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Reading the whole genome of 254 Swedish triple-negative cancers showed that 59% carry the signature of broken BRCA-type DNA repair, two-thirds of them explained by BRCA1 or BRCA2 mutation, BRCA1 or RAD51C promoter methylation or PALB2 loss, and that these patients did best on standard chemotherapy.
254 TNBCs from the population-based SCAN-B project (NCT02306096; TNBC was 9% of the cohort) were whole-genome sequenced; 237 (93%) gave sufficient data, with 3% failure at 30-fold depth and 11% at 15-fold. HRDetect classified 58.6% as HRDetect-high, 5.5% intermediate and 35.9% low; 88.5% of women under 50 were HRDetect-high. Of 139 high cases, 29 (21%) had biallelic BRCA1/2 loss (20 germline, 9 somatic), 55 (40%) BRCA1 promoter hypermethylation with loss of the other allele, five pathogenic germline PALB2 variants and five RAD51C hypermethylations; 33% were unexplained. A germline SINE-VNTR-Alu retrotransposition abrogating BRCA1 was discovered. HRDetect-high patients had better invasive disease-free survival (HR 0.42) and distant relapse-free interval (HR 0.31) on adjuvant chemotherapy; intermediate had the poorest outcome; about 4.7% of HRDetect-low tumours were mismatch-repair deficient and the low group was enriched for PIK3CA/AKT1 pathway abnormalities. The copy-number-based HRD assay had a 13% false-negative rate against HRDetect.
It is the best population-based estimate of how much TNBC is homologous recombination deficient, shows that most of it is not germline BRCA, and argues that whole-genome sequencing at diagnosis could stratify trials and pick out the low group that needs something other than DNA-damaging chemotherapy.
Shares HRD-positive (genomic instability score), Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, HRD & BRCA testing, Mutational signature.
Shares HRD-positive (genomic instability score), HRD & BRCA testing, Homologous recombination deficiency (HRD), BRCA1 / BRCA2 (HRD).
Shares HRD-positive (genomic instability score), Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, HRD & BRCA testing, Homologous recombination deficiency (HRD).
Shares HRD-positive (genomic instability score), Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, HRD & BRCA testing, Homologous recombination deficiency (HRD).
Shares HRD-positive (genomic instability score), Homologous recombination deficiency (HRD), Nature Medicine, BRCA1 / BRCA2 (HRD).
Shares RAD51C, PALB2, BRCA1 / BRCA2 (HRD), Triple-negative breast cancer (TNBC).
Shares Mutagenesis & mutational signatures, HRD & BRCA testing, Mutational signature, Homologous recombination deficiency (HRD).
Shares HRD & BRCA testing, Whole-exome & whole-genome sequencing, BRCA1 / BRCA2 (HRD), Triple-negative breast cancer (TNBC).