Epidemiology of Triple-Negative Breast Cancer

Molecular Epidemiology

At the turn of the 21st century, Perou and colleagues⁹ used gene expression profiling to identify several distinct profiles of breast cancer, including basal-like cancers, with expression of genes characteristics of basal epithelial cells.^9,10 Basal-like tumors were found to frequently lack expression of ER, PR, and HER2, several years prior to the designation of such an expression pattern as “triple-negative.”¹¹ However, triple-negative and basal-like are not entirely synonymous; when characterized by the PAM50 intrinsic subtype classifier, approximately 5% to 10% are luminal, HER2-enriched, or normal-like.¹² Further clustering analysis has also identified a claudin-low subtype of basal-like cancers, with low expression of tight junction and cell adhesion genes.¹³ Lehmann and colleagues¹⁴ used a similar approach to identify 6 unique triple-negative subtypes using gene expression data, termed basal-like 1, basal-like 2, mesenchymal, luminal androgen receptor, mesenchymal stem–like, and immunomodulatory; however further evidence suggests these latter 2 groups represented the transcriptome of infiltrating stromal cells.¹⁵ The basal-like subgroups were highly proliferative, with basal-like 1 tumor–expressing genes controlling cell cycle and basal-like 2 tumors expressing growth factor pathways—both are characterized by a high pathologic response rate to neoadjuvant chemotherapy. The luminal androgen receptor group features expression of hormonally regulated pathways in common with classical luminal tumors, perhaps driven by response to androgens given a high androgen receptor expression. Similarities between the mesenchymal and claudin-low subtypes, as well as luminal androgen receptors and luminal/HER2-enriched subtypes, raise the question as to whether these represent unique biologic groups or are separate names for the same entities.¹² Unfortunately, this highlights the challenge of describing the epidemiology and characteristics of TNBC as it is not one disease—and may contribute to the sometimes conflicting or inconsistent characteristics and risk factors for triple-negative cancers when studied in different populations. However, the epidemiology of basal-like cancers was explored in the Carolina Breast Cancer Study using immunohistochemistry, identifying that such tumors occurred more frequently in younger African American (AA) women, and was also associated with multiparity, earlier menarche, low rates of breastfeeding, elevated waist-to-hip ratio, and high adiposity.¹⁶ Gene expression analysis of patients in the Nurses’ Health Study failed to demonstrate the associations of parity and menarche with basal-like cancers, although an association with low rates of breastfeeding was seen.¹⁷ However, large cancer registries such as Surveillance Epidemiology and End Results and the National Cancer Database do not collect gene expression data even when performed as part of MammaPrint or PAM50 assays, making definitive epidemiologic conclusions about the many triple-negative subtypes challenging, with this review focusing on the epidemiology of triple-negative cancers as a whole. Furthermore, although approximately one-third of ER PR-negative breast cancer overexpresses HER2, many epidemiologic studies do not report HER2 status, and thus when more specific data are unavailable, this review uses HR-negative cancer as a proxy for the epidemiology of triple-negative disease.

Age

In contrast to the more common hormone addicted cancers that develop with a lifetime of estrogen exposure, relative rates of TNBC are higher in young patients. A population-based study from Atlanta found TNBC to be more common in patients aged 20 to 39 years in a multivariate analysis, both when compared with HR⁺ HER2⁻ tumors (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.34–3.39) and controls (OR, 1.77; 95% CI, 1.18–2.64).¹⁸ When controlling for body mass index (BMI), stage, and grade, 1 review of cases from the Henry Ford Health System estimated a 16% reduced risk of TNBC with each decade of life.¹⁹ This OR closely mirrors raw incidence data from the National Cancer Database from 2010 to 2011, where rates of triple-negative cancer declined from 23.3% of cases in patients 30 or younger, to 10% of cases in patients older than 70 years.²⁰ In the Carolina Breast Cancer Study, younger age was also associated with basal-like breast cancer (trend p < 0.01).¹⁶ Other studies have documented that a higher proportion of triple-negative cancers are basal-like in young patients, whereas nearly half of patients older than 65 years with triple-negative cancers have nonbasal subtypes.²¹ This may explain why some epidemiologic associations that appear age-dependent risk factors in younger patients may inform the pathogenesis of basal-like cancers, whereas risk factors in older patients may be reflective of the higher proportion of HER2-enriched and luminal triple-negative cancers.

