Fasching, Peter A.

Abstract Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. Cancer Res; 71(19); 6240–9. ©2011 AACR.

Abstract Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3–2.2, P = 2.0 × 10−5) and with overall variation in HGF (gene-level test, P = 3.7 × 10−4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r2 = 0.96 with rs1800793): TCGA HR = 2.4, CI = 1.4–4.1, P = 2.2 × 10−3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3–1.9, P = 7.0 × 10−5] and suggested genotype correlation with reduced HGF mRNA levels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9–1.1, P = 0.87). Conclusions: We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies. Cancer Epidemiol Biomarkers Prev; 20(8); 1638–48. ©2011 AACR.

Abstract Epidemiologic studies suggest that breast cancer risk factor associations vary by tumor marker expression; however, individual studies have had limited power to address this question. We pooled data from up to 35,568 invasive breast cancer cases from 34 studies participating in the Breast Cancer Association Consortium (BCAC) to evaluate associations between established risk factors (age at menarche, nulliparity, age at first full time birth [AFFTB], body mass index [BMI] and family history) and breast cancer subtypes, defined by immunohistochemical expression of ER, PR, HER2, and basal markers (CK5/6 or CK5, EGFR). We used polychotomous logistic regression to evaluate relationships between risk factors and tumor subtypes in case-only analyses and to estimate case-control odds ratios and 95% confidence intervals for the associations between risk factors and specific tumor subtypes in 11 population-based studies including up to 12,841 cases and 17,032 controls. In case-only analyses, we found that reproductive risk factors were more common in hormone receptor positive tumors: early age at menarche was most strongly related to PR status (34.6% vs. 32.4% of women with age at menarche ≤12 years among PR+ and PR- cases, respectively, P= 0.001); whereas nulliparity, and late AFFTB in parous women were most strongly related to ER status (15.3% vs. 13.6% nulliparous women, 17.1% vs. 15.2% women with late AFFTB [≥30 years], among ER+ and ER- cases, respectively, P=2.6×10−6 for nulliparity and P=2.0×10−7 for late AFFTB). Nulliparity and late AFFTB were less common among triple negative (TN) tumors overall and among TN tumors expressing basal markers. Elevated BMI in women aged 50 years or younger was more common in ER-&PR- than ER+&PR+ tumors (17.0% vs 13.6% women with BMI ≥30, respectively, P=1.3×10−7), whereas above age 50 years, elevated BMI was more common in ER+&PR+ than ER+&PR- tumors (20.9% vs 16.7% women with BMI ≥30, respectively, P=2.8×10−8 comparing BMI ≥30 to BMI <25). In case-control analyses, early age at menarche was associated with increased risk of PR+ tumors; nulliparity and late AFFTB were most strongly associated with increased risk of (ER+ or PR+)&HER2- tumors, and did not increase the risk of TN tumors. Having a family history of breast cancer increased the risk of all tumor subtypes, although the association was strongest for TN tumors expressing basal markers. Our data provide convincing evidence for etiological heterogeneity with respect to breast cancer risk factors stratified by ER and PR status. Stratification by additional markers provides additional insights about etiologic differences in breast cancer risk. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 870.

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)