Journal Article
. 2019 Oct;25(10).
doi: 10.1038/s41591-019-0582-4.

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

Johan Staaf 1 Dominik Glodzik 2 Ana Bosch 2 Johan Vallon-Christersson 2 Christel Reuterswärd 2 Jari Häkkinen 2 Andrea Degasperi 3 Tauanne Dias Amarante 3 Lao H Saal 2 Cecilia Hegardt 2 Hilary Stobart 4 Anna Ehinger 2 Christer Larsson 5 Lisa Rydén 6 Niklas Loman 2 Martin Malmberg 2 Anders Kvist 2 Hans Ehrencrona 7 Helen R Davies 3 Åke Borg 2 Serena Nik-Zainal 8 
Affiliations
  • PMID: 31570822
  •     19 citations

Abstract

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.

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