Association of germline polygenic risk for thyroid autoimmunity with overall survival in the I-SPY2 Trial.

Kirkpatrick B Fergus Department of Surgery, University of California, San Francisco, San Francisco, CA info_outline Kirkpatrick B Fergus, Pooja Middha, Zoe Quandt, Yiwey Shieh, Amrita B Basu, Rosalyn Sayaman, Paula R Pohlmann, Douglas Yee, Rebecca Arielle Shatsky, Claudine Isaacs, Michael J. Campbell, Gillian L. Hirst, Lamorna Brown Swigart, Laura van 't Veer, Elad Ziv, Laura Esserman

Authors Kirkpatrick B Fergus Department of Surgery, University of California, San Francisco, San Francisco, CA info_outline Kirkpatrick B Fergus, Pooja Middha, Zoe Quandt, Yiwey Shieh, Amrita B Basu, Rosalyn Sayaman, Paula R Pohlmann, Douglas Yee, Rebecca Arielle Shatsky, Claudine Isaacs, Michael J. Campbell, Gillian L. Hirst, Lamorna Brown Swigart, Laura van 't Veer, Elad Ziv, Laura Esserman Organizations Department of Surgery, University of California, San Francisco, San Francisco, CA, Department of Medicine, University of California, San Francisco, San Francisco, CA, University of California, San Francisco, Division of Endocrinology, San Francisco, CA, Weill Cornell Medicine Department of Population Health Sciences, New York, NY, University of California, San Francisco Department of Surgery, San Francisco, CA, University of California, San Francisco, San Francisco, CA, The University of Texas MD Anderson Cancer Center, Houston, TX, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, University of California, San Diego Medical Center, La Jolla, CA, Lombardi Cancer Center, Georgetown University, Washington, DC, UCSF Comprehensive Cancer Center, San Francisco, CA, Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, University of California, San Francisco Department of Medicine, San Francisco, CA Abstract Disclosures Research Funding Conquer Cancer, the ASCO Foundation U.S. National Institutes of Health Background: Germline genetic variation influences immune activity and risk of autoimmunity, and has been hypothesized to play a role in response to cancer therapeutics and survival. Prior studies of breast cancer have reported associations between genetic variation in thyroid autoimmunity and overall survival (OS). Here, we aim to investigate the association between a polygenic risk score for hypothyroidism (PRS-H) and response to therapy in women with early-stage breast cancer, and hypothesize that high PRS-H will be associated with better treatment response and survival. Methods: This study includes 1,368 women aged 18 years and above with stage II-III breast cancer of size > 2.5cm by clinical exam, with germline data available. It is an approved biomarker analysis of the I-SPY 2 trial, which is a phase II, adaptive, randomized platform trial across multiple sites studying novel cancer therapeutics across multiple arms for use as neoadjuvant chemotherapy for early-stage breast cancer. The outcome of survival is defined as alive at the most recent follow-up. Using the Cox proportional hazards model, we evaluate the association between a previously published PRS-H and overall survival. Models are adjusted for age at screening, immunotherapy status, and five principal components. Results: Among 1,368 early-stage breast cancer women, 33% (n=447) had pCR, and 85% (n=1,157) were alive at the last follow-up. Additionally, 16% (n=219) of women received immunotherapy. We observe a significant association between PRS-H and OS (HR = 0.78, 95% CI 0.66-0.92, p=0.004). Individuals in the top 10th percentile of the PRS-H (highest genetic risk) have improved survival (log rank p=0.04). Conclusions: Germline genetic variation in thyroid autoimmunity proclivity is associated with improved overall survival in our cohort of women with early-stage breast cancer receiving neoadjuvant chemotherapy. Our findings suggest that the genetic risk for autoimmunity may be important for long-term survival. We will expand this analysis to include the entire I SPY 2 population when all patients have completed genotyping. We plan to further characterize the role of germline autoimmunity profiles and survival. Clinical trial information: NCT01042379.

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