Disease-Specific Characteristics

The aggressive nature of TNBC is reflected by the characteristics of disease at presentation. In analysis of SEER from 2010 to 2013, TNBC represented only 8.2% of stage I cancers, as opposed to more than 15% of higher-stage disease at diagnosis.²² Additionally, triple-negative cancers represented only 8.5% of tumors diagnosed at less than 2 cm, and only 2.3% of low-grade cancers were triple-negative. Whereas long-term survival for stage I triple-negative cancers was similar to other receptor subtypes, outcomes dramatically worsen with increasing stage, with almost half of women dying of stage III disease within 4 years of diagnosis. The frequency, target age group, and imaging modality used in breast cancer screening programs may explain some of the disparities in stage between breast cancer subtypes. Cancers diagnosed between screening mammograms (interval cancers) are more than 6 times as likely to be ER-negative, are 3 times as likely to be TNBC, and are associated with a significantly worse breast cancer–specific mortality.^23,24 Triple-negative cancers often lack calcifications and other typical features of breast cancer on mammography and may occur in younger women where breast density limits interpretation, whereas magnetic resonance imaging (MRI) has been shown to be more sensitive for early detection and diagnosis.²⁵ Given the rapid growth of these tumors, novel-screening strategies such as the Chicago Alternate Prevention Study (NCT03729115), where women with high genetic risk for interval breast cancers are screened with biannual MRI, must be considered.

Reproductive Risk Factors

Although early menarche is a known risk factor for breast cancer, the risk for the triple-negative subtype is less well established. The Women’s Health Initiative found no association with TNBC and early menarche, whereas in the Atlanta case-control study, age at menarche of younger than 12 years was a significant risk factor.^18,26 In a pooled analysis of 4426 AA women, increasing age at menarche was associated with a decline in rates of triple-negative cancer for patients with menarche at 15 years or older compared with younger than 11 years (OR, 0.70; 95% CI, 0.49–1.01).²⁷ In a separate pooled case-case analysis of 14 studies, the risk of triple-negative disease in patients with early menarche did not differ significantly from ER⁺ disease, suggesting that this risk factor is applicable to both subtypes of breast cancer (OR, 1.08 for patients ≤12 vs. ≥15; 95% CI, 0.92–1.28).²⁸ The biologic plausibility of an association between puberty and TNBC is strengthened by a case-control study of cancers developing after therapeutic radiation, which found elevated rates of basal-like cancer, but only in those treated more than 4 years after menarche.²⁹ Several case-control studies failed to demonstrate a significant interaction between age at menopause and TNBC.^26,30 However, a meta-analysis of more than 100,000 women demonstrated significantly increased risks for ER-negative cancer with each year older at menopause (relative risk [RR], 1.020; 95% CI, 1.012–1.028), as well as with each year younger at menarche (RR, 1.049; 95% CI, 1.031–1.067).³¹

Exogenous estrogen exposure has also shown variable impact on the rates of TNBC. A 2017 meta-analysis of 11 studies, including data from the Women’s Health Initiative, the Carolina Breast Cancer Study, and the Black Women’s Health Study, found an association with oral contraceptive use and development of TNBC, both compared with other subtypes (OR, 1.31; 95% CI, 1.18–1.45) and compared with controls (OR, 1.21; 95% CI, 1.01–1.46).³² Although several case-control studies specifically analyzing risk of TNBC fail to find an association with postmenopausal hormone use, a comprehensive meta-analysis of 24 prospective studies found an elevated risk of estrogen-negative tumors in users of both estrogen only (RR, 1.25; 95% CI, 1.13–1.38) and combined hormone replacement therapy (RR, 1.42; 95% CI, 1.30–1.55).³³ No significant risk was associated with vaginal estrogen replacement in this meta-analysis. Studies of endogenous sex hormone levels (including estradiol and estrone) have shown association with increasing hormone levels and breast cancer.³⁴ When stratified by ER receptor status, no significant difference was seen between the risk of ER-positive and ER-negative disease with a doubling of sex hormone levels, although magnitude of risk was generally lower for ER-negative disease. These results suggest that estrogen does play a role in the development of TNBC, which is also supported by studies of prophylactic oophorectomy in BRCA1 mutation carriers,³⁵ as well as mouse xenograft models in which estrogen is essential for angiogenesis and stromal changes in ER-negative tumors.³⁶

