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

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.Financial support for this study was provided by the Swedish Cancer Society (CAN 2016/659, CAN 2018/685, and Senior Investigator Award SIA190013), the Mrs Berta Kamprad Foundation (FBKS-2018-3-166 and FBKS-2018-4-146), the Crafoord Foundation (20180543), the Swedish Research Council, the Lund-Lausanne L2-Bridge/Biltema Foundation (F 2016/1330), the Mats Paulsson Foundation (IACD 2017), the Gustav V:s Jubilee Foundation (174271), Governmental Funding of Clinical Research within the National Health Service (ALF) (2018/40612). Whole genome sequencing and analysis was funded by a Wellcome Trust Intermediate Clinical Fellowship (WT100183MA) and a CRUK Advanced Clinician Scientist Award (C60100/A23916) and a CRUK Grand Challenge Award (C60100/A25274)