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

作者：Telli, Melinda L.; Timms, Kirsten M.; Reid, Julia; Hennessy, Bryan; Mills, Gordon B.; Jensen, Kristin C.; Szallasi, Zoltan; Barry, William T.; Winer, Eric P.; Tung, NadineM.; Isakoff, Steven J.; Ryan, Paula D.; Greene-Colozzi, April; Gutin, Alexander; Sangale, Zaina; Iliev, Diana; Neff, Chris; Abkevich, Victor; Jones, Joshua T.; Lanchbury, Jerry S.; Hartman, Anne-Renee; Garber, Judy E.; Ford, James M.; Silver, Daniel P.^*; Richardson, Andrea L.

来源：Clinical Cancer Research, 2016, 22(15): 3764-3773.

DOI：10.1158/1078-0432.CCR-15-2477

• DNA-DAMAGE
• REPAIR
• CARBOPLATIN
• BRCA1
• HETEROZYGOSITY
• GEMCITABINE
• SENSITIVITY
• INHIBITION
• DEFECTS
• NUMBER

Purpose: 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). @@@ Experimental Design: 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. @@@ Results: 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; RCB0/I P = 0.0039, pCRP = 0.018 in the neoadjuvant cisplatin trials. @@@ Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy.

• 出版日期2016-8-1