Association Between Benign Breast Disease in African American and White American Women and Subsequent Triple-Negative Breast Cancer

Key Points

Question  Does race/ethnicity affect breast cancer risk among women with benign breast disease?

Findings  A review of a cohort comprising 2588 African American (AA) women and 3566 white American (WA) women with biopsy-proven benign breast disease revealed subsequent ductal carcinoma in situ in 30 (1.18%) AA patients and 30 (0.85%) WA patients and subsequent invasive cancer in 73 (2.8%) AA patients and in 111 (3.1%) WA patients. Of the subsequent invasive cancers, triple-negative breast cancer was more common among AA members than among WA members of the cohort (16 [24.2%] vs 7 [7.4%], respectively).

Meaning  African American identity is a risk factor for triple-negative breast cancer among women with benign breast disease.

Importance  Compared with white American (WA) women, African American (AA) women have a 2-fold higher incidence of breast cancers that are negative for estrogen receptor, progesterone receptor, and ERBB2 (triple-negative breast cancer [TNBC]). Triple-negative breast cancer, compared with non-TNBC, likely arises from different pathogenetic pathways, and benign breast disease (BBD) predicts future non-TNBC.

Objective  To determine whether AA identity remains associated with TNBC for women with a prior diagnosis of BBD.

Design, Setting, and Participants  This study is a retrospective analysis of data of a cohort of 2588 AA and 3566 WA women aged between 40 and 70 years with a biopsy-proven BBD diagnosis. The data—obtained from the Pathology Information System of Henry Ford Health System (HFHS), an integrated multihospital and multispecialty health care system headquartered in Detroit, Michigan—include specimens of biopsies performed between January 1, 1994, and December 31, 2005. Data analysis was performed from November 1, 2015, to June 15, 2016.

Main Outcomes and Measures  Subsequent breast cancer was stratified on the basis of combinations of hormone receptor and ERBB2 expression.

Results  Case management, follow-up, and outcomes received or obtained by our cohort of 2588 AA and 3566 WA patients were similar, demonstrating that HFHS delivered care equitably. Subsequent breast cancers developed in 103 (4.1%) of AA patients (mean follow-up interval of 6.8 years) and 143 (4.0%) of WA patients (mean follow-up interval of 6.1 years). More than three-quarters of subsequent breast cancers in each subset were ductal carcinoma in situ or stage I. The 10-year probability estimate for developing TNBC was 0.56% (95% CI, 0.32%-1.0%) for AA patients and 0.25% (95% CI, 0.12%-0.53%) for WA patients. Among the 66 AA patients who developed subsequent invasive breast cancer, 16 (24.2%) developed TNBC compared with 7 (7.4%) of the 94 WA patients who developed subsequent invasive breast cancers and had complete biomarker data (P = .01).

Conclusions and Relevance  This study is the largest analysis to date of TNBC in the context of racial/ethnic identity and BBD as risk factors. The study found that AA identity persisted as a significant risk factor for TNBC. This finding suggests that AA identity is associated with inherent susceptibility for TNBC pathogenetic pathways.

Incidence of triple-negative breast cancer (TNBC), which is negative for the estrogen receptor (ER), the progesterone receptor (PR), and ERBB2, is 2-fold higher in African American (AA) women than in white American (WA) women.¹

Most TNBC belongs to the inherently aggressive basal subtype and arises from different pathogenetic pathways compared to non-TNBC.^2,3 Benign breast disease (BBD) is associated with increased risk for ER-positive/non-TNBC.^4,5 In this study, we sought to determine whether AA identity is associated with TNBC among a cohort of AA and WA women who were initially diagnosed with BBD.

From January 1 through December 31, 2013, we queried the HFHS Pathology Information System to identify AA and WA women patients aged 40 to 70 years who were diagnosed with BBD by biopsy performed between January 1, 1994, and December 31, 2005. Patients with prior breast cancer were excluded. Patients whose breast cancer was diagnosed within 6 months of BBD biopsy were excluded to avoid including cases of coexisting BBD and cancer.

Self-reported race/ethnic identity, date of birth, and follow-up were obtained from electronic medical records at HFHS. Invasive carcinoma or ductal carcinoma in situ detected during follow-up was recorded as subsequent cancer.

An automated Dako immunostainer was used for ER/PR staining. ERBB2 immunostaining was performed using HercepTest (Dako). Immunohistochemistry complied with established guidelines.^6,7 Briefly, tumors with less than 1% nuclear staining were scored as ER/PR-negative. ERBB2 grading (0-3+) was based on the extent of membranous staining: 0 or 1+ was negative; 3+ was positive. Tumors with 2+ staining underwent fluorescent in situ hybridization. Benign breast disease was classified as fibrocystic/proliferative/hyperplasia without atypia, with atypia, or with lobular carcinoma in situ.

