Current insights into breast and ovarian cancer risk: a contemporary review

Abstract

Breast and ovarian cancer account for millions of new cancer diagnoses worldwide annually. An individual’s risk of breast and/or ovarian cancer is the result of a complex interplay between non-modifiable and modifiable factors. This review provides a comprehensive map of the current state of our understanding of breast and ovarian cancer risk as conducted through a literature review utilizing PubMed and Cochrane review as primary databases and the selection process prioritized year of publication for up-to-date research and journal impact factor as criteria of research credibility. We review non-modifiable risk factors, such as genetic variations, age, sex assigned at birth, and reproductive history as well as how advances in genetic mapping have led to increased insight in pathogenic germline variants. Additionally, we discuss modifiable factors such as lifestyle and environmental exposures which allow the opportunity for intervention to reduce risk. Contemporary high risk screening tools, including understanding their strengths and weaknesses, are discussed and how they can lend to the determination of eligibility for preventive measures, including risk-reducing operations. The unique challenges of under-represented groups, such as non-Hispanic Black women, transgender/nonbinary/and gender-diverse individuals, and Asian and Pacific Islander populations are reviewed in the context of breast and ovarian cancer risk. Future research on improving risk assessment tools and identifying genomic variants will yield improved personalized healthcare solutions.

Breast cancer is the second leading cause of cancer worldwide, constituting 11.6% of all cancer diagnoses and is the fourth cause of cancer-related deaths.¹ With millions of new cases diagnosed each year globally, it is crucial for providers and patients to understand the various risk factors, including modifiable lifestyle choices, environmental influences and non-modifiable genetic predispositions to effectively address and reduce disease burden. Understanding these risk factors has led to the development and implementation of risk model assessment tools such as the Gail and the Tyrer-Cuzick risk models. The application of these models has become vital in personalized medicine aiding in the determination of patients who would benefit from early breast cancer screening, genomic testing, and risk-reducing surgeries, such as risk-reducing mastectomies and/or bilateral salpingo-oophorectomy. Additionally, ovarian cancer is the third most common gynecological cancer globally and the most lethal gynecological cancer. In 2020 over 300,000 global cases were diagnosed with a poor survival rate of only 17% when diagnosed at an advanced stage. The widespread prevalence and high mortality rate of ovarian cancer highlight the importance of understanding ovarian cancer risk factors and procedures to reduce disease risk.²

This review explores the intricate relationships between breast and ovarian cancer risk factors, examines current risk stratification models, reviews clinical screening guidelines, and discusses considerations for risk-reducing surgeries. Additionally, the value in this review is that it is among the first to address specific challenges and disparities often faced by North American under-represented groups including transgender and gender-diverse (TGD) individuals, non-Hispanic Black women, and Asian and Pacific Islander women, providing an inclusive and current understanding of breast and ovarian cancer.

Methodology

A thorough literature search was complete focusing on studies published from 1980 to 2024 with a focus on breast and ovarian cancer. A narrative review approach was utilized and included studies with multiple research designs with a prioritization of high-quality evidence from meta-analysis, systemic reviews, and large cohort and clinical trials. The articles were retrieved from PubMed and the search was utilized using key words such as “ovarian cancer,” “breast cancer,” “risk factors,” “underrepresented populations,” and “gene variants.” Studies were included if they focused on the key aspects of this review such as risk factors, pathogenic germline variants, and risk reduction options.

Non-modifiable risk factors for breast and ovarian cancer

Risk factors for breast cancer can be widely categorized as non-modifiable or modifiable. Non-modifiable risk factors include intrinsic factors such as sex assigned at birth, age, family history, genetic variants, race, ethnicity, reproductive history, breast density, benign breast diseases, and prior radiation therapy.³ Female sex (defined as sex assigned at birth) is a major risk factor for breast cancer, as less than 1% of all breast cancer diagnoses occur in persons assigned male sex at birth. Increased circulating estrogen and progesterone hormones and alterations in their balance over time can result in an elevated breast cancer risk.⁴ Another significant unmodifiable breast and ovarian cancer risk factor is advancing age, with risk increasing later in life.² The occurrence of cancer in older age is due to accumulation of cellular alterations as well as exposure to carcinogens resulting in increased carcinogenesis over time.⁴ Reproductive history is a risk factor for breast and ovarian cancers due to exposure to endogenous hormones. Early menses (prior to age 12) and late menopause (after age 55), as well as nulliparity, later parity (after age 30) and no history of breast feeding are factors which increased risk for breast and ovarian cancer.^{2, 4}

Breast density is also a major risk factor for breast cancer, regardless of age at mammography or ethnic background of the study population. When comparing women with dense breasts with women with scattered fibroglandular densities, the relative risk of breast cancer is 1.2–1.5 for heterogeneously dense breasts and 2.1–2.3 for extremely dense breasts.⁵ Dense breast tissue is also associated with markedly decreased mammographic sensitivity and increased risk for interval breast cancers as cancer has the same X-ray attenuation as fibroglandular breast tissue and can mask disease.⁶

Radiation therapy to the chest prior to the age of 30 is associated with increased risk for breast cancer.⁴ The incidence of breast cancer for children and young adults treated with thoracic radiation is as high as 29% by age 55.⁷ Patient age during therapy, overall radiation dose, use of alkylating chemotherapy agents, and therapy related suppression of ovarian function impact the overall degree of breast cancer risk attributable to radiation therapy.⁸

Many benign breast diseases are associated with elevated risk for breast cancer. Atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are considered markers of increased risk for future breast cancer in either breast. They are estimated to increase breast cancer risk 3- to 5-fold.⁹ Lobular carcinoma in situ (LCIS) is another high-risk lesion that is associated with a relative risk of future breast cancer of 6.9–11.⁹

Pathogenic germline variants

Pathogenic variants in several genes are associated with increased risk for breast and ovarian cancer with proposed variant categories as high, moderate, or low penetrance. High penetrance genes are associated with greater risk for cancer development and consensus guidelines have been developed for risk management.¹⁰ High penetrance breast cancer and ovarian cancer genes have been proposed to include BRCA1, BRCA2, TP53 (Li-Fraumeni Syndrome), PALB2 and STK11 (Peutz-Jeghers Syndrome)^10–14 (Table I). Moderate and lower penetrance genes are less well established and therefore management guidelines for these pathogenic variants are often individualized based on personal and family history. Examples of moderate penetrance variants for breast cancer include ATM, CHEK2, RAD51C, and RAD51D.^{9, 11, 13} Due to the complexity and individualized nature of pathogenic variants the proposed categories of high, moderate and low should be regarded more of a spectrum and less than defined categories. This should be considered as known genes have specific variants yielding varied risk factors, for example, the CHEK2 variants Ile157Thr and Ser428Phe are associated with a lower risk of breast cancer than protein-truncating variants in CHEK2.¹¹

Table I.—

A review of pathogenic germline variants associated with breast and ovarian cancer development along with their reported Odds ratio and confidence interval.^{9, 15, 16}

