Development and validation of a model to predict future breast cancer risk after ER-positive and HER2-negative breast cancer.

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10524 Background: Request for bilateral mastectomy after a unilateral breast cancer (BC) diagnosis is increasing. In many cases the benefit of bilateral mastectomy is likely to be small and offset by substantial risks of morbidity, financial toxicity and overburdening of healthcare systems. It is difficult to accurately determine personal risk of developing a future BC. Existing risk prediction models only predict risk for contralateral BC. Australian consumers identified an unmet need for a model that estimates risk of developing BC in any residual breast tissue (ipsi- or contra-laterally); to help women diagnosed with unilateral BC make informed decisions about bilateral mastectomy. Methods: Data from 1,162 female BC cases participating in two Australian cohort studies were used to develop a model to predict risk of BC for women who developed a 1st invasive ER positive, HER2 negative BC after cohort entry or within 2 years prior to cohort entry. Women with a germline pathogenic variant in a BC predisposition gene, and those who received neoadjuvant systemic therapy were excluded. 187 (88 ipsilateral, 96 contralateral, 3 unknown laterality) BC events (161 invasive and 26 DCIS) occurred over a median follow-up of 13.8 years. Flexible parametric survival analysis was used, with time since diagnosis as the time scale, and death due to any cause considered as a competing event. Potential predictors of future BC risk were investigated, including age at 1st BC, age at 1st birth, parity, breastfeeding duration, menopausal hormone therapy use, BMI, number of 1st-degree relatives with BC, BC polygenic risk score (PRS-313), contralateral mammographic density, surgery (breast conservation vs unilateral mastectomy), tumor grade and size, number of positive axillary nodes, associated LCIS, and use of adjuvant chemotherapy or radiation. Retained in the final risk prediction algorithm (all P < 0.05) were age at diagnosis of 1st BC, surgery type, radiation therapy, family history, and PRS-313. For external validation of the model, data from 3,136 cases (eligibility criteria as per the training set) with 181 subsequent BC events participating in the international Breast Cancer Association Consortium were used. Calibration and a time-dependent area under the curve (AUC) at 10 years were assessed to determine model performance. Sensitivity analysis excluding PRS-313 was also performed (as it is usually not available in clinical practice). Results: Discriminatory ability at 10 years was AUC = 0.66 (95% CI 0.62-0.70) or 0.65 (95% CI 0.61-0.69) if PRS-313 was excluded. The model was well calibrated; expected (176 cases) to observed (181 cases) ratio = 0.97 (95% CI 0.84-1.13). Conclusions: This model provides valid estimates of 10-year BC risk after a 1st ER-positive HER2-negative BC and may be useful in collaborative decision-making between patients and their surgeons when considering bilateral mastectomy.

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