Comprehensive molecular profiling of Taiwanese breast cancers revealed potential therapeutic targets: prevalence of actionable mutations among 380 targeted sequencing analyses

Abstract

IntroductionBreast cancer is one of the leading causes of cancer-related deaths in women, and the annual incidence of breast cancer has continuously increased throughout the past two decades in Taiwan. There is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response and recurrence rate. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) target panel.Materials and methodsThe study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo FisherTM OncomineTM Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT).Results.A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%).ConclusionTargeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.

Prevalence of tumor genomic alternations in homologous recombination genes among Taiwanese breast cancers

“…There is a demand to identify therapeutics based on genetic pro ling from breast cancer samples to improve treatment response and suppress recurrence rate. Our previous study has determined the molecular alternations underpinning breast oncogenesis and identi ed potential biomarkers from a large cohort of Taiwanese breast cancers using tumor-only targeted sequencing [15]. In current study, we focused on the prevalence of HRR genes to shed light on the potential application of PARP inhibitors and subsequent synthetic lethargy.…”

“…The full protocol of the VGH-TAYLOR: Comprehensive precision medicine research on the heterogeneity of Taiwanese breast cancer patients, and results of initial 380 targeted sequencing have been descripted elsewhere [15]. The study comprised a broad clinical spectrum of breast cancers, including Group 1: planned to receive rstline surgery and followed by adjuvant therapy, or early relapse within three years.…”

“…Luminal B2 breast cancers were those with both ER and HER2 positive phenotypically. Assay v3 (Thermo Fisher Scienti c, Waltham, MA) was adopted for next-generation sequencing (NGS), which enabled detections of 161 cancer-related genes and identi ed SNVs, CNVs, gene fusions, and indels [15].…”