Abstract 620: Evaluating multiple tumor markers in a novel analysis of reproductive factors and breast cancer risk
Authors: Jung Audrey Y. , Ahearn Thomas U. , Behrens Sabine , Zhang Haoyu , Middha Pooja , Schmidt Marjanka , Chatterjee Nilanjan , Garcia-Closas Montserrat , Chang-Claude Jenny ,   on behalf of the Breast Cancer Association Consortium
Published: August 2019

Abstract
Background: Reproductive factors are reported to be differentially associated with risk of breast cancer (BC) subtypes; however, subtype defining markers are highly correlated and clarifying which markers are sources of heterogeneity is challenging. We aimed to define the association of parity, age at first full-term pregnancy (AFFTP), and breastfeeding duration (BFD) with BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), the human epidermal growth factor receptor 2 (HER2), and grade, and to identify which tumor markers are heterogeneity sources.
Methods: We included 56,545 cases and 65,332 controls from 33 population-based studies in the Breast Cancer Association Consortium. A standard polytomous logistic regression with parity (nulliparous (ref), 1, 2, 3, ≥4), AFFTP (&lt;20 years (ref), 20-&lt;25, 25-&lt;30, ≥30), BFD (0 months (ref), &gt;0-6, &gt;6-12, &gt;12-24, &gt;24), age and study was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) with BC subtypes. Subtypes were defined by in situ and invasive intrinsic-like subtypes: luminal A (HR+, HER2-, grade 1&2), luminal B-HER2- (HR+, HER2-, grade 3), luminal B-HER2+ (HR+, HER2+), HER2-enriched (HR-, HER2+) and triple-negative (TN; HR-, HER2-). We used a two-stage polytomous logistic regression to evaluate heterogeneity sources among ER, PR, HER2, grade, and TN specific associations, adjusting for each other and accounting for missing tumor marker data.
Results: Luminal A and TN risk patterns were most distinct. Luminal A risk was inversely associated with parity (OR (95%CI): 0.81 (0.73-0.91), 0.71 (0.64-0.79), 0.64 (0.58-0.72), and 0.53 (0.47-0.59), for 1, 2, 3, ≥4 livebirths, respectively), positively associated with later AFTTP (1.00 (0.93-1.08), 1.14 (1.05-1.23), and 1.36 (1.25-1.49) for 20-&lt;25, 25-&lt;30, ≥30 years, respectively) in parous women, but not associated with BFD. In contrast, parous women had a higher TN risk attenuating with more livebirths: 1.38 (1.15-1.65), 1.26 (1.06-1.49), 1.16 (0.97-1.38), and 1.02 (0.84-1.22) for 1, 2, 3, ≥4 livebirths, respectively. TN risk was also inversely associated with late AFFTP (0.92 (0.82-1.03), 0.86 (0.76-0.98), 0.81 (0.69-0.94) for 20-&lt;25, 25-&lt;30, ≥30 years, respectively) as well as with longer BFD (0.93 (0.83-1.04), 0.76 (0.66-0.88), 0.8 (0.68-0.93), and 0.79 (0.64-0.96) for &gt;0-6, &gt;6-12, &gt;12-24, &gt;24 months, respectively). Risk patterns for the other intrinsic-like subtypes and in situ were most like luminal A. Notable sources of heterogeneity for parity and BFD was TN vs non-TN (Phet=0.003 and Phet=0.005, respectively) and for AFFTP were ER (Phet&lt;0.001) and HER2 (Phet=0.003), while grade was not an important source of heterogeneity after accounting for ER, PR, and HER2.
Conclusion: We found strong evidence of strong heterogeneity among parity, AFFTP, and BFD with BC subtypes with distinct patterns of associations for TN vs luminal A and other tumor subtypes.
Citation Format: Audrey Y. Jung, Thomas U. Ahearn, Sabine Behrens, Haoyu Zhang, Pooja Middha, Marjanka Schmidt, Nilanjan Chatterjee, Montserrat Garcia-Closas, Jenny Chang-Claude, on behalf of the Breast Cancer Association Consortium. Evaluating multiple tumor markers in a novel analysis of reproductive factors and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 620.