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Clinical Trial
. 2016 Aug 1;22(15):3764-73.
doi: 10.1158/1078-0432.CCR-15-2477. Epub 2016 Mar 8.

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

Melinda L Telli  1 , Kirsten M Timms  2 , Julia Reid  2 , Bryan Hennessy  3 , Gordon B Mills  3 , Kristin C Jensen  1 , Zoltan Szallasi  4 , William T Barry  5 , Eric P Winer  5 , Nadine M Tung  6 , Steven J Isakoff  7 , Paula D Ryan  8 , April Greene-Colozzi  9 , Alexander Gutin  2 , Zaina Sangale  2 , Diana Iliev  2 , Chris Neff  2 , Victor Abkevich  2 , Joshua T Jones  2 , Jerry S Lanchbury  2 , Anne-Renee Hartman  2 , Judy E Garber  5 , James M Ford  1 , Daniel P Silver  10 , Andrea L Richardson  11
Affiliations
Clinical Trial

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

Melinda L Telli et al. Clin Cancer Res. .

Abstract

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; RCB 0/I P = 0.0039, pCR P = 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. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

G.B. Mills has ownership interest (including patents) in Catena Pharmaceuticals, PTVVentures, Spindletop Ventures, and Myriad Genetics, reports receiving speakers bureau honoraria from AstraZeneca, Eli Lilly, ISIS Pharmaceuticals, Nuevolution, and Symphogen, is a consultant/advisory board member for Adventist Health, AstraZeneca, Blend, Catena Pharmaceuticals, Critical Outcome Technologies, HaIaI Bio Korea, ImmunoMET, Millennium Pharmaceuticals, Nuevolution, Precision Medicine, Provista Diagnostics, Signalchem Life-sciences, and Symphogen, and reports receiving commercial research grants from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies, Komen Research Foundation, and Nanostrong. S.J. Isakoff is a consultant/advisoryboard memberforMyriad Genetics. K.M.Timms, A. Gutin, and V. Abkevich have ownership interest (including patents) in Myriad Genetics Inc. J.E. Garber reports receiving commercial research grants from Ambry Genetics and Myriad Genetics. J.M. Ford reports receiving commercial research grants from Myriad Genetics and Natera. D.P. Silver and A.L. Richardson are listed as co-inventors on a patent on telomeric allelic imbalance, which is owned by the Dana-Farber Cancer Institute and licensed to Myriad Genetics. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
HRD score distribution in the combined breast and ovarian training set. BRCA-deficient tumors include those with a BRCA1/2 mutation and/or BRCA1 methylation.
Figure 2.
Figure 2.
Box plot of HRD score versus RCB class for all patients with HRD scores PrECOG 0105 (n = 68; A) and Cisplatin trials cohort (n = 48; B). Box outlines the 25th and 75th percentiles; solid line is the median; whiskers extend to the most extreme data point that is no more than 1.5 times the IQR. Red dots, BRCA1/2 wild-type; blue triangles, BRCA1/2-mutant; black circles, failed mutation screening.
Figure 3.
Figure 3.
Relative response rates for PrECOG 0105 (A) and in the cisplatin cohort (B) stratified by HRD score, BRCA1/2 mutation status, and HR deficiency status. WT, wild-type, M, mutant.
See this image and copyright information in PMC

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