Germline variant	Breast odds ratio (95% CI)	Ovarian odds ratio (95% CI)
ATM	2.10 (1.71–2.57)	2.4 (1.2–4.7)
BRCA1	10.57 (8.02–13.93)	29.0 (22.7–37.1)
BRCA2	5.85 (4.85–7.06)	12.7 (9.7–16.4)
CHEK2	2.54 (2.21–2.91)	0.4 (0.2–0.9)
PALB2	5.02 (3.73–6.76)	4.4 (2.1–9.1)
BARD1	2.09 (1.35–3.23)	4.2 (1.4–12.5)
RAD51C	1.93 (1.20–3.11)	3.4 (1.5–7.6)
RAD51D	1.80 (1.11–2.93)	10.9 (4.6–26.0)
PTEN	2.25 (0.85–6.00)	Not applicable
NF1	1.76 (0.9–63.21)	Not applicable
TP53	3.06 (0.63–14.91)	2.9 (1.2–6.9)
MSH6	1.96 (1.15–3.33)	1.92 (1.19–3.10)
CDH1	0.86 (0.37–1.98)	Not applicable
STK11	1.60 (0.48–5.28)	41.9 (5.55–315)

An overlap occurs between the breast and ovarian high penetrance genes BRCA1 and BRCA2. The moderate penetrance ovarian cancer susceptibility genes that overlap with breast cancer are ATM and RAD51C. Additional moderate penetrance ovarian variants are MLH1, MSH2, MSH6, and EPCAM.^{10, 12}

Pathogenic variants in the aforementioned genes are known to have an effect on breast and/or ovarian cancer development. Germline genetic testing typically involves sequencing the entirety of the genes of interest. This is done to identify pathogenic variants that negatively alter the function of the gene products resulting in increased cancer risk. This is extensive normal variation in all genes, and many variants have not yet been sufficiently studied to determine whether they are pathogenic or benign variants. Due to this, the results of germline genetic testing often include Variants of Uncertain Significance (VUS).¹³ As VUS data accumulates over time, the majority of VUS are reclassified as benign, but based on historical data, up to one-fourth will eventually be determined to be pathogenic.¹³ In most cases, a VUS should not be used to determine medical care, as this could lead to potential improper recommendations for treatment and surveillance protocols.¹⁰ Genomic datasets, such as ClinVar, have been developed to allow for greater data sharing to help further clarify and classify genetic variations. There are specialized genetic providers, such as genetic counselors and geneticists, that can provide in-depth and personalized evaluation of variants, including VUS, that can aid in clinical decisioning. These providers taking into account a patient’s personal and family history, data from the literature, and data from sets like ClinVar. In some cases, a genetics provider may offer supplementary testing, such as that of family members, tumor sequencing or RNA analysis to clarify the significance of a variant.

Non-genetic familial syndromes

Approximately 5–10% of breast cancer cases can be found to be familial in nature and BRCA1 and BRCA2 susceptibility genes may be implicated as the major contributor for familial breast cancer.¹⁴ However, BRCA1/2 can be attributed to less than 17–28% of these familial cases.¹⁴ Despite testing, many cases of familial breast and/or ovarian cancer cannot be explained by any known identifiable pathogenic variants.¹⁴ In cases where breast cancer clusters in a family, and there is a not a single identifiable inherited gene mutation, the term non-genetic familial syndrome is applied. Recent studies have utilized whole-genome sequencing to map out a comprehensive landscape of somatic mutations present within tumors and provide promise to identifying other oncogenic factors. The clinical implication to identifying tumor specific mutations within families resulted in the development of HRDetect. HRDetect is a prediction model that can estimate non-BRCA1/2 high-risk familial breast cancer patients’ response to platinum-based chemotherapy lending to patient specific chemotherapies.¹⁴

Risk models and contributing factors

Risk models use modifiable and non-modifiable risk factors to estimate a person’s risk of developing breast and ovarian cancer. Table II displays a summary of the variables included in the selected risk models discussed in this review. Risk prediction models are used to identify those that may benefit from genetic counseling, supplemental breast imaging, and risk-reducing therapies such as surgery and medication therapy.

Table II.—

Breast and ovarian cancer risk models.

Model	Risk factors	Population and age (years)	Benefits	Limitations
Gail	Age; ethnicity; age at menarche; age at first live birth; breast biopsy history; history of atypia; and number of first-degree relatives with breast cancer.	Women, ≥35	Used to assess benefit of chemoprevention. Available online, easy to use.	Limited to first degree relatives. Does not include BRCA1 or BRCA2 risk. Cannot predict risk with history of DCIS/LCIS.
Claus	Family history including breast and ovarian cancer. Includes age at diagnosis and paternal history.	Women, 20–79	Includes ovarian cancer and paternal family history.	Does not include non-hereditary risk factors.
BCSC	Age, race/ethnicity, family history of breast cancer in a first-degree female relative, history of benign breast disease diagnosis, breast density.	Women, ≥35	Used to assess benefit of chemoprevention. Available online, easy to use.	Limited family history data.
Tyrer-Cuzick	Age at menarche, age at first live birth, age at menopause, parity, height, weight, LCIS, Atypia, benign breast disease, family history of breast and ovarian cancer. Mammographic breast density.	Women, 18–85	Able to be downloaded online. Combines genetic segregation model for familial risk and regression model for other risk factors. Used to determine eligibility for breast MRI screening.	Requires detailed family history. Can overestimate risk if history of LCIS or atypia. Predicts risk of BRCA1 and BRCA2 not other susceptibility genes.
BRCAPRO	Extensive family history of first- and second-degree relatives with breast and ovarian cancer. Race/ ethnicity and tumor markers.	Women, No age limitation	Used to determine eligibility for genetic testing, supplemental breast MRI.	Does not consider susceptibility genes other than BRCA1 and BRCA2. Only uses history of first- and second-degree relatives.
BOADICEA	Extensive family history and nongenetic risk factors, such as hormonal factors. Timor pathology and breast density.	Women, No age limitation	Online tool CanRisk. Used to determine risk of other susceptibility genes including PALB2, CHEK2, ATM, RAD51D, RAD51C, or BARD1.	Requires a detailed family history and dedicated software.

Women here represent persons assigned female sex at birth.

Gail Model/Breast Cancer Risk Assessment Tool

The Gail model, also known as the Breast Cancer Risk Assessment Tool (BCRAT), was developed in 1989 by Mitchell Gail and colleagues using data from Caucasian women aged 35–74 years to calculate invasive and non-invasive breast cancer risk.¹⁷ The model has undergone several modifications over time to include incidence of Black and other non-White women and personal history of breast atypia. The Gail model is freely available through the National Cancer Institute at https://bcrisktool.cancer.gov. Risk factors used in this model include age of menarche, first parity, number of breast biopsies, presence of atypical hyperplasia, and number of affected first degree relatives with breast cancer. The model provides breast cancer risk estimates for five-year and lifetime risk for women who are age ≥35 years.¹⁷ The model is used to identify women with a 5-year breast cancer risk of ≥1.7% who would benefit from risk-reducing medications such as tamoxifen.¹⁸

A limitation to the Gail model is the hypothesized underestimation of breast cancer risk in individuals with a strong family history of breast cancer outside of first-degree relatives. Additionally, the Gail model does not take into consideration age at breast cancer onset in first-degree relatives, paternal family history, and other cancers that could be associated with familial cancer syndromes (i.e., pancreatic, gastric, etc.). Additionally, the Gail model does not adjust risk for women carrying a breast-cancer-producing mutation in BRCA1 or BRCA2, women with a previous history of invasive or in-situ disease and may underestimate risk in Black and Hispanic women.¹⁹

