The epidemiology of triple-negative breast cancer, including race.
ABSTRACT Predictors of intrinsic breast cancer subtypes, including the triple-negative (TN) subtype, are largely unknown. We evaluated whether anthropometrics, demographics, and reproductive history were associated with distinct breast cancer subtypes.
Invasive breast tumors from a population-based case-control study of 476 (116 black and 360 white) Atlanta women aged 20-54, diagnosed between 1990 and 1992, were centrally reviewed and immunohistochemically analyzed for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2); then grouped [TN (ER-PR-HER2-); ER-PR-HER2+; ER/PR+HER2+; ER/PR+HER2- (case-only reference group)]. Data were from interviews and anthropometric measurements; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression, including both case-only and case-control comparisons.
From the case-only analyses and compared with the ER/PR+HER2- subtype, women with TN tumors were more likely to be obese than normal/underweight [OR = 1.89 (95% CI = 1.22, 2.92)]. Regardless of HER2 status, ER-PR- tumors were associated with black race, young age at first birth, having a recent birth, and being overweight.
Distinct breast cancer subtypes have unique sociodemographic, anthropometric and reproductive characteristics and possibly different pathways for development.
[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Differences in the incidence and outcome of breast cancer among Hispanic women compared with white women are well documented and are likely explained by ethnic differences in genetic composition, lifestyle, or environmental exposures. METHODOLGY/PRINCIPAL FINDINGS: A population-based study was conducted in Galicia, Spain. A total of 510 women diagnosed with operable invasive breast cancer between 1997 and 2010 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. The different breast cancer tumor subtypes were compared on their clinico-pathological characteristics and risk factor profiles, particularly reproductive variables and breastfeeding. Among the 501 breast cancer patients (with known ER and PR receptors), 85% were ER+/PR+ and 15% were ER-&PR-. Among the 405 breast cancer with known ER, PR and HER2 status, 71% were ER+/PR+/HER2- (luminal A), 14% were ER+/PR+/HER2+ (luminal B), 10% were ER-/PR-/HER2- (triple negative breast cancer, TNBC), and 5% were ER-/PR-/HER2+ (non-luminal). A lifetime breastfeeding period equal to or longer than 7 months was less frequent in case patients with TNBC (OR = 0.25, 95% CI = 0.08-0.68) compared to luminal A breast cancers. Both a low (2 or fewer pregnancies) and a high (3-4 pregnancies) number of pregnancies combined with a long breastfeeding period were associated with reduced odds of TNBC compared with luminal A breast cancer, although the association seemed to be slightly more pronounced among women with a low number of pregnancies (OR = 0.09, 95% CI = 0.005-0.54). CONCLUSIONS/SIGNIFICANCE: In case-case analyses with the luminal A cases as the reference group, we observed a lower proportion of TNBC among women who breastfed 7 or more months. The combination of longer breastfeeding duration and lower parity seemed to further reduce the odds of having a TNBC compared to a luminal A breast cancer.PLoS ONE 01/2012; 7(7):e40543. · 4.09 Impact Factor
Article: Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant mice.[show abstract] [hide abstract]
ABSTRACT: Women who carry a BRCA1 mutation typically develop "triple-negative" breast cancers (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor and Her2/neu. In contrast to ER-positive tumors, TNBCs frequently express high levels of epidermal growth factor receptor (EGFR). Previously, we found a disproportionate fraction of progenitor cells in BRCA1 mutation carriers with EGFR overexpression. Here we examine the role of EGFR in mammary epithelial cells (MECs) in the emergence of BRCA1-related tumors and as a potential target for the prevention of TNBC. Cultures of MECs were used to examine EGFR protein levels and promoter activity in response to BRCA1 suppression with inhibitory RNA. EGFR was assessed by immunoblot and immunofluorescence analysis, real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR) and flow cytometry. Binding of epidermal growth factor (EGF) to subpopulations of MECs was examined by Scatchard analysis. The responsiveness of MECs to the EGFR inhibitor erlotinib was assessed in vitro in three-dimensional cultures and in vivo. Mouse mammary tumor virus-Cre recombinase (MMTV-Cre) BRCA1flox/flox p53⁺/⁻ mice were treated daily with erlotinib or vehicle control, and breast cancer-free survival was analyzed using the Kaplan-Meier method. Inhibition of BRCA1 in MECs led to upregulation of EGFR with an inverse correlation of BRCA1 with cellular EGFR protein levels (r² = 0.87) and to an increase in cell surface-expressed EGFR. EGFR upregulation in response to BRCA1 suppression was mediated by transcriptional and posttranslational mechanisms. Aldehyde dehydrogenase 1 (ALDH1)-positive MECs expressed higher levels of EGFR than ALDH1-negative MECs and were expanded two- to threefold in the BRCA1-inhibited MEC population. All MECs were exquisitely sensitive to EGFR inhibition with erlotinib in vitro. EGFR inhibition in MMTV-Cre BRCA1flox/flox p53⁺/⁻ female mice starting at age 3 months increased disease-free survival from 256 days in the controls to 365 days in the erlotinib-treated cohort. We propose that even partial loss of BRCA1 leads to an overall increase in EGFR expression in MECs and to an expansion of the highly EGFR-expressing, ALDH1-positive fraction. Increased EGFR expression may confer a growth advantage to MECs with loss of BRCA1 at the earliest stages of transformation. Employing EGFR inhibition with erlotinib specifically at this premalignant stage was effective in decreasing the incidence of ER-negative breast tumors in this mouse model.Breast cancer research: BCR 03/2011; 13(2):R30. · 5.24 Impact Factor
Article: Parity and lactation in relation to estrogen receptor negative breast cancer in African American women.[show abstract] [hide abstract]
ABSTRACT: Estrogen receptor (ER)-negative breast tumors and progesterone receptor (PR)-negative breast tumors occur more commonly in women of African ancestry. Recent research indicates that the effects of reproductive factors may differ by hormone receptor status. We assessed the relation of parity and lactation to incidence of ER(-)/PR(-) and ER(+)/PR(+) breast cancer in a cohort of African American women. From 1995-2009, 457 incident cases of ER(+)/PR(+) and 318 cases of ER(-)/PR(-) breast cancer were confirmed by review of pathology data among 59,000 African American women followed in the Black Women's Health Study through biennial questionnaires. HRs and two-sided 95% CIs for the incidence of breast cancer subtypes were derived from proportional hazards regression models that controlled for age, reproductive variables, and breast cancer risk factors. Higher parity was associated with an increased risk of ER(-)/PR(-) breast cancer (HR = 1.48, 95% CI: 0.98-1.84 for 3+ versus 0 births, P(trend) = 0.009), and with a reduced risk of ER(+)/PR(+) cancer (HR = 0.53, 95% CI: 0.39-0.73 for 3+ versus 0 births, P(trend) = 0.0002). Among women who had breastfed, high parity was no longer associated with increased incidence of ER(-)/PR(-) breast, but the inverse association with ER(+)/PR(+) cancer persisted. The higher incidence of ER(-)/PR(-) breast cancer in African American women may be explained in part by their higher parity and lower prevalence of breastfeeding relative to white women. Increased breastfeeding may lead to a reduction in the incidence of this breast cancer subtype.Cancer Epidemiology Biomarkers & Prevention 08/2011; 20(9):1883-91. · 4.12 Impact Factor