Comprehensive genomic profiling of Taiwanese triple-negative breast cancer with a large targeted sequencing panel

Breast cancer is a leading cause of cancer-related deaths in women, particularly those with the triple-negative (TN) phenotype. Although novel therapeutic options are emerging, most are biomarker-driven. This study used comprehensive genomic profiling (CGP) via targeted sequencing to identify actionable alterations in a TN subcohort of the VGH-TAYLOR study.

The study included patients with either early-stage (defined by first-line surgery or neoadjuvant therapy) or late-stage (defined by relapse or de novo metastatic disease) breast cancer. CGP was performed using the Illumina TruSight Oncology 500 assay. The level of actionability was assessed using the European Society for Medical Oncology (ESMO) Scale of Clinical Actionability of Molecular Targets (ESCAT) criteria, with additional annotations provided by the PierianDx software and OncoKB database.

CGP was successfully performed on 104 TN breast cancer samples. The most common actionable genes (occurring in >10% of cases) were PIK3CA (38%), BRCA2 (25%), PTEN (13%), BRCA1 (13%), ERBB2 (12%), and ERBB3 (11%). After applying a stringent per-variant filter, these frequencies were reduced to 22%, 6%, 5%, 4%, 4%, and 1% for PIK3CA , PTEN , BRCA2 , BRCA1 , AKT1 , and PALB2 , respectively. Based on the standard cut-off of 10 mutations/megabase, 24 samples were classified as tumor mutation burden (TMB)-high, whereas 80 were TMB-low. The proportion of TMB-high cases was lower among the early-stage patients compared to the late-stage patients (19% vs 36%; p < 0.05).

This study demonstrates the clinical feasibility and utility of large-scale CGP, enabling the investigation of a broad range of genes and multi-gene signatures, such as TMB and microsatellite instability (MSI). The identification of actionable biomarkers offers the potential to expand therapeutic opportunities for TN breast cancer patients.