Tyrer-Cuzick (IBIS)

The Tyrer-Cuzick model was developed using data from the International Breast Cancer Intervention Study (IBIS) in 2004. The model is used to calculate likelihood of having a BRCA1 or 2 variants as well as both ten-year and lifetime risk of breast cancer in patients aged 18–85. Risk factors used in this model include hormone history, known BRCA status, breast density, and familial status. The Tyrer-Cuzick model includes family history from both affected and non-affected family members with breast, ovarian, and male breast cancers. In addition, risk factors identified from a previous breast biopsy for benign/non-proliferative disease, hyperplasia, ADH, ALH, and LCIS are taken into account when adjusting patient risk.²⁰ Version 8 (the most recent version) is easily accessible online (at https://tools.bscs-scc.org/BC5yearRisk/calculator.htm). Benefits of this model is that it can be used to identify those who should be recommended supplemental breast screening and risk-reducing medications. This model calculates breast cancer risk up to age 85 and places risk of death from breast cancer against competing mortality causes. A limitation is that prior studies have demonstrated that this model overestimates breast cancer risk in women with LCIS, ADH, and ALH and that the model was developed using largely non-Hispanic White women and may not perform well in estimating risk in other races and ethnicities.^{21, 22} Additionally this model does not consider or estimate risk for the highly penetrant germline pathogenic variants such as TP53, PTEN, STK11, PALB2 and CDH1 mutations.

CLAUS

Claus and colleagues developed a breast cancer risk prediction model based on data from the Cancer and Steroid Hormone Study, a large population-based control study of women aged 20–54 years. The Claus model includes probability tables that were developed using family historical data on breast and ovarian cancer. Risk estimates are provided in 10-year increments as well as reporting a lifetime cumulative risk by age 79. The Claus model takes into consideration patient age as well as the patient’s first and/or second-degree relatives age of onset of breast cancer and incidence of first-degree relatives with ovarian cancer.²³ This model predicts risk of invasive cancer and ductal carcinoma in situ in women without a pathogenic variant and can be used to identify women eligible for supplemental breast cancer screening.²⁴

A benefit of the CLAUS model is it has been validated to counsel woman between ages 29–35 years with a family history of breast cancer.²⁵ A limitation of this tool is that the probability is based largely on family history without consideration of additional risk factors. In a study comparing the predictive accuracy of validated breast cancer risk models, the Claus model was inferior to the above-mentioned models.²⁵

BRCAPRO

The BRCAPRO model is widely used tool by genetic counselors. It is used to calculate family or personal probabilities of being a carrier of an inherited pathogenic variant in BRCA1 and BRCA2 as well as future risk of breast and ovarian cancer.^{26, 27} Predictions of pathogenic variant carrier status are extrapolated based on one’s family history and published estimates of population prevalence and penetrance of BRCA1 and BRCA2 baseline rates. The individual patient factors assessed in BRCAPRO are age, breast or ovarian cancer status, age of cancer diagnosis if affected, pathologic biomarkers for known breast cancer cases, race, ethnicity, and history of risk-reducing mastectomy or oophorectomy. Benefits of BRCAPRO include the utilization in both males and females with and without a family history of breast or ovarian cancer. This model is used to determine who would benefit from genetic testing.²⁸ Additionally, those with a calculated lifetime breast cancer risk >17% are often referred for supplemental breast cancer screening.²⁴ The model can be accessed through the BayesMendel software package and data shows that it performs well among Black, Hispanic, and other minoritized patient populations.²⁹ A limitation of this model is that it is specific to BRCA1 and BRCA2 and does not include additional high penetrance susceptibility genes.

BOADICEA

The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a genetic model for familial breast cancer, which considers the simultaneous effects of BRCA1, BRCA2 and multiplicative effects of carrying multiple genes (polygenic component).³⁰ Similar to BRCAPRO, this model predicts both the probability of a person carrying a BRCA1 or BRCA2 pathogenic variant (or the proposed polygenic component) and their risk of developing breast and ovarian cancer over time.³⁰ The tool calculates the risks of breast and ovarian cancer in women based on their risk factors (e.g. lifestyle, hormonal exposure, etc.), genetic testing results, and family history. It also calculates the probability that they are carriers of any cancer-associated pathogenic variant in the BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D or RAD51C genes. BOADICEA provides a 5 or 10 year and lifetime breast cancer risk, ovarian cancer risk and contralateral breast cancer risk for a patient with a personal history of cancer. Compared to other risk models BOADICEA does not restrict family history to a particular degree or relatives but was largely developed using a White cohort of women.³⁰ BOADICEA is available through the Web-based CanRisk Tool.

Breast Cancer Surveillance Consortium

The Breast Cancer Surveillance Consortium Model (BCSC) estimates five and ten-year invasive breast cancer risk for women age ≥35 years, without prior breast cancer, mastectomy or breast augmentation.³¹ In comparison, the BCSC model is similar to the Gail Model; however, it also takes into account breast density. The addition of density is based on a study by Tice et al. which demonstrated addition of results from Breast Imaging Reporting and Data System (BI-RADS) improved discrimination for invasive breast cancer in White women.¹⁹ Because the model provides five and ten-year risk estimates, it can be implemented as a tool to determine eligibility for risk-reducing medications.³² A limitation of this model is that in validation studies, BCSC slightly underestimates risk in women aged 40–44, Asian women, Hispanic women, Black women, and those with fatty breast density.¹⁹ The tool is available online (at Https://tools.bscs-scc.org/BC5yearRisk/calculator).

Modifiable risk factors

Modifiable risk factors for breast and ovarian cancer include lifestyle choices, environmental exposures, utilization of hormonal oral contraceptive pills (OCPs), and hormone replacement therapies (HRT). Modifiable risk factors should be able to be adjusted by individuals to reduce their future risk of developing breast or ovarian cancer. Examples of modifiable risk factors include smoking, alcohol use, and obesity. Tobacco abuse in relation to both correlation and causation of many forms of cancer is a subject of extensive research. A recent umbrella review of systemic reviews looked at the relative risk ratio of tobacco use on breast cancer. The subgroup of being an ‘ever smoker’ incurred a relative risk ratio of 1.08 (95% CI 1.06–1.10).³³

Alcohol has been theorized to increase breast cancer risk due to multiple metabolic effects of ethanol. One effect of alcohol consumption is an increase in blood estrogen levels, and another is that alcohol consumption produces the metabolite acetaldehyde, a carcinogenic molecule. Lastly the long-term use of alcohol overconsumption can often lead to folate deficiency affecting DNA synthesis. These metabolic pathways are speculated to be the pathophysiologic explanation as to why in a large systematic review alcohol consumption was associated with an increase in breast cancer risk with a statistically significant relative ratio of 1.61 (95% CI 1.33–1.94).³³

Another modifiable risk factor associated with breast cancer is obesity. Like alcohol consumption, increased weight leads to higher volume fatty tissues which in turn increases the levels of circulating estrogen which can promote breast cancer. A review paper that examined multiple definitions of obesity revealed that an increased waist to hip ratio, corresponding to increased central obesity, increases the risk of breast cancer with a relative risk of 1.95 (95% CI 1.10–3.46).^{33, 34} Additionally in cisgender women with a family history of breast cancer and personal history of obesity the incidence of breast cancer was 2.06-fold that of absence of either risk factors.³⁵