Likewise, pregnancy is associated with breast angiogenesis, stromal changes, and a unique hormonal milieu that may give rise to TNBC. In a case-case analysis adjusting for age at first full-term pregnancy, cancers diagnosed within 2 years of a pregnancy were more likely to be triple-negative (19.6% of cases vs. 7.1%, OR not provided, P = 0.002).³⁷ It is commonly believed that pregnancy is associated with an increased risk of breast cancer that declines over time, eventually becoming protective.³⁸ However, a pooled analysis of patient data from 15 studies calls this teaching into question for ER-negative cancers.³⁹ The authors found risk of ER-negative breast cancer to be highest 2.2 years after birth (hazard ratio, 1.77; 95% CI, 1.34–2.33), but interestingly, the risk remained elevated even 35 years after birth (hazard ratio, 1.38; 95% CI, 1.01–1.88), in stark contrast to ER-positive disease. In a separate pooled case-case analysis of 15 studies, nulliparity was associated with a reduced risk of triple-negative cancer compared with ER-positive disease (OR, 0.69; 95% CI, 0.59–0.81).²⁸ This same study also demonstrated that older age at first full-term birth was associated with fewer cases of triple-negative disease among parous women (OR, 0.89 per 5-year increase in age; 95% CI, 0.83–0.95).

The true impact of breastfeeding on cancer risk can be difficult to ascertain given numerous confounders including parity and ethnic variation in breastfeeding rates. A 2015 meta-analysis demonstrated a protective effect against TNBC with ever breastfeeding—both in comparison to other parous women (0.72; 95% CI, 0.63–0.84), as well as when limited to studies adjusting for age, BMI, parity, and family history (OR, 0.78; 95% CI, 0.66–0.91).⁴⁰ Although only 3 studies were included for the latter adjusted analysis, a similar risk reduction was seen in the more robust analysis of ER/PR-negative disease.

Lifestyle Factors

Obesity has been linked to a multitude of cancers, with postulated mechanisms including alterations in sex hormone metabolism and the production of cytokines in adipose tissue termed adipokines.⁴¹ The relationship between body weight and breast cancer has been most clearly established in postmenopausal women,^42,43 but the risk varies by receptor subtype. A meta-analysis of 13 studies found an increased risk of triple-negative disease compared with HR⁺/HER2⁻ cases in women 50 years or younger with a BMI of 30 kg/m² or greater (OR, 1.80; 95% CI, 1.42–2.29) and no increased risk for the same comparison in older women (OR, 1.09; 95% CI, 0.91–1.29).²⁸ Similarly, a separate meta-analysis that included 9 studies with documented ER and PR status found no increased risk of ER⁻/PR⁻ disease in the overweight (RR, 1.06; 95% CI, 0.95–1.18) or obese (RR, 0.98; 95% CI, 0.78–1.22) postmenopausal women, whereas a clear increased risk was seen for ER⁺/PR⁺ cancers.⁴⁴ In this same meta-analysis, 4 studies were pooled to assess risk in premenopausal women, finding an increased risk of ER⁻/PR⁻ cancers in the overweight category (RR, 1.26; 95% CI, 1.07–1.49). Conversely, a pooled analysis of more than 700,000 cases found no increased risk of triple-negative disease for premenopausal women older than 25 years and a protective effect for each 5-unit BMI gained in the 18- to 24-year-old population (OR, 0.83; 95% CI, 0.70–0.99).⁴⁵ Unfortunately, analysis by receptor subtype in this study was limited as these data were available for only a small fraction of patients.