Distributions of clinicopathologic variables between AA and WA patients were compared using t test, Mantel-Haenszel test, or Wilcoxon rank sum test. Polychotomous multivariable logistic regression evaluated features that are associated with TNBC. Kaplan-Meier methods generated estimates of breast cancer incidence with log-rank P values. All statistical tests were 2-sided, and analyses were performed using SAS, version 9.3 (SAS Institute Inc), and known biomarker data.

The Henry Ford Health System (HFHS) Institutional Review Board approved this research, with informed-consent exemption. Data analysis was performed from November 1, 2015, to June 15, 2016.

The study cohort included 2588 AA patients and 3566 WA patients. Mean age at BBD diagnosis was similar: 51.7 years for AA patients and 52.1 years for WA patients (P = .07). Mean follow-up was also similar: 10.3 years for AA patients and 10.2 years for WA patients. (There was no follow-up for 36 [1.4%] AA patients and 40 [1.1%] WA patients.) Benign breast disease biopsies evaluated screening mammography abnormalities in 2019 (78.0%) AA patients and 2800 (78.5%) WA patients; 555 (21.4%) AA patients and 748 (21.0%) WA patients underwent biopsy for clinical findings (P = .47). More than 90% of each subset had hyperplasia without atypia (2438 [94.2%] in AA patients and 3283 [92.1%] in WA patients). Atypia was more common among WA patients than among AA patients (283 [7.9%] vs 150 [5.8%], respectively; P = .001). Three (0.1%) patients in each subset had lobular carcinoma in situ.

Thirty (1.18%) AA patients and 30 (0.85%) WA patients were diagnosed with subsequent ductal carcinoma in situ (P = .26) at mean ages of 58.4 years and 61.8 years, respectively (P = .16) and at mean follow-up of 6.5 years and 6.1 years, respectively (P = .64). The ER was positive in 86.4% of AA ductal carcinoma in situ cases and 88.9% of WA ductal carcinoma in situ cases (P = .81). The PR was positive in 77.3% of AA ductal carcinoma in situ cases and 77.8% of WA ductal carcinoma in situ cases (P = .97).

Subsequent invasive breast cancer was diagnosed in 73 (2.8%) AA patients and 111 (3.1%) WA patients (P = .58) at similar follow-up intervals and mean ages (Table 1). Approximately half of each subset was diagnosed with stage I disease. Triple-negative breast cancer was detected in 3 times as many AA patients as in WA patients (16 [24.2%] vs 7 [7.4%], respectively; P = .01) with subsequent invasive breast cancer (Table 2).

Polychotomous logistic regression (performed on 157 cohort members who developed subsequent breast cancer) revealed that AA identity and high-grade disease were the 2 statistically significant features associated with TNBC. African American identity remained significantly associated with TNBC after adjusting for tumor grade. Among those who developed invasive breast cancer, the odds of TNBC vs ER/PR-positive/HER2-negative was 4.34 times (95% CI, 1.28-14.68; P = .02) higher in AA patients than in WA patients.

Kaplan-Meier risk estimates are shown in the Figure. There were no significant differences between AA patients and WA patients when all phenotypes were grouped together (log-rank P = .45), with an estimated 10-year incidence of 2.5% (95% CI, 1.9%-3.2%) and 3.2% (95% CI, 2.6%-4.0%), respectively. Most subsequent invasive breast cancers were non-TNBC for both AA and WA patients; however, risk of subsequent TNBC was significantly higher for AA patients than for WA patients (log-rank P = .004), and risk of subsequent non-TNBC was higher for WA patients than for AA patients (log-rank P = .048). Ten-year estimates for incidence of TNBC were 0.56% (95% CI, 0.32%-1.0%) and 0.25% (95% CI, 0.12%-0.53%) for AA patients and WA patients, respectively. Ten-year estimates for incidence of non-TNBC were 1.76% (95% CI, 1.27%-2.43%) and 2.85% (95% CI, 2.30%-3.55%) for AA patients and WA patients, respectively.