Environmental exposures are often classified as modifiable risk factors however, environment is debatably a non-modifiable risk factor closely linked to an individual’s country of origin and socioeconomic status. Environmental exposures of toxicologic, chemical, and social origin are frequently being identified with many unique exposures associated to increasing incidence of breast and gynecologic cancers.³⁶ Some such environmental factors include personal hygiene products with endocrine disrupting properties and structural constructs such as redlining, and socioeconomic status.³⁶ Parabens and phthalates are two common compounds found in personal hygiene products such as antiperspirant, cosmetics, and lotions that have been linked to carcinogenic properties. The mechanism of action is that these compounds act as partial estrogen receptor agonists that can stimulate breast or uterine cancer development. Lye containing products such as hair relaxers and dye have been associated with increased incidences of uterine, ovarian, and breast cancers.³⁷ Another common household product is talc powder and data reveals an association between perineal application of talc powder and ovarian cancer development. It should be noted that direct causal association is still debated and there is no clear proposed mechanism for this relationship.³⁸

Environmental factors that affect health go beyond one’s home. Discriminatory practices such as redlining, and mortgage discrimination are both ongoing and historic practices that are linked to poorer health outcomes. Specifically, these polices are associated with a higher likelihood of late-stage breast cancer diagnosis, an increased risk of hormone receptor (HR) negative breast cancer, and higher mortality rates.³⁹ The connection between social and chemical environmental factors with cancers highlights the urgent need to understand these risks in order to address them on both individual and societal levels. Improving societal and provider knowledge and can lead to better treatment and prevention strategies for patients against the risk of breast and ovarian cancer.

Hormonal oral contraceptives

Oral hormonal contraceptive pills (OCPs) are frequently regarded as a low-cost and relatively low risk medication class that is used worldwide. However, the administration of progesterone with or without estrogen has variable effects on breast and ovarian cancer development. Early research has suggested that OCPs temporarily increase the risk of developing breast cancer but are associated with a reduced risk of developing ovarian cancer.⁴⁰ The two main forms of OCPs – progesterone only versus combination estrogen and progesterone pills – have both been implicated with increased odds of developing breast cancer.⁴⁰ However, it has recently been revealed that this increased risk is limited to those currently using or who have recently been using OCPs. The effects of hormonal contraceptives are believed to return to baseline levels, similar to those who have never used them, within 5 years after discontinuation.⁴⁰ The exact mechanism of exogenous progesterone’s effect on the development of breast cancer remains an on-going topic of research.

In contrast there is a well-established reduced risk in the development of ovarian cancer in patients who take OCPs.⁴¹ This relationship depends on the duration of OCP use. Patients who have used OCPs for any length of time have lower rates of ovarian cancer compared to those who have never used OCPs. Those who have used OCPs for ≥10 years’ experience a reduction in ovarian cancer incidence of more than 50%.⁴¹ Overall, recognizing the tumor specific effect OCPs have on individual neoplastic processes can lead to informed, and personalized health care based on individual patient risk factors.

Hormone replacement therapy

Hormone replacement therapy (HRT) may be used for patients to mitigate perimenopausal symptoms, menopausal symptoms, or to treat premature ovarian failure. HRT, similar to OCPs, has an associated with an increased risk for breast cancer development.⁴² The Woman’s Health Initiative trial in the early 2000s, sought to determine the benefits and risks of HRT in regard to prevention of chronic diseases of aging such as coronary artery disease and cognitive impairment. The pre-determined safety outcome was incidence of invasive breast cancer, and the trial was prematurely closed due to an increased breast cancer incidence within study participants.⁴² During this trial and similar studies, it was noticed that risk of developing breast cancer was increased with being an ever-time user of systemic estrogen-only and estrogen-progestogen preparations of HRT, however there was no increase in breast cancer relative risk with application of vaginal estrogens.^{42, 43}

A large metanalysis found that when women between the ages of 40–59 received 5 years of HRT, there was an appreciable increase in thelikelihood of developing breast cancer between the ages of 50–69. The first HRT preparation examined was estrogen with daily progestogen which showed an increase in the absolute incidence of breast cancer by about 2%. For patients receiving estrogen and intermittent progestogen there was an absolute lifetime increase in breast cancer incidence of 1.4%. and those on estrogen-only regimens had an increased incidence of breast cancer by only 0.5%.⁴³

The selection of which specific HRT regimen a woman is placed on is frequently made in the context of the presence of an intact uterus as progestogens play a key role in prevention of estrogen-driven unchecked endometrial proliferation which can potentially result in endometrial cancer. However, the need for dual estrogen/progesterone HRT places patients with an intact uterus at a higher risk for breast cancer when compared to patients post hysterectomy with no OCP use.⁴⁴ Not only does incidence of breast cancer increase due to dual HRT, but it also results in architectural changes to breast tissue that leads to increased number of abnormal mammograms leading to additional diagnostic imaging procedures and breast biopsies.⁴⁴

Allostatic load

To better understand the effect environment has on an individual’s biochemical processes there has been on-going research into the field of allostatic load (AL). AL was first defined in 1993 as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenges.⁴⁵ The use of this measure is that AL presents a cumulative measure of physiological damage that combines primary and secondary factors related to the body’s stress response systems, such as cortisol and C-reactive protein, and relates these factors to tertiary outcomes such as the development of cancer. Research has revealed that populations with increased AL have increased exposure to economic and social stressors such low socioeconomic status or being a member of a marginalized group.⁴⁶ Current research shows that increased AL is directly correlated to an increased incidence of chronic diseases (i.e., hypertension, diabetes, etc.), cancer diagnoses, and all-cause mortality.⁴⁷ Not only is disease burden increased in those with high AL, but the application of this principle has also revealed a 22% increase in all-cause mortality rates when compared to patients with a relatively lower AL.^{48, 49} When specifically examining patients with breast cancer, a higher AL is associated with increased primary tumor size and estrogen receptor negative (ER−) tumors.⁴⁹ Additionally when examining overall mortality in patients undergoing surgery for early-stage breast cancer, an elevated AL was linked to a 46% increased risk of death, even after accounting for sociodemographic, clinical, and treatment factors.⁴⁶ Future work is needed to understand how AL can be incorporated into current risk models for breast and ovarian cancer risk as currently it is not factored into any risk modeling. Overall, AL is a unique and measurable indicator that can identify individuals with increased risk of mortality and may prove to be a measurable mark when examining the social determinants of health in the breast cancer population.

Screening options

Cisgender women at average risk for breast cancer

A unique challenge that medical professionals face is non-standardized breast cancer screening guidelines for the average risk cisgender woman. Overall, the six main governing organizations all agree that the optimal gold-standing imaging modality is screening mammography⁵⁰ (Table III). However, organizational guidelines vary on both the ideal time interval between studies and initial age to begin screening patients. The goal of guidelines is to balance the benefits of early breast cancer detection with potential harms such as false negative results, false positive results, additional medical interventions (specifically biopsies and additional imaging), patient medical anxiety, potential exposure to radiation, and over diagnosis.⁵⁰

Table III.—

2024 breast cancer screening recommendations.

