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

¹ Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden. johan.staaf@med.lu.se.
² Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
³ Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
⁴ Independent Cancer Patients' Voice, London, UK.
⁵ Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁶ Division of Surgery, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁷ Department of Clinical Genetics and Pathology, Department of Laboratory Medicine, Office for Medical Services, Lund, Sweden.
⁸ Academic Department of Medical Genetics, The Clinical School University of Cambridge, Cambridge Biomedical Research Campus, Cambridge, UK. snz@mrc-cu.cam.ac.uk.

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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