Abstract
Background
Breast cancer is one of the leading causes of cancer-related deaths in women. Limited therapeutic options currently available, especially for those with triple negative breast cancer, demands identification of more biomarkers to facilitate precision medicine. This study adopted an updated large comprehensive genomic profiling (CGP) for targeted sequencing to reveal actionable alterations associated with novel therapeutics from a sub-cohort of the VGH-TARLOR study.
Method
The study population comprised of patients with either early (defined by first-line surgery or neoadjuvant therapy) or late (defined by relapse or de novo metastatic disease) breast cancer. CGP was conducted with the Illumina TruSight Oncology 500 assay. Level of actionability was evaluated against the European Society for Medical Oncology (ESMO) Scale of Clinical Actionability of molecular Targets (ESCAT) criteria with additional annotations from the PierianDx software and the OncoKB database.
Results
A total of 108 breast cancers were successfully assayed, with the majority (n = 104) being triple. The most common alterations (> 5% of study cohort) among actionable genes were PIK3CA (39%), BRCA2 (24%), PTEN (15%), ERBB2 (13%), BRCA1 (12%), and ERBB3 (10%). With the standard cut-off of 10 mutations/mega-base, 25 samples were tumor mutation burden (TMB)-high and 83 were TMB-low. The proportion of TMB-high was much lower among the early than late breast cancer patients (19% vs. 34.5%, respectively; P = 0.0499).
Conclusion
Our study showed the clinical applicability and feasibility of large-sized CGP, with more genes and multi-gene signatures such as TMB and microsatellite instability (MSI) investigated. Detection of more actionable biomarkers could potentially expand therapeutic opportunities for patients: e.g., immune checkpoint inhibitors (for TMB-high and MSI), poly ADP- ribose polymerase (PARP) inhibitor (for BRCA1/2 and PALB2), selective estrogen receptor degrader (for ESR1), tyrosine kinase inhibitor (for ERBB2/3), phosphoinositide 3-kinase inhibitor (for PIK3CA).