.

Stay safe during physical activity

Staying safe during physical activity is important. Here are some tips to keep in mind.

Drink liquids

Drinking liquids helps prevent dehydration , or the loss of too much water in your body. Drinking water is a way to stay hydrated. Sports drinks often have a lot of sugar and calories , and you don’t need them for most moderate physical activities.

Avoid low blood glucose

Check your blood glucose level before, during, and right after physical activity. Physical activity often lowers the level of glucose in your blood. Low blood glucose levels may last for hours or days after physical activity. You are most likely to have low blood glucose if you take insulin or some other diabetes medicines, such as sulfonylureas.

Ask your health care professional if you should take less insulin or eat carbs before, during, or after physical activity. Low blood glucose can be a serious medical emergency that must be treated right away. Take steps to protect yourself. You can learn how to treat low blood glucose , let other people know what to do if you need help, and use a medical alert bracelet.

Avoid high blood glucose and ketoacidosis

Taking less insulin before physical activity may help prevent low blood glucose, but it may also make you more likely to have high blood glucose. If your body does not have enough insulin, it can’t use glucose as a source of energy and will use fat instead. When your body uses fat for energy, your body makes chemicals called ketones .

High levels of ketones in your blood can lead to a condition called diabetic ketoacidosis (DKA) . DKA is a medical emergency that should be treated right away. DKA is most common in people with type 1 diabetes . Occasionally, DKA may affect people with type 2 diabetes  who have lost their ability to produce insulin. Ask your health care professional how much insulin you should take before physical activity, whether you need to test your urine for ketones, and what level of ketones is dangerous for you.

Take care of your feet

People with diabetes may have problems with their feet because high blood glucose levels can damage blood vessels and nerves. To help prevent foot problems, wear comfortable and supportive shoes and take care of your feet  before, during, and after physical activity.

If you have diabetes, managing your weight  may bring you several health benefits. Ask your health care professional or health care team if you are at a healthy weight  or if you should try to lose weight.

If you are an adult with overweight or obesity, work with your health care team to create a weight-loss plan. Losing 5% to 7% of your current weight may help you prevent or improve some health problems  and manage your blood glucose, cholesterol, and blood pressure levels. 2 If you are worried about your child’s weight  and they have diabetes, talk with their health care professional before your child starts a new weight-loss plan.

You may be able to reach and maintain a healthy weight by

• following a healthy meal plan
• consuming fewer calories
• being physically active
• getting 7 to 8 hours of sleep each night 3

If you have type 2 diabetes, your health care professional may recommend diabetes medicines that may help you lose weight.

Online tools such as the Body Weight Planner  may help you create eating and physical activity plans. You may want to talk with your health care professional about other options for managing your weight, including joining a weight-loss program  that can provide helpful information, support, and behavioral or lifestyle counseling. These options may have a cost, so make sure to check the details of the programs.

Your health care professional may recommend weight-loss surgery  if you aren’t able to reach a healthy weight with meal planning, physical activity, and taking diabetes medicines that help with weight loss.

If you are pregnant , trying to lose weight may not be healthy. However, you should ask your health care professional whether it makes sense to monitor or limit your weight gain during pregnancy.

Both diabetes and smoking —including using tobacco products and e-cigarettes—cause your blood vessels to narrow. Both diabetes and smoking increase your risk of having a heart attack or stroke , nerve damage , kidney disease , eye disease , or amputation . Secondhand smoke can also affect the health of your family or others who live with you.

If you smoke or use other tobacco products, stop. Ask for help . You don’t have to do it alone.

Feeling stressed, sad, or angry can be common for people with diabetes. Managing diabetes or learning to cope with new information about your health can be hard. People with chronic illnesses such as diabetes may develop anxiety or other mental health conditions .

Learn healthy ways to lower your stress , and ask for help from your health care team or a mental health professional. While it may be uncomfortable to talk about your feelings, finding a health care professional whom you trust and want to talk with may help you

• lower your feelings of stress, depression, or anxiety
• manage problems sleeping or remembering things
• see how diabetes affects your family, school, work, or financial situation

Ask your health care team for mental health resources for people with diabetes.

Sleeping too much or too little may raise your blood glucose levels. Your sleep habits may also affect your mental health and vice versa. People with diabetes and overweight or obesity can also have other health conditions that affect sleep, such as sleep apnea , which can raise your blood pressure and risk of heart disease.

NIDDK conducts and supports clinical trials in many diseases and conditions, including diabetes. The trials look to find new ways to prevent, detect, or treat disease and improve quality of life.

What are clinical trials for healthy living with diabetes?

Clinical trials—and other types of clinical studies —are part of medical research and involve people like you. When you volunteer to take part in a clinical study, you help health care professionals and researchers learn more about disease and improve health care for people in the future.

Researchers are studying many aspects of healthy living for people with diabetes, such as

• how changing when you eat may affect body weight and metabolism
• how less access to healthy foods may affect diabetes management, other health problems, and risk of dying
• whether low-carbohydrate meal plans can help lower blood glucose levels
• which diabetes medicines are more likely to help people lose weight

Find out if clinical trials are right for you .

Watch a video of NIDDK Director Dr. Griffin P. Rodgers explaining the importance of participating in clinical trials.

What clinical trials for healthy living with diabetes are looking for participants?

You can view a filtered list of clinical studies on healthy living with diabetes that are federally funded, open, and recruiting at www.ClinicalTrials.gov . You can expand or narrow the list to include clinical studies from industry, universities, and individuals; however, the National Institutes of Health does not review these studies and cannot ensure they are safe for you. Always talk with your primary health care professional before you participate in a clinical study.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

NIDDK would like to thank: Elizabeth M. Venditti, Ph.D., University of Pittsburgh School of Medicine.