Given the association of obesity and other metabolic factors with breast cancer, several observational and randomized trials have demonstrated protective effects of dietary habits and physical activity. Only a subset has examined the impact of dietary modification on TNBC rates. Twenty-year follow-up from the Women’s Health Initiative Dietary Modification trial, which randomized nearly 50,000 postmenopausal women to usual diet or an intervention of reduced fat and increased vegetable, fruit, and grain intake, demonstrated a significant reduction in death from breast cancer (hazard ratio, 0.79; 95% CI, 0.64–0.97).⁴⁶ However, overall breast cancer incidence rates (hazard ratio, 0.95; 95% CI, 0.89–1.02), as well as rates of triple-negative disease, were not different in the 2 groups. In the Spanish EpiGEICAM study, 1017 breast cancer patients were matched to an identical number of control subjects, and dietary patterns were assessed with a 117-item survey. Increasing adherence to a Mediterranean diet, as assessed by the Alternate Mediterranean Diet Score, was associated with a reduced risk of TNBC (OR, 0.80 per standard deviation increase in adherence; 95% CI, 0.65–0.99).⁴⁷ In a meta-analysis of 7 studies, physical activity was associated with a decreased incidence of ER⁻/PR⁻ breast cancer (RR, 0.77; 95% CI, 0.65–0.90), and this risk reduction was greater than that seen for ER-positive tumors.⁴⁸

Recreational substance use has been widely studied in relation to breast health, with theorized risks of cancer due to direct toxicity of carcinogenic metabolites^49,50 or disruptions in hormone metabolism.^51,52 Even light alcohol consumption, consistently defined as ≤12.5 g/d of alcohol, is associated with an increased risk of breast cancer, with a clear dose-response relationship with increasing consumption.^53,54 A pooled analysis of 20 cohort studies found an increased risk of ER⁻PR⁻ cancers with 5 to less than 15 g/d alcohol consumption (RR, 1.18; 95% CI, 1.07–1.30) and even greater risk with higher alcohol consumption (p value for trend, 0.002).⁵⁵ Most data suggest a modestly increased risk of breast cancer in smokers, but studies specifically examining receptor subtypes suggest the increased risk is isolated to ER-positive cancers.^56–58 For example, a study of 73,388 women from the Cancer Prevention Study II Nutrition Cohort demonstrated no increased risk of ER-negative breast cancer in current (hazard ratio, 0.85; 95% CI, 0.53–1.36) or former smokers (hazard ratio, 0.97; 95% CI, 0.78–1.20), whereas risk of ER-positive cancers were elevated in these groups.⁵⁷ One cohort study found no elevated risk of breast cancer in nontobacco smokers who reported 6 or more lifetime usages of marijuana (RR, 0.8; 95% CI, 0.5–1.3); however, no data regarding triple-negative cancers are available, and further study is needed given increasing legalization.⁵⁹ No association is seen between caffeine or coffee exposure and breast cancer, and a meta-analysis of 6 studies found this held true regardless of ER/PR status.⁶⁰

Ethnicity

A multitude of studies demonstrate the racial disparity in the diagnosis of TNBC (Fig. 2), with ORs generally suggesting a 2- or 3-fold increased risk in Black Americans.^{16,18,20,61–65} The impact of ethnicity on aggressive breast cancer subtypes is also captured in worldwide epidemiology data. In the Global Cancer Observatory 2018 report, mortality rates ranged from 15.4 to 18.4 per 100,000 in Africa; mortality was lower in Europe and North America despite incidences double to triple that seen in Africa, suggesting a more aggressive disease phenotype in African patients. Although receptor subtype was not captured in this report, this difference is likely in part due to higher incidence of triple-negative disease, which may be as high as 59% in a Nigerian population.⁶⁶ Indeed, there is significant heterogeneity among different groups of Black women, with the highest rates seen in AA (triple-negative representing 23.7% of cases) and West African women (24.1%), and lower rates seen in East African (11.6%) and Caribbean women (21.2%).⁶⁷ Heritable factors may explain the similar risk in West Africans and AAs, as the latter group features predominantly West African genomic ancestry, perhaps as a result of the transatlantic slave trade.^68,69 However, the increased risk of mortality in Black women is not entirely explained by a higher incidence of triple-negative disease—among triple-negative patients, Black women have an 5-year survival that is 6% lower than other ethnicities.⁸ Even controlling for delay in follow-up or treatment initiation, stage at diagnosis, comorbidities, and socioeconomic factors such as poverty index and education, AA women with TNBC remain at an increased risk of death (hazard ratio, 2.0; 95% CI, 1.0–3.7).⁷⁰

