Hereditary Breast Cancer as a Model of Familial Cancer in Asia: From Genes to Personalized Therapy and Prevention of Breast Cancer

Abstract

Considering individual’s genetic background and characteristics of the tumors with the advances in genetic profiling from next generation sequencing, this enhances the understanding of the intra- and inter-tumor heterogeneity to facilitate a personalized therapeutic management of breast cancer patient. However, the major challenges are the interpretation and genetic counseling of the test results and the lack of actionable drugs even when inherited gene mutations are found which are of lower penetrance and rare. Moreover, there is a complete lack of study and knowledge in Asians to date. Therefore, we sought to dissect the mutational profile in Chinese HBOC patients by NGS, which may offer a personalized treatment strategy for these patients. In local Chinese cohort, with over 2750 breast and ovarian cancer patients, the overall BRCA mutation frequency is 9.4%. Other susceptibility genes, such as PALB2 and RAD51D, contributed to 2.15%. Recently, RECQL, a high penetrance breast cancer susceptibility gene, has been reported in Canada and Poland with European ancestry. Notably, we discovered a different RECQL mutation spectrum in Chinese. These variations in mutation spectrum suggested the importance of implementing ethnic-specific multigene panels. On the other hand, we identified 51 pathogenic or likely pathogenic somatic variants from 81 tumors in patients who tested germline negative. Of which, the most frequently mutated genes in this patient cohort were PIK3CA (26%) and TP53 (13.7%). These provide useful information to identify actionable drugs which may represent a personalized treatment for patients with no BRCA mutation.