Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer

TLDR

BRCA1/2‑mutated and some sporadic triple‑negative breast cancers have DNA repair defects and are sensitive to DNA‑damaging therapeutics. The study tested whether a combined homologous recombination deficiency (HRD) score predicts response to platinum‑containing neoadjuvant chemotherapy in triple‑negative breast cancer. The authors calculated an unweighted HRD score from loss of heterozygosity, telomeric allelic imbalance, and large‑scale state transitions in three neoadjuvant TNBC trials of platinum‑based therapy. HR deficiency, defined as HRD score ≥ 42 or BRCA1/2 mutation, consistently predicted pathologic complete response and residual cancer burden 0/I in platinum‑based neoadjuvant trials, with odds ratios up to 17.00 and significance retained after multivariable adjustment, including in BRCA1/2‑negative tumors. Published in Clinical Cancer Research 22(15):3764‑73, ©2016 AACR.

Abstract

BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy.In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials.HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.