Organization	Average risk in cisgender women	Average risk cisgender women – dense breast	Elevated risk in cisgender women
USPSTF	Women 40–74: biennial MMG Women ≥75: insufficient to assess benefits and harms of screening MMG *Defines women as cisgender women and all other persons assigned female at birth	Insufficient evidence to support use of supplement screening with US or MRI	High risk screening not addressed by USPSTF
ACS	Women 40–44: option to begin annual MMG Women 45–54: annual MMG Women ≥55: annual or biennial MMG until life expectancy is <10 years	Insufficient evidence to support use of supplement screening MRI for women with heterogeneously or extremely dense breast	Consider annual MRI in addition to annual MMG typically starting around age 30 for:   • Lifetime risk >20%   •Genetic variants   •Prior chest radiation Insufficient evidence for an MRI in ADH/ LCIS/ALH or prior hx of breast cancer
ECIBC	Women 45–49: biennial or triennial MMG Women 50–69: biennial mammogram Women 70–74: triennial MMG	Insufficient evidence to support the use of supplement screening with ABUS, handheld U/S or MRI	High risk screening not addressed in the ECIBC recommendations
NCCN	Women 25–39: clinical encounter every 1–3 years Women ≥40: annual clinical encounter and MMG with tomosynthesis	Consider supplemental screening with MRI or ABUS for women with heterogenous or extremely dense breast in women ≥40	Annual MRI (ABUS/CEM/MBI if unable to have MRI) in addition to annual MMG:   • Lifetime risk >20%   • Genetic variants   • Prior chest radiation   • ADH/LCIS/ALH Start 10 years younger than a family member diagnosis, not to start prior to 25 for MRI and 30 for MMG
ASBrS	Women ≥40 with non-dense breast: annual MMG with tomosynthesis MMG to continue until life expectancy is <10 years	Consider supplemental screening with MRI or ABUS for women with heterogenous or extremely dense breast in women ≥40	Annual MRI starting at 25 and annual MMG at age 30   • Genetic variants   • Prior chest radiation Annual MMG and MRI at age 35   • Lifetime risk >20%   • Strong family history
ACR	Women ≥40: annual MMG	Consider supplemental imaging with breast MRI for women with dense breasts	Consider annual MRI (ABUS/CEM if unable to have MRI) in addition to annual MMG:   • Lifetime risk >20%   • Genetic variants   • Prior chest radiation   • ADH/LCIS/ALH Start MRI between the ages of 25–30 and mammogram between the ages of 25–40

MMG: mammogram; ABUS: automated breast ultrasound; CEM: contrast-enhanced mammogram; MBI: molecular breast imaging.

The USA Preventative Service Task Force (USPSTF) recommends biennial screening mammograms for cisgender women ages 40–74 years. The USPSTF reports there is insufficient evidence to routinely recommend mammograms beyond the age of 75 years. The American Cancer Society (ACS) recommends giving cisgender women the option to initiate annual screening mammogram between the ages of 40–44 years with all annual screening mammograms recommended for women aged 45–54 years. The ACS gives the option to continue annual screening mammograms or transitioning to biennial mammogram for cisgender women aged ≥55 years with the caveat that mammograms should continue if a woman is expected to live another 10 years based on their other medical co-morbidities.

The European Commission Initiative on Breast Cancer (ECIBC) recommends cisgender women initiate screening mammograms at the age of 45 years with either a biennial or triennial screening interval for women 45–49, biennial interval for women aged 50–69 years, and triennial interval for women 70–74 years of age.⁵¹ The National Comprehensive Cancer Network (NCCN) guidelines recommend a clinical breast exam every 1–3 years for cisgender women ages 25–39 years with initiation of annual clinical breast exams and screening mammogram with tomosynthesis at the age of 40. The American Society of Breast Surgeons (ASBrS) and the American College of Radiology (ACR) both recommend initiation of an annual screening mammograms for women aged 40 years and older.⁵² The ASBrS also recommends continuing annual screening mammograms as longs as the woman’s life expectancy is >10 years which is in alignment with ACS recommendations (Table III).⁵²

There is an increasing emphasis to consider supplemental breast imaging in cisgender women at average risk of developing breast cancer with dense breast tissue. The BIRADs breast density classification is utilized to determine breast density for every screening mammogram (Table IV).⁵³ BIRAD C and D density represent heterogeneously dense and extremely dense breast tissue respectively. NCCN, ASBrS, and ACR recommend providers consider adding supplemental breast imaging to include whole breast ultrasonography or breast magnetic resonance imaging (MRI) for women with dense breasts. The NCCN and ASBrS recommend ultrasound or MRI while ACR recommends MRI only.^{18, 52} In contrast, currently the USPSTF, ACS, and ECIBC report there is insufficient evidence to support the use of supplemental breast imaging in women with dense breast tissue.^{50, 53}

Table IV—

Bi-Rads breast density categories.⁵¹

BI-Rads category	BI-Rads description	Density
A	Breasts are almost entirely fatty	Non-dense
B	Breasts have scattered fibroglandular density	Non-dense
C	Breasts are heterogenous dense	Dense
D	Breasts are extremely dense	Dense

Cisgender women at elevated risk for breast cancer

Patients at high risk for breast cancer development are those with pathogenic germline variants, a lifetime breast cancer risk ≥20% by risk modeling calculators, radiation exposure to the chest or breast between the ages of 10–30 years, and a personal history of breast atypia or LCIS.^{18, 52, 54} Annual screening mammograms and annual supplemental breast imaging, most commonly a breast MRI, are recommended for cisgender women who have an increased risk of developing breast cancer. Occasionally due to cost, claustrophobia, and resource distribution not all women are able to undergo a breast MRI, and in these cases whole breast ultrasound, contrast enhanced mammography, or molecular breast imaging are alterative studies to consider.^{18, 52}

The recommended age to initiate screening breast imaging will vary based on what classifies the patient as high-risk. For cisgender women with pathogenic germline variant, the age to start both annual screening mammograms and supplemental imaging will vary based on which pathogenic variant a woman has; but often starts between the ages of 25–40 years. The NCCN guidelines outline breast screening recommendations for the most common pathogenic variant associated with breast cancer.¹⁸ For women with a lifetime breast cancer risk over ≥20%, screening breast imaging should begin 10 years prior to the youngest family member’s breast cancer diagnosis, but not before the age of 30 for mammograms, and 25 for breast MRI.^{18, 52} Women with radiation exposure to the chest or breast between the ages of 10–30 should initiate annual mammograms and supplemental screening 8 years after the completion of radiation treatment, but not before the age of 25.¹⁸ There are varying recommendations for supplemental imaging in women with a history of atypia or LCIS but NCCN and ACR recommend consideration for supplemental imaging if, at the time of diagnosis, the woman’s lifetime risk is also ≥20% this defers from ACS who reports there is insufficient evidence to recommend supplemental imaging^{18, 52} (Table III).

