Journal Article

Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study

Glodzik, Dominik, Larsson, Christer, Häkkinen, Jari, Hegardt, Cecilia, Stobart, Hilary, Saal, Lao H, Ehrencrona, Hans, Borg, Åke, Davies, Helen R, Vallon-Christersson, Johan, Reuterswärd, Christel, Bosch, Ana, Loman, Niklas, Rydén, Lisa, Staaf, Johan, Ehinger, Anna, Kvist, Anders, Tauanne Dias Amarante, Degasperi, Andrea, Nik-Zainal, Serena, Malmberg, Martin

2019

Overview

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network–Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2–0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13–0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.

• Publisher: Nature Publishing Group
• Subject: Abnormalities / AKT1 protein / Algorithms / BRCA1 protein / BRCA2 protein / Breast / Breast cancer / Chemotherapy / Confidence intervals / Decision making / Gene sequencing / Genomes / Homologous recombination / Homology / Invasiveness / Mutation / Population studies / Population-based studies / Repair / Retrotransposition / Tumors / Whole genome sequencing