Lifestyle and societal differences may be contributing to the elevated risk in this population. As previously described, in the Carolina Breast Cancer Study, a variety of reproductive and metabolic risk factors were more prevalent in young AA women and also associated with a basal-like IHC expression pattern, including lack of breastfeeding, early menarche, early parity, waist-to-hip ratio, and weight gain since childhood.¹⁶ Although ORs for most reproductive risk factors were adjusted for age and race, the possibility of population-level differences between Black and White patients must be considered—and studies of Nigerian women have suggested parity is protective for breast cancer in general.⁷¹ As described earlier, obesity remains an inconclusive risk of premenopausal triple-negative cancers and has no effect in postmenopausal women—and similar findings are seen in subgroup analyses of Black women.^44,45 However, body fat distribution may have a unique impact in Black women—in the Carolina Breast Cancer study, premenopausal Black women demonstrated an increased risk of ER/PR-negative cancers with a waist-to-hip ratio of 0.84 or greater compared with less than 0.77 (OR, 2.32; 95% CI, 1.26–4.29), whereas the same comparison for White women was not significant.⁷² In a population of Nigerian women, elevated waist-to-hip ratio was associated with both premenopausal and postmenopausal breast cancer; receptor subtypes were not reported, but triple-negative disease predominates in this population.⁷³ It has been proposed that breast density may also contribute to ethnic disparities,⁷⁴ as Black women have an 18% to 65% higher odds of greater breast density as measured via a number of metrics when compared with White women.⁷⁵ However, although breast density is associated with higher rates of cancer, mammographic density is associated with an equally increased risk of both luminal A and basal-like disease.⁷⁶

Regarding other ethnic associations, several case-control studies suggest a similar rate of triple-negative disease among Hispanic and non-Hispanic Whites.^61,62 There is significant heterogeneity within the Hispanic population, with rates of breast cancer varying between Cubans, Puerto Ricans, and Mexicans, and further study is needed to identify groups at high risk of triple-negative cancer.⁷⁷ Asian women, on the other hand, have significantly lower rates of TNBC, but have unique disease kinetics.^61,62 Compared with non-Hispanic Whites, Asians, on average, demonstrate lower rates of premenopausal triple-negative disease, but rates do not decline with increasing age.⁷⁸ Consistent results were seen in the Breast Cancer Etiology in Minorities study, where an increased risk of HR-negative breast cancer was seen in postmenopausal as compared with premenopausal Asian Americans (OR, 1.45; 95% CI, 1.01–2.09).⁷⁹ No protective effect for late menarche was seen for Asian women, and contrary to the aforementioned pooled analyses, they were also the only subgroup to show a protective trend with increasing parity (OR, per full-term pregnancy 0.86; 95% CI, 0.77–0.97).⁷⁹

Genetics

Ethnic predisposition, family history, and genetic underpinnings of cancer are inextricably intertwined. Although family history is clearly associated with breast cancer risk, among all patients with family history of breast cancer in a first-degree relative, the risk of all receptor subtypes is approximately equal.²⁸ An analysis of more than 1 million women from the Breast Cancer Study Group found that even with 2 affected first-degree relatives, or if a relative with breast cancer was diagnosed before age 50 years, the magnitude of risk elevation was similar for ER-positive and triple-negative cancers.⁸⁰