Technological advancements in breast cancer imaging

As previously noted, the gold-standard screening modality is that of mammography. The ACR has determined that the target cancer detection rate is 3–8 cancers per 10,000 mammograms with a recall rate of 5–12% for radiologists.⁵⁵ The addition of regular screening mammography has resulted in a reported 66% reduction in risk of dying from breast cancer.⁵⁵ Additionally, the rate of detection of large tumors (>2 cm) has decreased with a respective increase in small tumor (<2 cm or in-situ carcinoma) detection.⁵⁵ As traditional 2D mammography has limitations in detecting cancers in dense breast tissue there are several new technological advancements including digital breast tomosynthesis, or 3D mammography.^{55, 56} These techniques aim to provide clearer, layered breast images for improved interpretation by the radiologist. The topic of radiomics and artificial intelligence driven image analysis is also newly being explored.^{57, 58} Additional new structural advancements such as contrast-enhanced mammography and molecular breast imaging may provide functional insights when utilized. The goal of these advancements is to enhance early detection which in turn may result in fine-tuned treatment approaches and improved patient survival.^55–57

Cisgender women at elevated risk for ovarian cancer

While there are no standard screening examinations or tests currently indicated for women at average risk for ovarian cancer, there are two options women at an elevated risk for ovarian cancer can consider: 1) biannual transvaginal ultrasonography; and 2) measurement of the cancer antigen 125 (CA125).⁵⁹ Candidates to consider these screening options are those who have a known pathogenic germline variant that increases the risk for ovarian cancer development or a known familial syndrome without an identifiable pathogenic germline variant.

Transvaginal ultrasonography screening can detect structural changes of the ovaries that may indicate an underlying or development carcinoma. However, this tool has very low specificity and patients should be aware that it may not impact overall mortality. Similarly, testing of blood serum levels of the glycoprotein CA125 is another option, as 50% of patients with Stage 1 ovarian cancer will have elevated levels. Although implementation of this lab has limited clinical utilization as baseline CA125 varies amongst people and false positives are common so to overcome these limitations repeated measurements are often required if one has an isolated elevated value.⁶⁰ Symptoms of ovarian cancer can be non-specific and at-risk women need education on warning signs in order to promptly notify their providers of any major health changes. Additionally, women with pathogenic BRCA1 or BRCA2 germline variants should strongly consider prophylactic salpingo-oophorectomy once they are finished having children.⁵⁶

Risk-reducing surgery

Bilateral risk-reducing mastectomy (BRRM), also sometimes referred to as a prophylactic mastectomy, is a surgery in which a non-pathologic breast is surgically removed with the primary goal of preventing future breast cancer. Similarly, risk-reducing bilateral salpingo-oophorectomy (RRBSO) is a surgery in which both the fallopian tubes and ovaries are removed to reduce incidence of cancer.

Bilateral risk-reducing mastectomies (BRRM)

Women with pathogenic BRCA1 and BRCA2 germline variants

The BRCA1 and BRCA2 genes, have dramatically impacted the management of hereditary breast cancer including risk-reducing strategies.⁶¹ Pathogenic variants in BRCA1 and BRCA2 genes are estimated to confer a 69% and 72% cumulative risk, respectively, for breast cancer by age 80, and a 44% and 17% cumulative risk, respectively, for ovarian cancer.⁶² For patients with a BRCA pathogenic or likely pathogenic variants, the NCCN guidelines recommend healthcare providers discuss and consider risk-reducing mastectomies with patients but does not make formal recommendations on which specific patients should undergo the procedure. This recommendation stems from ongoing evidence that suggests risk-reducing mastectomies reduce the risk of breast cancer but there are no randomized control trials to evaluate the effects of BRRM vs. high risk screening on breast cancer specific mortality. However, it should be noted that retrospective data does strongly suggest a mortality benefit for patients with a pathogenic BRCA1 variant who undergo BRRM.⁶³

In women with a pathogenic BRCA germline variant, BRRM reduces the personal incidence of breast cancer by 89.5–100%.⁶⁴ This data was shown in the Prevention and Observation of Surgical Endpoints (PROSE) study which followed women with pathogenic BRCA germline variants for an average of 6.4 years after BRRM.⁶⁵ However it should be noted that BRRM did not confer a mortality benefit in the PROSE study. A systematic review by Ludwig et al. did identify a mortality benefit for women with pathogenic BRCA germline variants but only in those who underwent both a BRRM and risk-reducing BSO (bilateral salpingo-oophorectomy).⁶⁶

Selection of patients for BRRM should also be considered for women with other pathogenic germline variants, such as PTEN, TP53, CDH1, and STK11 amongst others (see above).⁶⁷ Patients with these inherited pathogenic variants associated with high risk of breast cancer may choose to pursue BRRM to reduce their future breast cancer risk; however, there is no data at this time that supports BRRM has a mortality benefit.

Other high-risk populations

In patients diagnosed with unilateral breast cancer, there have been increasing rates of contralateral risk-reducing mastectomies (CRRM).⁶⁸ However, the Society of Surgical Oncology recommends against generalized CRRM except in cases where surveillance of the contralateral breast would be difficult, surgery would improve cosmetic symmetry, or in identified high-risk patients based on personal or family history.⁶⁹ Patients who are considering CRRM in the setting of unilateral breast cancer should be counseled on risk of recurrence and risk of new primary cancer and that CRRM is not expected to reduce the risk of recurrence.⁷⁰

An additional high risk patient population are those who have received chest wall irradiation before the age 30 years, for example in treatment of Hodgkin lymphoma or other malignancy.^{70, 71} The increase in breast cancer risk post irradiation occurs about 8 years later and is associated with a cumulative risk by age 50 that is similar to those with BRCA1 variants.⁷⁰

Risk-reducing bilateral salpingo-oophorectomy (RRBSO)

The most effective ovarian cancer risk-reduction strategy for women with known BRCA1/2 variant remains RRBSO. In this population, RRBSO decreases the risk of ovarian cancer by 80–90%, the risk of breast cancer by 50%, and cancer-related mortality by 60%.⁷² Therefore, women with BRCA1, BRCA2, or other pathogenic variants predisposing to ovarian cancer should be offered RRBSO.⁷³ While this maintains as a widespread recommendation, hesitation in the patient population exists and is often contributed to the risks associated with early surgical menopause. The consequences of estrogen deficiency include vasomotor symptomatology, urogenital atrophy, increased risk of osteoporosis, as well as cardiovascular disease.⁷² HRT may be able to address these patient concerns in specific patient populations, however, patients with personal history of ER+ breast cancer are not recommended systemic HRT.⁷⁴

Greater benefit is derived for breast cancer risk reduction the earlier oophorectomy is performed.⁷³ NCCN recommends RRBSO between age 35–40 years for patients with BRCA1 and age 40–45 year for patients with BRCA2 unless family history warrants earlier intervention.¹⁸ A multi-center cohort study demonstrated that women with BRCA1 or BRCA2 undergoing RRBSO had a lower risk of ovarian breast cancer as well as lower all-cause mortality and ovarian cancer specific mortality.⁷⁵

While RRBSO offers the greatest known risk reduction for breast and ovarian cancer in BRCA1 and BRCA2 pathogenic variant carriers, currently there are no studies that directly compare mortality outcomes of prophylactic salpingectomy vs. BSO for high-risk women without a known pathogenic germline variant. Analysis from RRBSO pathology at the time of preventive surgery has revealed that occult cancers may be detected in the BRCA1/2 population at a rate of 1.9% to 9.1%. Additionally, while the ovary is the most common site for malignancy, the fallopian tube may be the original site in up to 90% of cases.⁶⁶

With increasing evidence that many “ovarian” cancers start in the fallopian tube, there have been studies that evaluate Risk-Reducing Salpingectomy (RRS) role in cancer risk. Salpingectomy reduces the risk of ovarian cancer in the general population and is an option for premenopausal patients with hereditary cancer risk who are not yet ready for oophorectomy.¹⁸ There are ongoing studies evaluating whether RRS could be an effective alternative for BRCA1/2 carriers, however, current guidelines do not yet support RRS as a substitute for RRBSO. There is no long-term mortality data comparing the two strategies in high-risk populations.

