300P Mutational patterns across breast cancer subtypes during metastatic disease progression

Abstract

Treatment options for metastatic breast cancer include endocrine therapies for hormone receptor positive (HR+) patients, Herceptin therapy for Her2+ patients and chemotherapy for TNBC (triple negative breast cancer) patients. While temporarily effective, these treatments are all undermined by the eventual emergence of resistance. We have used NGS-based liquid biopsy to profile genomic alterations in HR+, Her2+ and TNBC metastatic breast cancer patients during disease progression following first-line treatment, and report the emergence of distinct mutational patterns across clinical subtypes. Blood samples from 159 metastatic breast cancer patients were collected at baseline prior to first-line treatment at the Beijing Cancer Hospital. Additional samples were collected from a subset of 31 patients at the time of disease progression. A targeted NGS-based liquid biopsy assay (PredicineCARE™) was used to profile somatic mutations and copy number variations across 152 genes in circulating tumor DNA. The most frequently detected alterations across all patients at baseline were TP53 (44%), PIK3CA (28%) and ERBB2 (25%). Across subtypes, Her2+ patients harbored a higher frequency of ERBB2 amplifications (70%) compared to HR+ (0%) (p = 1.1E-15) and TNBC patients (3%) (p = 3.5E-11), as well as a higher frequency of TP53 alterations (64%) compared to HR+ (31%) patients (p = 0.004). To survey the emergence of new alterations during metastatic progression across clinical subtypes, profiles were also generated at the time of disease progression. New alterations were detected in 7/11 (64%) HR+, 0/8 (0%) Her2+ and 2/12 (17%) TNBC patients at progression (p = 0.006). New variants in the HR+ group included ESR1, TP53, PIK3CA, CDKN2A, FGFR1, ERBB2, and PTEN alterations. HR+ patients treated with endocrine therapies exhibited a much higher frequency and diversity of ctDNA-based alterations at the time of disease progression relative to HER2+ and TNBC patients receiving Herceptin and chemotherapy treatments, respectively. These patterns underscore the powerful selective pressure exerted by endocrine therapies, resulting in distinct resistance mechanisms.