Journal Article

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

Lien, Pei-Ju, Tseng, Ling-Ming, Chiu, Jen-Hwey, Hsu, Chih-Yi, Chao, Ta-Chung, Huang, Chi-Cheng, Tsai, Yi-Fang, Lin, Yen-Shu, Feng, Chin-Jung, Liu, Chun-Yu

2021

Overview

Background Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. 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) targeted panel. Methods The 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 Fisher™ Oncomine™ 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 (all variants combined within each sample) 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%). Conclusion Targeted 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / AKT1 protein / Antitumor activity / Biomarkers / Biomedical and Life Sciences / Biomedicine / BRCA1 protein / BRCA1 Protein - genetics / BRCA2 protein / BRCA2 Protein - genetics / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Cancer Research / Cancer therapies / Care and treatment / Class I Phosphatidylinositol 3-Kinases - genetics / Clinical outcomes / Clinical trials / Deoxyribonucleic acid / Diagnosis / DNA / ErbB-2 protein / ErbB-3 protein / ESR1 protein / Female / Gene expression / Gene mutations / Genetic aspects / Genetics / Genome-wide association studies / Genomes / genomics and epigenetics / Genotype / Health aspects / Health Promotion and Disease Prevention / High-Throughput Nucleotide Sequencing / Humans / Identification and classification / Laboratories / Mammography / MDM2 protein / Medical diagnosis / Medical prognosis / Medical screening / Medicine/Public Health / Metastasis / Methods / Middle Aged / Molecular diagnostic techniques / Mutation / Next-generation sequencing / Oncology / Paraffin / Patients / Population studies / Precision medicine / PTEN protein / Receptor, ErbB-2 - genetics / Receptor, ErbB-3 - genetics / Research Article / Software / Surgery / Surgical Oncology / Surveillance / Taiwan / Targeted panel / Therapeutic applications / Therapeutic targets