Bilateral salpingectomy with delayed oophorectomy is a strategy previously noted to increase quality of life and may be an acceptable alternative for those unwilling to undergo concurrent BSO.⁷² There are no definitive recommendations regarding concurrent hysterectomy at the time of RRBSO, and its implementation remains controversial.⁷⁴ However, there is evidence to suggest that patients with BRCA1 have an increased risk of serous or serous-like endometrial neoplasms and the risk should be discussed with patients undergoing RRBSO.⁷⁶

BRRM and RRBSO have been shown to reduce the risk of breast and ovarian cancer, and RRBSO can provide additional risk reduction in regard to both overall and ovarian cancer specific mortality. While surgical approach can reduce incidence of breast/ovarian cancer, this must be balanced with potential surgical risks. The decision to pursue risk-reducing surgery should be made through shared decision making between the patient and physicians, weighing breast and ovarian cancer risk in the context of fertility/family planning goals, and personal beliefs that may affect quality of life.

Special populations

Black women and triple-negative breast cancer

Triple-negative breast cancer (TNBC) describes malignant breast tumors that lack the expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of human epidermal growth factor 2 (HER2) on immunohistochemistry or fluorescence in situ hybridization.⁷⁷ While TNBC only accounts for 12–15% of breast cancers diagnosed in the United States, it constitutes a disproportionately high number persons with later stage disease at time of diagnosis and worsened long-term survival. Late-stage disease diagnoses underlines the aggressive nature of this type of tumor.⁷⁷ More common in younger ages, TNBC has been shown to decrease in incidence with each decade of life.⁷⁷ This poses a challenge with early diagnosis given both the age at when current imaging guidelines recommend beginning screening and technical difficulties obtaining screening mammograms as younger women tend to have increased breast density.⁷⁷ Importantly, TNBC is more commonly seen in Non-Hispanic Black (NHB) patients, with a 2- to 3-fold increase, which contributes to the increased risk of mortality from breast cancer in this population.^{77, 78} This suggests that the mere biologic aggressiveness of the tumor biology does not fully explain the disparity.

NHB women have an increased incidence of TNBC and increased overall mortality compared to other races and ethnicities.^{77, 79} Research conducted in West Africa has shown similar elevated risk for TNBC as that for NHB Americans which points to potential heritable factors amongst members of the African diaspora.⁸⁰ Though TNBC most often occurs in patients with BRCA1 pathogenic variant, less than 25% of NHB patients with TNBC have a pathogenic germline variant. This suggests that the molecular events that lead to TNBC in NHB women may be distinct from their non-Black counterparts. While research is currently underway to better understand genetic variants underlying the prevalence of TNBC across ethnic backgrounds, no targeted therapies or clinical practice changes have been made to account for these ethnic differences.⁸⁰ In addition to disparities in disease prevalence, the breast cancer mortality rate for NHB women is 40% greater than NH-White patients.⁷⁹ Though some of the increase in mortality can be attributed to a higher incidence of TNBC, this does not account for the mortality disparity in its entirety.⁷⁹ There are several biologic factors that are thought to contribute to the increased incidence and mortality disparity such as obesity. As previously discussed, obesity can promote dysregulation of several cellular functions, as well as create a proinflammatory state through upregulation of inflammatory mediators such as TNF-alpha. The prevalence of TNBC in overweight and obese NHB women is twice that of ideal body weight NHB women.⁸¹ Other biologic contributors include increased mutations in the tumor suppressor gene, TP53 seen in NHB women. In a 2017 study, TP53 mutations were observed to have a statistically significant discord in prevalence between NHB vs. NHW women. The study revealed 46% of all NHB women versus only 27% of all NHW women had TP53 mutations.⁸²

Sociodemographic factors also contribute to the increased risk of TNBC found in NHB women. Risk factors include reproductive considerations, decreased or absent duration of breastfeeding, higher parity, higher body mass index, and waist-to-hip ratio.⁸³ While these factors are designated as modifiable patient level risk factors, the social and economic context in which patients live impacts social norms, access to fresh foods, physical safety, and access to healthcare.⁸⁴ Women with lower socioeconomic status are more likely to present at later stages of breast cancer diagnosis which impacts treatment and outcomes. Studies that try to discern the impact that sociodemographics carry in the mortality disparity have shown that when socioeconomic status is controlled for, mortality rates between lower and higher socioeconomic status become similar.⁸⁵ However, data is mixed as other studies found that even when controlling for demographics, poverty index, delay in treatment, comorbidities, and type of treatment, NHB women maintained poorer breast cancer survival than NHW women.⁸⁶ Related to patterns of care, Daly and Oladape discuss how delay, misuse, and underuse of treatment are significant when NHB patients are presenting with more aggressive breast cancer subtypes.⁸⁷ Chu et al. demonstrated that NHB patients with TNBC had lower odds of receiving surgery and chemotherapy even after adjusting for sociodemographic, clinicopathologic, and county-level factors.⁸⁵

Transgender, nonbinary, and gender-diverse persons

Gender-affirming hormone therapy for transgender, nonbinary, and gender-diverse (TGD) persons is typically estrogen-based for transfeminine individuals and testosterone-based for transmasculine persons. Gender-affirming estrogen therapy prompts development of breast tissue once initiated with its maximum effect peaked at 9–12 months after initiating treatment.⁸⁸ Gender-affirming testosterone causes atrophy of breast tissue; however, this does not eliminate malignancy risk. Atypical cells and early cancers have been identified in breast tissue specimens in TGD persons assigned female at birth even after a history of gender-affirming testosterone. Population data from the Netherlands has estimated the incidence of breast cancer in TGD persons assigned male sex at birth to be 47-times higher than cisgender men (standardized incidence ratio 46.7, 95% CI 27.2–75.4) and 30% lower than cisgender women (standardized incidence ratio 0.3, 95% CI 0.2–0.4). The estimated incidence of breast cancer in TGD persons assigned female sex at birth is lower than cisgender women (standardized incidence ratio 0.2, 95% CI 0.1–0.5), although gender-affirming testosterone does not appear to be fully protective of breast cancer development in transmasculine persons.^{88, 89}

Gender-affirming surgeries for TGD populations are becoming increasingly common across the United States over the past decade.⁹⁰ Recent population level data identified that over half of gender-affirming operations performed were breast and/or chest operations. Additionally, the majority of these surgeries are being performed in persons aged 18–40 years.⁹⁰ While gender-affirming surgeries provide substantial psychological and social benefits to TGD persons, there is limited research on their impact on breast cancer risk. TGD persons assigned female or intersex at birth may undergo gender-affirming chest masculinization surgery.⁹¹ Gender-affirming chest masculinization surgery removes a substantial amount of fibroglandular breast tissue; however, the surgical technique for this procedure is not synonymous with oncologic BRRM as the degree of fibroglandular tissue removed in a BRRM is often greater.⁹² Studies have theorized that while gender-affirming chest masculinization surgery may reduce breast cancer risk in TGD persons assigned female or intersex at birth, the overall risk likely remains increased when compared to those who undergo oncologic BRRM.

