39. Associations between somatically altered genes and recurrence outcomes in estrogen receptor positive breast cancer

Abstract

The relationships between somatic mutations, copy number alterations (CNA) and outcomes in estrogen receptor positive (ER+) breast cancer is understudied. We have earlier published associations between rare and low frequency mutations and clinical outcomes in ER+ disease (PMID:30181556). As an extension of the study, FFPE blocks were obtained from 889 additional patients from the TransATAC study, an Anastrozole (A) or Tamoxifen (T) alone or combined randomized trial with 10-year follow-up. Tumor samples were reviewed, DNA isolated, and targeted sequencing performed for 83 genes. Mutation calling methods were previously reported. Average Copy number (CN) ratios were estimated for 875 tumors and 94 unmatched normal breast tissues using CNVkit. 841 samples met minimum quality and coverage criteria. For a given gene, gains and losses were defined as tumor CN-ratio above or below 95% confidence-interval of the distribution of normal CN-ratios. Hazard ratio was calculate for recurrence free survival (RFS) for somatically altered genes. TP53 mutations was one of the most important prognostic markers in this cohort. Non-silent mutations in ATM, ERBB3, ERBB4, KMT2C and NF1 associated with poor RFS. Co-deletion and co-amplification of genes respectively on chromosomal region 1p (MAGI3, JAK1, ARID1A, MTOR) and 20q13 (MYBL2, NCOA3, AURKA) associated with poor RFS. Deletion of FZD7 and PPP2R2A and amplification of MAP3K4, MAP3K13, LYN and BRAF associated with poor RFS. In summary, we present the prognostic role of multiple recurrently altered genes and their association with poor RFS in ER+ breast cancer. This warrants further investigation within clinical subtypes and treatment-specific sub-populations.