Abstract A61: Tandem duplicator phenotype: A potentially targetable genomic subgroup in pancreas cancer
Authors: Amy X. Zhang, Grainne M. O'Kane, Robert E. Denroche, Gun Ho Jang, Sandra E. Fischer, Sarah Picardo, Ilinca Lungu, Anna Dodd, Julie Wilson, Yifan Wang, George Zogopoulos, Elina Elimova, Elaine Bouttell, Rebecca Prince, Raymond Jang, James J. Biagi, Faiyaz Notta, Steve Gallinger, Jennifer J. Knox
Journal: Cancer Research (2019)

Abstract Background: There is a paucity of predictive genomic biomarkers in pancreas cancer (PDA) that can direct personalized treatment. Patients with tumors that are deficient in homologous recombination repair deficiency (HRD) may benefit from platinum and/or PARP inhibition. Biallelic inactivation of BRCA1 can result in a tumor with characteristics of HRD and a tandem duplicator phenotype (TDP), where tandem duplications (TDs) are randomly distributed throughout the genome. The TDP has been described in breast and ovarian cancer, associated with perturbations in BRCA1, CDK12, FBXW17, and CCNE1. In this study, we evaluated the prevalence of the TDP and outcomes in a large cohort of sequenced PDA. Methods: Whole-genome sequencing (WGS) was performed in 192 resected and 190 advanced cases within the PanCuRx initiative and COMPASS trial at the Ontario Institute for Cancer Research and Princess Margaret Cancer Centre. Tumors underwent laser capture enrichment prior to sequencing. Duplicator classification was applied using the previously described TDP score by Menghi et al. In addition, HRDetect scores were determined. Outcomes of patients with TDP tumors were evaluated. Results: Of 382 sequenced PDAC, 28 were classified as TDP (7.3%)—14 resected, 14 advanced. We identified three TDP groups based on etiology, including 6 BRCA1 inactivated tumors, 1 CCNE1 amplified tumor, and 21 tumors with no specific etiology, i.e., there were no genetic alterations in TDP-related genes (BRCA1, CCNE1, CDK12, and FBXW17). BRCA1 inactivated tumors were characterized by small TDs (median=12kb), whereas the one CCNE1 amplified case had much larger TDs (median=239kb). TDs in duplicators of unknown etiology spanned a wide range of sizes (median=91kb). TDP tumors were associated with high HRDetect scores (score &amp;gt; 0.7; p&amp;lt;0.0001, Fisher’s exact test), including all TDPs with BRCA1 inactivation, the tumor with CCNE1 amplification, and 10/21 with unknown etiology. In the resected cohort, there was no difference in overall survival comparing duplicators (n=12) to typical cases (n=162) (median 23.7 vs. 21.6 months, p=0.334). Disease-free survival was longer for duplicators compared to typical cases (18.3 vs. 12.4 months), but not significant (p=0.602). In patients with advanced disease receiving platinum therapy, superior responses were observed for patients with TDP (n=12) compared to typical tumors (n=88) (p&amp;lt;0.05). There was also a trend towards longer survival in TDPs vs. typicals on platinum (median 12.8 vs. 9.3 months, p=0.07). Conclusions: The TDP is evident in approximately 7% of PDA. This patient cohort may have a superior response to platinum chemotherapy or DNA-damaging agents, which warrants further investigation. Citation Format: Amy X. Zhang, Grainne M. O'Kane, Robert E. Denroche, Gun Ho Jang, Sandra E. Fischer, Sarah Picardo, Ilinca Lungu, Anna Dodd, Julie Wilson, Yifan Wang, George Zogopoulos, Elina Elimova, Elaine Bouttell, Rebecca Prince, Raymond Jang, James J. Biagi, Faiyaz Notta, Steve Gallinger, Jennifer J. Knox. Tandem duplicator phenotype: A potentially targetable genomic subgroup in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A61.