Henry Lynch described the first cases of hereditary breast and ovarian cancer,⁸¹ leading to the subsequent discovery of the BRCA1 gene on chromosome 17q21 by Mary-Claire King.⁸² Nearly 70% of breast cancers in premenopausal BRCA1 carriers are triple-negative,⁸³ and estimated lifetime incidence of a TNBC is 18% in such patients.⁸⁴ These mutations are notably enriched in Ashkenazi Jews, where more than 2% of the population has 1 of 3 founder mutations in BRCA1 and BRCA2. Notably, breast cancer–specific survival is lower for nonmetastatic breast cancer patients with germline BRCA1 (hazard ratio, 1.45; 95% CI, 1.01–2.07) and BRCA2 carriers (hazard ratio, 1.29; 95% CI, 1.03–1.62), but interestingly, the presence of a germline BRCA mutation is a positive prognostic factor for TNBC (hazard ratio for overall survival, 0.49; 95% CI, 0.26–0.92).⁸⁵ This seemingly discordant finding is likely due to the increased incidence of triple-negative cancers in BRCA carriers leading to an inflated mortality rate, but the higher sensitivity to chemotherapy may lead to improved outcomes when compared with the general population of triple-negative patients.

Aside from BRCA mutations, a variety of other hereditary syndromes are found in patients with TNBC (Fig. 3). A comprehensive analysis of pathogenic variants of 21 genes in 10,901 TNBC patients compared with controls identified an increased risk with mutations in PALB2 (OR, 11.05; 95% CI, 8.14–15.09), BARD1 (OR, 7.35; 95% CI, 4.8–11.17), CDKN2A (OR, 7.71; 95% CI, 2.3–24.10), RAD51D (OR, 4.33; 95% CI, 2.19–8.66), MLH1 (OR, 3.37; 95% CI, 1.05–9.64), RAD51C (OR, 2.97; 95% CI, 1.86–4.75), TP53 (OR, 2.51; 95% CI, 1.21–4.98), and BRIP1 (OR, 2.41; 95% CI, 1.52–3.76).⁸⁴ The distribution of subtypes that develop in each hereditary cancer syndrome varies drastically. Several genetic syndromes, aside from BRCA mutations, give rise to a disproportionate number of triple-negative cancers, including BARD1, RAD51C/D, and PALB2. Conversely, some mutations such as CHEK2 are only associated with a risk of HR-positive cancers.^84,86

The disproportionate burden of TNBC in AA women would make a germline susceptibility seem likely, and such a genetic etiology has been uncovered using modern sequencing techniques. The rate of deleterious BRCA mutations in AAs ranges from approximately 1 in 4 for high-risk families to approximately 1% of all those diagnosed with breast cancer.^87,88 In Black women younger than 50 years, the rate of BRCA mutations reaches 12.4% and may be as high as 26% for those diagnosed before age 45 years, underscoring the need for genetic testing in this population.^89,90 Furthermore, in a study of 103 AAs diagnosed with TNBC, 25% were found to have pathogenic BRCA mutations.⁹⁰ It must also be noted that Black women tend to have higher rates of sequence variations or mutations of unknown pathogenicity. Thus, the rates of truly pathogenic mutations may be underestimated because of lack of data in this population or a more subtle impairment of BRCA than is seen with protein truncating mutations, creating an urgent need for diverse ancestral representation in genomic data repositories. Genome-wide association studies may further uncover the drivers of TNBC risk and have identified a TERT gene variant, as well as the single-nucleotide polymorphisms rs8170 and rs13074711 as further potential contributors to HR-negative breast cancer in Black women.^91–93 In particular, rs13074711 may serve as a regulator of the downstream gene TNFSF10, which plays an important role in apoptosis and antitumor immune response, and reduced expression may contribute to the aggressive ER-negative phenotype seen in AA women.⁹³ The future of risk stratification will require a thorough understanding of both clinical risk factors and polygenic risk. In 1 study, combining a polygenic risk score with clinical models such as Gail and Tyrer-Cuzick resulted in 40% of AAs and 20% of Hispanics moving to a higher risk category.⁹⁴

