Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer

Abstract

Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI). HRDetect predicted status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; = 0.006) with the same optimal threshold, even after adjusting for mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT ( = 0.0003) and 1.3-year extended median OS ( = 0.04). Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of mutation status and hope this work will guide the development of clinical trials..

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

“…A second approach defined six new mutational signatures from whole genome sequencing of breast cancer patients that were predictive of BRCA1/2 deficiency. They integrated these in a weighted model, termed 'HRDetect,' which identifies BRCA1/BRCA2-deficient tumors with high (98.7%) sensitivity and also identifies tumors with somatic loss or functional BRCA1/BRCA2 deficiency [36,37]. HRDetect was validated in an independent dataset and evaluation for clinical utility is ongoing [37].…”

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

“…Therefore, optimal use of these therapeutic approaches will require more accurate identification of HR deficient cases. A similar diagnostic problem was addressed in the case of breast and ovarian cancer using HR deficiency induced mutational signatures [10,27]. We decided to apply the same approach here.…”

A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures

“…Since high HRDetect scores were reported to be associated with better clinical outcome in platinum treated breast cancer [21], we were wondering whether lung cancer cases below and above the HRDetect thresholds that we determined in the WES data have significantly different outcome when treated with platinum-containing therapy. However, higher HRDetect-scores were not associated with better outcome in these cohorts.…”