Abstract P3-06-11: Homologous recombination deficiency (HRD) assay predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer
Authors: Richardson Andrea L , Silver Daniel P , Szallasi Zoltan , Birkbak Nicolai J , Wang Zhigang C , Iglehart J  Dirk , Mayer Erica L , Winer Eric P , Tung Nadine M , Ryan Paula D , Isakoff Steven J , Barry William T , Greene-Collozi April , Gutin Alexander , Reid Julia , Neff Chris , Jones Joshua , Timms Kirsten , Hartman Anne-Renee , Garber Judy E 
Published: May 2015

Abstract
A significant proportion of triple negative breast cancers (TNBC) carry defects in DNA repair including Homologous Recombination (HR) defects and are sensitive to therapies that target these pathways. Several clinical trials have demonstrated improvement in pathologic response with the addition of platinum to standard of care neoadjuvant regimens but at a cost of increased toxicities. Recently three DNA based metrics (LOH, Abkevich et al. 2012 Br J Cancer; TAI, Birkbak et al. 2012 Cancer Discov; LST, Popava et al. 2012 Cancer Res) have been developed, shown to be highly associated with BRCA1/2 mutation status, and found to predict sensitivity to platinum based chemotherapy in TNBC. The HRD Score was defined as the sum of LOH, TAI, and LST measurements, and a threshold separating tumors with high and low HRD Scores was established. This study assesses the association of HRD Score with response to cisplatin neoadjuvant chemotherapy in patients with TNBC. A clinical test that identifies tumors with defects in HR may distinguish those patients more likely to benefit from the addition of platinum.
Methods: Archival tumor samples were obtained from 74 patients with TNBC from 2 separate clinical trials conducted at DFHCC under IRB approved protocols. One trial enrolled 28 patients who received neoadjuvant cisplatin monotherapy (Silver et al., 2010 J Clin Oncol). The second trial enrolled 51 patients who received cisplatin and bevacizumab chemotherapy (Ryan, et al.,2009 J Clin Oncol). HRD Score and tumor BRCA1/2 mutation status were determined. BRCA1/2 deficiency was defined as the presence of BRCA1/2 mutation with loss of the second allele in the tumor. Response was categorized by the residual cancer burden (RCB) score with responders defined as RCB0 or 1, and non-responders as RBC2 or 3. A second measure of response, pathologic complete response (pCR), was defined as RCB0 and non-responders as RCB1,2 or 3. Logistic regression was used to evaluate HRD Score in combination with BRCA1/2 deficiency as a predictor of response to neoadjuvant therapy. All analysis was conducted according to a pre-specified Statistical Analysis Plan.
Results: As of May 29, 2014 41 samples have been processed. Seven carried deleterious mutations in BRCA1/2 (17%). Thirty-three of the tumors produced SNP data of sufficient quality for HRD score calculation. HRD scores in the passing samples ranged from 7 – 74, with an average score of 45. The HRD scores observed in BRCA1/2 mutation carriers (n=6) ranged from 43 – 57 with an average HRD score of 55. We anticipate that all molecular data will be generated by July 1, 2014. Correlation with pCR and RCB0/1 will be assessed.
Conclusions: The LOH, TAI, and LST metrics have been shown in previous studies to predict response to platinum-based neoadjuvant chemotherapy in patients with TNBC. This study will be a validation of LOH, TAI and LST in the form of a combined score, and will demonstrate that HRD Score can be used as a tool to identify patients with breast tumors with underlying HR deficiency who may benefit from platinum therapy.
Citation Format: Andrea L Richardson, Daniel P Silver, Zoltan Szallasi, Nicolai J Birkbak, Zhigang C Wang, J Dirk Iglehart, Erica L Mayer, Eric P Winer, Nadine M Tung, Paula D Ryan, Steven J Isakoff, William T Barry, April Greene-Collozi, Alexander Gutin, Julia Reid, Chris Neff, Joshua Jones, Kirsten Timms, Anne-Renee Hartman, Judy E Garber. Homologous recombination deficiency (HRD) assay predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-11.