Future Directions

For 2 decades, TNBC has been recognized as the most aggressive subtype of breast cancer, with nearly a quarter of all patients diagnosed dying of the disease within 5 years.⁸ Many risk factors for ER-positive breast cancer also raise the risk of triple-negative disease, including early menarche, late menopause, exogenous hormone use, and alcohol consumption. Parous women are at a lifelong increased risk of triple-negative cancers, whereas obesity is not a clear risk factor, at least in postmenopausal women. Most notable, however, is that triple-negative cancers disproportionately affect Black women and carriers of germline BRCA mutations, contributing to increased incidence of early-onset breast cancer and premature mortality in these patient populations. The patterns of care of AA breast cancer patients amplify the morbidity of TNBC—with longer time to follow-up of abnormal mammography findings⁹⁵ and higher rates of false-positives,⁹⁶ delays in diagnosis and treatment,⁹⁷ and disparities in the use of appropriate adjuvant therapy.^98,99 Reports of inappropriate omission or dose reductions of chemotherapy are especially concerning given the chemosensitivity and high absolute benefit of adjuvant treatment of triple-negative cancers. Removing economic and insurance-based barriers to care, emphasizing culturally competent doctor-patient communication, and instituting effective patient navigation could help mitigate these disparities.¹⁰⁰ Although mammography rates have equalized for Black and White patients,¹⁰¹ the American College of Radiology has recognized Black and Ashkenazi women as at higher risk, recommending risk assessment by age 30 years, which may lead to earlier use of genetic testing and risk-stratified use of MRI for early detection and diagnosis to improve outcomes in these groups.^102–104 Appropriate tools for risk stratification in diverse populations of women will allow for focused intensive screening protocols for high-risk individuals. Risk models specifically developed for Black women can more accurately predict risks of ER-negative cancer and will be essential for identification of patients for high-risk screening programs.^105,106 With the poor mammographic detection and rapid growth of these tumors, novel imaging programs such as biannual dynamic contrast-enhanced MRI may increase the detection of cancers at an early stage in high-risk women.¹⁰³ Given the lethality of TNBC, ensuring that patients are diagnosed early with effective screening and receive appropriate adjuvant therapy could have a dramatic impact on the burden of disease.

Triple-negative breast cancer is molecularly heterogeneous, comprising predominantly basal-like breast cancer but with an increasingly appreciated diversity in gene expression patterns. As registries move toward gene expression–based classification of breast cancer, new patterns may emerge to further explain the disparity within triple-negative disease. With ongoing and ever-increasing clinical information collected for patients, including genomics, histology, radiographic images, and electronic health records, big data techniques may have an increased role in the care of TNBC patients. Automated detection of patients at risk of hereditary cancer syndromes may aid in early detection and screening.¹⁰⁷ Artificial intelligence approaches may identify novel drivers and therapeutic targets in TNBC,¹⁰⁸ and predict latent disease features directly from breast histology.^109,110 Computer-aided detection of mammographic abnormalities is performed with the majority of mammograms¹¹¹—although studies do not reliably suggest improvement in diagnosis, as computer-aided detection continues to evolve it may lead to more equitable outcomes, providing expert precision in community settings where at-risk patients are more likely to get mammography.¹¹² Deep learning models that integrate clinical risk factors and mammographic features may more accurately assess breast cancer risk than traditional clinical models such as Tyrer-Cuzick, as well as provide equitable outcomes in both White and Black patients.¹¹³ As we move to the era of big data in medicine, it will be imperative that data repositories have adequate minority representation, to ensure that conclusions drawn are applicable to all patients.¹¹⁴

Since the importance of triple-negative receptor status was first recognized almost 2 decades ago, our understanding of the genetics and behavior of this disease has grown tremendously, but prognosis remains dismal. To level the playing field, we must integrate genomic predictors of disease derived from diverse datasets and epidemiologic characteristics specific to molecular breast cancer subtypes to provide a personalized risk assessment for each patient. By leveraging our understanding of biology, genetics, and public health, we can begin to provide equitable care to those at higher risk of TNBC through developing and implementing intensive screening programs for early detection.