Recent data has identified that implementation of a formal breast cancer risk assessment for TGD persons assigned female or intersex at birth considering gender-affirming chest masculinization surgery can aid in patient-physician discussion regarding benefits and risks of gender-affirming chest masculinization surgery vs. BRRM.⁹³ This is most significant for TGD persons who are found to have an elevated breast cancer risk as they may choose to undergo oncologic BRRM rather than conventional gender-affirming chest masculinization surgery especially given that cases of breast cancer development after gender-affirming chest masculinization surgery are well documented.⁹³ Future research is needed to determine how gender-affirming chest masculinization surgery affects breast cancer risk in TGD individuals and to assess patient-reported outcomes related to their cancer risk.

Assessing personal ovarian cancer risk in TGD persons assigned female or intersex should also be performed for those considering undergoing gender-affirming phalloplasty or metoidioplasty. If patients are found to be at high risk for hereditary ovarian cancers based upon family history or pathogenic germline variant, RRBSO should be considered when undergoing gender-affirming surgery.⁹²

A growing number of societies and organizations have released breast cancer screening recommendations for TGD persons. However, the evidence used to develop screening recommendations has been extrapolated from data for cisgender women and consensus statements rather than prospective screening data.⁹¹ Recommendations are primarily based upon an individual’s sex assigned at birth, history of gender-affirming hormone therapy, history of gender-affirming chest masculinization surgery, and family history of breast cancer. It should be noted that neither the USPSTF nor the ACS provide evidence-based breast cancer screening guidelines for TGD persons. Despite this, healthcare providers should have shared discussions with TGD persons regarding breast cancer screening options.⁹¹ An additional barrier TGD persons face is financial as insurance coverage for breast cancer screening varies by insurance carrier. TGD persons should consider their insurance policy’s coverage for screening mammography prior to obtaining an imaging to minimize potential out-of-pocket cost if not covered based on their sex assigned at birth or prior gender-affirming operations.⁹⁴

Asian and Pacific Islander populations

Breast cancer is the most diagnosed cancer among women in Asian countries and presents at a younger age in a more advanced stage when compared to Western counterparts.⁹⁵ There are many reasons that women face barriers to screening mammography that are unique to this group. A review by Parsa et al. identified social perceptions of disease, poverty, strong beliefs in traditional medicine, cultural attitudes, modesty, education levels, fear, lack of social support or insurance, and lack of encouragement by family and physicians were all previously cited as barriers to screening mammography in Asian women.⁹⁵

An increased percentage of research on Asian women has focused on those who identify as Asian-American Pacific Islanders (AAPI). AAPI are the fastest growing racial/ethnic group in the USA and cancer is the leading cause of death among this population.^{96, 97} With respect to breast cancer, AAPI women have the lowest mortality of all racial/ethnic groups.⁷⁸ However, when this group is disaggregated, there are disparities in mortality.

Specifically, Southeast Asian women have the highest mortality from breast cancer and have the highest rates of stage IV disease at presentation when compared with other Asian subgroups.⁹⁸ This finding has been attributed to multiple factors including cultural views on screening including modesty, access to health care, education, language barriers, and discrimination.⁹⁹ A cross-sectional data analysis using the 2019 National Health Interview Survey conducted by the Centers for Disease Control and Prevention found that breast cancer screening rates for NH Asian Americans were lower than all groups except American Indian and Alaska Natives.¹⁰⁰ Population data from 1999–2018 has shown that the incidence of breast cancer has increased among AAPI with an average influx of 1.4% a year from 2005–2018.¹⁰¹ Despite an increase in incidence, screening rates in this population declined by over 10%.¹⁰² Data from the California Health Interview Survey in 2009 demonstrated that variation among subgroups of the AAPI population with respect to screening mammography. Vietnamese women having the highest rates (93.6%) and Korean women with the lowest (64.7%).¹⁰³ Similar variations in mammography screening rates have been seen throughout different Asian countries.⁹⁵

Evidence shows that Asian women who have migrated to the USA and lived over 50% of their life in the USA were on average three times more likely to have breast cancer compared with USA-born Asian American women.¹⁰⁴ There may be a social assumption that women who have migrated to the USA have a lower risk of developing breast cancer, however their risk is higher than that of the average Asian American woman born in the USA.

Sociodemographics only partially contributes the screening challenges and risk of developing breast cancer in this population. Asian women have been found to have denser breasts, a risk factor for breast cancer, which can result in technical difficulties with mammogram interpretation.⁶ When trying to determine the risk of an individual AAPI woman, traditional breast cancer risk models have lower reliability in the AAPI population.¹⁰⁵ With less reliable screening and risk models, patients and physicians have a greater challenge in identifying AAPI patients at an elevated risk for breast cancer. On a global scale, Asian women face many country-specific barriers to screening mammography which needs to be targeted from a socioeconomic, cultural and psychosocial standpoint to address increased breast cancer mortality.

Overall, Asian women have a lower incidence of ovarian cancer both in the USa and globally.¹⁰⁶ However, when data is disaggregated, disparities between population subgroups is prevalent. National USA data from 1990–2014 compared age-adjusted incidence rates for ovarian cancer and found that Asian Indian/Pakistani women had the highest incidence of ovarian cancer while Korean women had the lowest.¹⁰⁰ The authors of this study also found a higher incidence of clear-cell ovarian cancer in Chinese, Filipino and Japanese women. Maleki et al. performed a meta-analysis of 1-, 3- and 5-year survival rates of ovarian cancer across 12 Asian countries and found the mean 1 year survival rate to be 73.65% with Iran having the highest 1 year survival rate at 93.8% and Singapore having the lowest rate at 63.23%.¹⁰⁶ Just as studies have shown disparities in mammography screening rates among different subgroups within the Asian population, similar disparities exist in ovarian cancer incidence and mortality. Physicians and healthcare providers must recognize these disparities to effectively treat these populations in order to improve early detection, mitigate risk factors, and advance disease management.

Conclusions

Breast and ovarian cancer risk are determined through the interplay of non-modifiable and modifiable factors. Non-modifiable risk factors include genetic pathogenic variant and familial syndromes that can significantly contribute to an individual’s risk of malignancy. Modifiable factors, including lifestyle choices and environmental exposures, tobacco use, alcohol consumption and increased BMI also contribute to a person’s breast and/or ovarian cancer risk. Additionally, understanding the impact of allostatic load and hormonal treatments can help drive patient-centered care and risk management. Understanding of risk factors lends to improved screening strategies that can assess a patient candidacy for risk-reducing surgeries such as prophylactic mastectomy or salpingectomy. Additionally, to effectively treat diverse populations healthcare professionals need education on under-represented groups. Through continued investigation and intentional interventions, health care professionals can reduce the burden of breast cancer for all individuals.