Association of BRCA1/2defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes

Abstract

IntroductionHomologous recombination (HR) DNA repair is of clinical relevance in breast cancer. Three DNA-based homologous recombination deficiency (HRD) scores (HRD-loss of heterozygosity score (LOH), HRD-telomeric allelic imbalance score (TAI), and HRD-large-scale state transition score (LST)) have been developed that are highly correlated with defects in BRCA1/2, and are associated with response to platinum therapy in triple negative breast and ovarian cancer. This study examines the frequency of BRCA1/2 defects among different breast cancer subtypes, and the ability of the HRD scores to identify breast tumors with defects in the homologous recombination DNA repair pathway.Methods215 breast tumors representing all ER/HER2 subtypes were obtained from commercial vendors. Next-generation sequencing based assays were used to generate genome wide SNP profiles, BRCA1/2 mutation screening, and BRCA1 promoter methylation data.ResultsBRCA1/2 deleterious mutations were observed in all breast cancer subtypes. BRCA1 promoter methylation was observed almost exclusively in triple negative breast cancer. BRCA1/2 deficient tumors were identified with BRCA1/2 mutations, or BRCA1 promoter methylation, and loss of the second allele of the affected gene. All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10-17; HRD-TAI: P = 1.5 × 10-19; HRD-LST: P = 3.5 × 10-18). A combined score (HRD-mean) was calculated using the arithmetic mean of the three scores. In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10-8; HRD-TAI: P = 2.9 × 10-7; HRD-LST: P = 2.8 × 10-8; clinical variables: P = 1.2 × 10-16).ConclusionsThe HRD scores showed strong correlation with BRCA1/2 deficiency regardless of breast cancer subtype. The frequency of elevated scores suggests that a significant proportion of all breast tumor subtypes may carry defects in the homologous recombination DNA repair pathway. The HRD scores can be combined to produce a more robust predictor of HRD. The combination of a robust score, and the FFPE compatible assay described in this study, may facilitate use of agents targeting homologous recombination DNA repair in the clinical setting.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0475-x) contains supplementary material, which is available to authorized users.

Molecular signatures in breast cancer

“…These three genome-based scores (telomeric AI, LST and LOH) have been assessed as a combined homologous recombination deficiency (HRD) score (HRD Index) in various cohorts of breast cancer samples. The assay, developed using next generation sequencing, was collectively a more sensitive predictor of BRCA deficiency than individual parameters [92] and identified patients with increased benefit to neoadjuvant platinum based therapy [66,93]. Similar findings have been reported reflecting the burden of allelic imbalanced copy number alterations and response to platinum-based chemotherapy [70].…”

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

“…The Homologous Recombination Deficiency ('HRD') assay measures levels of genomic instability or 'scarring' caused by any number of alterations in DNA repair capacity. At present, the HRD assay incorporates three measures of genomic instability: telomeric allelic imbalance (TAI; the number of regions with allelic imbalance that extend to the subtelomere, but do not cross the centromere), loss of heterozygosity (LOH; the number of regions > 15 Mb and less than one chromosome lost across the genome), and large-scale state transitions (LST; the number of chromosomal breaks between adjacent genomic regions longer than 10 Mb after filtering regions < 3 Mb) [25][26][27]. The HRD score is currently calculated by adding the LOH, TAI, and LST scores and is a continuous score from 0 to 100 with a score of < 41 (previously < 10) as HR proficient and ≥ 42 (previously ≥ 10) as HR deficient.…”

“…Recently, multiple groups have reported that the HRD assay can be used to identify both BRCA1/2 mutant and wild-type TNBC patients more likely to achieve a favorable response to platinum-based neoadjuvant chemotherapy [27]. In the neoadjuvant PrECOG 0105 trial, responders to this platinum-based therapy had significantly higher mean HRD-LOH scores compared to non-responders; this was true for both BRCA1/2 wild-type and mutant responders [28].…”

Adenoviral vectors for modulation of poly(ADP-ribose) polymerase-1 (PARP1) – dependent DNA repair as a predictive tool for chemotherapy

“…The viral vectors presented here may be used as part of a homologous recombination deficiency test to determine whether a cancer patient would be a good candidate for treatment with PARP inhibitors. Previous and ongoing investigations to develop a laboratory test that detects homologous recombination deficiency use deep sequencing-based genomic analysis of the loss of heterozygosity, as they are caused for example by the mutation of BRCA1/2 genes [42,43]. In contrast, blocking PARP activation using DBD expression followed by low dose exposure to radiation or radiomimetic chemicals inducing DNA strand breaks would identify cells that are hypersensitive compared to appropriate controls as a quick first round screening approach.…”