Her2 status of breast cancer in diverse populations: improving genetic prediction and understanding molecular correlates

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PROJECT SUMMARY Breast cancer is the most common cancer in women and the second leading cause of cancer death in the United States (US). Although women included in the US Census racial/ethnic categories Hispanic/Latina (H/L) and Asian American/Pacific Islander (AA/PI) have relatively low breast cancer incidence compared to non-Hispanic White (NHW) women, multiple studies have reported a higher proportion of human epidermal growth factor receptor positive (HER2+) tumors in these groups (18-30%) compared to NHWs (14-18%). Expression of HER2 is clinically significant because it determines if a patient can receive targeted treatment. HER2+ disease, independent of hormone receptor (HR) status, is also associated with poor outcome compared to the most common HR+ HER2- subtype. The use of European-centric data to predict cancer risk and prognosis in non- Europeans remains a critical barrier for equity in the implementation of precision medicine. Overall, there is a gap in knowledge regarding the genetic factorsand molecular correlates relevant to the etiology of HER2+ breast cancer in diverse populations. Supported by a) our previous work showing a consistent association between Indigenous American ancestry and HER2+ subtypes in H/L breast cancer patients, b) the higher proportion of HER2+ tumors described in AA/PI and Asian populations, c) the closer genetic distance between these populations relative to European groups, and d) promising preliminary data, we hypothesize that germline variants more common in Indigenous American and Asian genomes contribute to the higher risk of HER2 amplification/expression in breast tumors of individuals with these ancestries. To test this hypothesis, we propose to integrate and leverage our own existing studies for a total of 17,049 cases (~4,200 HER2+) and 15,409 controls for discovery, and the NCI’s Confluence Project Data for replication (~600,000 cases and controls combined). Our main goal is to discover germline genetic variants contributing to the higher incidence of HER2+ breast cancer in women of Latin American and Asian heritage. To achieve this goal, we will 1) identify germline variation associated with HER2+ breast cancer in H/L and Asian women and replicate across diverse ancestries, 2) develop, validate, and test trans-ancestry and ancestry-specific polygenic risk scores for HER2+ disease, and 3) identify genes associated with HER2+ breast cancer risk in H/L and Asian women. The results of our study will lead to the discovery of genetic factors contributing to the observed HER2 subtype-ancestry association in women of Indigenous American and Asian ancestry for improved prediction, and provide a better understanding of HER2+ tumor etiology, which could lead to improved precision prevention strategies and the development of new targeted treatments for HER2+ disease.