Abstract P3-07-12: Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis

Abstract

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy regimens than TNBC patients whose tumors are HR non-deficient. We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to better estimate the pCR rates amongst HR deficient and HR non-deficient tumors. Methods: Patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00148694/NCT00580333 (N=50), NCT01372579 (N=26), TBCRC 008 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Logistic regression models were used to adjust for study effects. The addition of data from the TNBC platinum-treated arm of GeparSixto (n=101) to this pooled analysis will be available at the time of presentation bringing the total sample size to 267. Results: pCR was achieved in 51 patients (31%) and 104 patients (63%) were HR deficient (31 with high HRD score and tBRCA mutation, 67 with high HRD score only, and 6 with tBRCA mutation only). Patients with HR deficient tumors were more likely to achieve a pCR than those with HR non-deficient tumors: 44% vs. 8% (p<0.01). When adjusting for study effects in separate logistic regression models, patients with HR deficient tumors (OR=12.5), with tBRCA mutations irrespective of HRD score (OR=2.3), or with high HRD scores (OR=14.6) were more likely to have a pCR (see Table). Likelihood of pCR adjusting for studyModel #Predictor VariablePopulation (n)Adjusted Odds RatioLower 95% CIUpper 95% CIP Value1HR DeficiancyAll (166)12.54.237.3<0.012tBRCA mutationAll (166)2.31.025.10.0453High HRD scoretBRCA non-mutants (124)14.64.250.1<0.01 Conclusion: HR deficiency status is a robust predictor of pCR across different neoadjuvant platinum-based regimens. This pooled analysis suggests that HRD can be used to identify TNBC patients with a high probability of obtaining pCR with a platinum-based neoadjuvant chemotherapy regimen. Citation Format: Telli ML, McMillan A, Ford JM, Richardson AL, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar W, Stearns V, Connolly RM, Loibl S, Elkin EP, Timms K, Hartman A-R, von Minckwitz G. Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-12.

Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors

“…The dichotomized HRD score was significantly associated with both RCB 0/I (no residual cancer burden or minimal residual disease) and pCR in both cohorts. Moreover, HRD was still able to significantly predict RCB 0/I and pCR also when adjusted for clinical variables [58]. Concordant results have been found in a small trial addressed to patients with early stage TNBC enrolled to receive neoadjuvant platinum-based therapy.…”

“…In “myChoice HRD” (Myriad genetics) test, loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LTS) are measured and can be combined in an HRD score. The predictive power of a specific HRD threshold derived from the combined HRD score has been evaluated retrospectively by Telli et al [58]. In this study, HR deficiency (defined as an HRD score ≥ 42 and/or the presence of BRCA1 or BRCA2 mutation) was evaluated as a predictor of response to neoadjuvant platinum-based chemotherapy for TNBC in two different clinical cohorts.…”

Disease extent at secondary cytoreductive surgery is predictive of progression-free and overall survival in advanced stage ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study

“…[27] In a recent study of neoadjuvant chemotherapy in breast cancer, patients who had deficiencies in homologous re-combination DNA repair had a significantly higher rate of pathologicCR 58% versus 18%. [28] It is likely molecular profiling of ovarian cancer patients will identify a subgroup of patients who are more likely to have a complete pathologic response.…”

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

“…In a pooled analysis of six phase 2 neoadjuvant platinum-based TNBC trials (n = 267), the adjusted odds ratio for pathological response in HR deficient compared to non-deficient tumors was 4.64 (95% CI 2.32-9.27; p = < 0.0001) [29]. In addition to assessments in multiple single-arm studies of neoadjuvant platinum, in the randomized phase 2 GeparSixto trial, patients with high HRD score or tumor BRCA mutation were more likely to achieve pCR (55.9% vs. 29.8%), odds ratio 2.51 (p = 0.009) in multivariate analyses [30].…”