Triple-negative breast cancer has become a surrogate for the aggressive basal breast cancer subtype in clinical practice,² is a marker of hereditary breast cancer susceptibility, is more common among AA women, and has different risk factors. Multiple pregnancies, for example, reduce the likelihood of developing ER-positive breast cancer, but multiparity appears to increase the risk of TNBC.²

Benign breast disease that results in multiple biopsies is a well-established breast cancer risk factor and is a key element of the Gail individualized breast cancer risk-assessment model.⁸ Benign breast disease without atypia approximately doubles breast cancer risk.⁹ Histopathologic indices of abnormal proliferation confer higher risks: 4- to 5-fold relative risk for atypia and 10-fold relative risk for lobular carcinoma in situ.^9-11 Several studies have confirmed that BBD is a breast cancer risk factor in both AA and WA women.^12,13

Until recently, studies that correlate BBD with breast cancer risk grouped all phenotypes together. Insights regarding the diversity of breast cancer prompted scrutiny of BBD and phenotype-stratified risk. One model of breast cancer pathogenesis suggests that fibrocystic proliferative changes are precursors for relatively more indolent patterns, including ER-positive disease.³ The Mayo Clinic BBD cohort demonstrated that 84% of 1273 cancers detected among more than 13 000 BBD cases were ER-positive.⁴ Similarly, the Cancer and Steroid Hormone Study found that BBD was associated with increased risk for luminal A breast cancer but not hormone receptor–negative or TNBC disease.⁵

The etiology of the association between TNBC and AA identity is poorly understood, but environmental, reproductive, and genetic factors have been proposed.¹⁴ The contribution of germline genetic factors is supported by studies that demonstrated an increased frequency of TNBC among western sub-Saharan African women, a population likely to have shared ancestry with AA women as a consequence of the colonial transatlantic slave trade.^14,15

Although the majority of cancers that developed in our cohort of AA and WA patients with BBD were ER positive, AA identity was a statistically significant risk factor for TNBC. This finding suggests that African ancestry is not only associated with a woman’s inherent susceptibility for pathways to developing TNBC but also relevant in discussions of chemoprevention.

As an integrated health care system, HFHS is well suited to study breast cancer disparities because it comprises multiple facilities and hospitals that provide care to large indigent as well as affluent populations in diverse communities of metropolitan Detroit and southeast Michigan; it also offers a robust employee-based insurance plan (Health Alliance Plan). Our study revealed that HFHS’s AA and WA patients with BBD received or obtained similar care management, follow-up, and outcomes, providing evidence that the health care system delivers equitable quality of care.

To our knowledge, this study is the largest report on TNBC in the context of racial/ethnic identity and BBD as risk factors. We acknowledge the limitation of self-reported race/ethnicity; future research will attempt to account for admixture and risk factors, such as obesity and family history. We hope that our observations will be reevaluated in other communities.

Accepted for Publication: September 29, 2016.

Corresponding Author: Lisa A. Newman, MD, MPH, Breast Oncology Program, Department of Surgery, International Center for the Study of Breast Cancer Subtypes, Henry Ford Health System, 2799 W Grand Blvd, Detroit, MI 48202 (lnewman1@hfhs.org).

Published Online: December 22, 2016. doi:10.1001/jamaoncol.2016.5598

Author Contributions: Drs Newman and Stark had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Newman, Stark, Chitale, Pepe, Worsham, Nathanson, Miller, Patriotis, Engstrom.

Acquisition, analysis, or interpretation of data: Newman, Stark, Chitale, Pepe, Longton, Worsham, Nathanson, Miller, Bensenhaver, Proctor, Swain, Engstrom.

Drafting of the manuscript: Newman, Stark, Worsham.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Newman, Stark, Pepe, Longton.

Administrative, technical, or material support: Newman, Stark, Chitale, Nathanson, Miller, Proctor, Patriotis, Engstrom.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by the National Institutes of Health/National Cancer Institute’s Early Detection Research Network (EDRN): Clinical Validation Center grant CA113916 and EDRN: Data Management and Coordinating Center grant CA86368 and by the Henry Ford Health System Research Fund. Drs Stark, Chitale, and Engstrom were supported by EDRN: Clinical Validation Center grant CA113916 (principal investigator: Dr Engstrom). Mr Longton and Dr Pepe were supported by EDRN: Data Management and Coordinating Center grant CA86368 (principal investigator: Dr Pepe). Drs Newman, Worsham, Nathanson, Miller, Bensenhaver, Proctor, and Swain were supported by the Henry Ford Health System Research Fund. No other disclosures were reported.

Role of the Funder/Sponsor: Funds from EDRN: Clinical Validation Center grant CA113916 were applied to the design and implementation (data collection and management) of the study. Funds from EDRN: Clinical Validation Center grant CA113916 and EDRN: Data Management and Coordinating Center grant CA86368 were applied to the conduct of statistical analyses, data interpretation, and results interpretation. Preparation, review, and approval of this manuscript were supported by funds from the Henry Ford Health System Research Fund and from the EDRN: Clinical Validation Center grant CA113916 and EDRN: Data Management and Coordinating Center grant CA86368. The funding sources had no role in the decision to submit the manuscript for publication.