ESR1 and ESR2 polymorphisms in BIG 1−98 comparing adjuvant letrozole (L) versus tamoxifen (T) or their sequence for early breast cancer.

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1002 Background: Polymorphisms of ERα and ERβ have been associated with multiple endocrine-mediated physiological mechanisms, including lipid profile, mammographic density, VTE and cognition, and inconsistently with breast cancer risk and BMD changes. We investigated if SNPs in ESR1 and ESR2 genes predict outcome and side effects of adjuvant endocrine therapies. Methods: BIG 1−98 compared adjuvant hormonal therapies in 8010 postmenopausal pts with operable, ER-positive breast cancer: 5 yrs of T; 5 yrs of L; 2 yrs T followed by 3 yrs L (TL); and the reverse (LT). DNA was isolated from FFPE primary tumor specimens. The analytic cohort was 3303 (of 3685 with DNA) pts genotyped for 8 SNPs of ESR1 and ESR2 using SNPstream; 4 were successful {ESR1: rs9340799 (XbaI), rs2077647, rs11963577; ESR2 rs4986938} and PvuII is being rerun on Taqman. Cox models tested for association of ESR1+2 variants with breast cancer-free interval (BCFI), adverse bone events (grade 3−5 osteoporosis or bone fracture), and for genotype-by-treatment interaction. With 10% BCFI events, 40% variant prevalence there was 80% power to detect HR=1.50 (alpha=0.05). 8% of pts had bone events. Results: Rare homozygotes of XbaI, rs2077647 and ESR2 were associated with higher Ki-67 expression but not other disease features (each P≤0.05). Presence of ≥1 rare variant allele in XbaI, rs2077647 and ESR2 tended to have reduced hazard of BCFI vs wt after adjusting for disease features (HR=0.81, 95% CI (.64−1.02); 0.77 (.59−1.01); 0.83 (.63−1.09)). Treatment-by-genotype interactions were not significant. For bone events, T pts with rare Xbal homozygotes had increased hazard vs wt and het, whereas L pts had decreased hazard (P=.07 interaction). Rare rs2077647 homozygotes had increased hazard in L and T pts (HR=1.52 (1.08−2.13)) vs wt and het. Conclusions: In this large postmenopausal breast cancer population treated with endocrine therapy, we paradoxically observed that rare ESR1 homozygous polymorphisms were associated with 1) lower recurrence, but also with high Ki−67, a poor prognostic feature and 2) higher risk of bone side effects, which possibly differ by treatment. The final analysis will include longer follow-up and PvuII results.