2019 ASCO Annual Meeting!
Session: Gastrointestinal (Noncolorectal) Cancer
Type: Poster Session
Time: Monday June 3, 8:00 AM to 11:00 AM
Location: Hall A
Association of BRCA-mutant pancreatic cancer with high tumor mutational burden (TMB) and higher PD-L1 expression.
Gastrointestinal (Noncolorectal) Cancer
2019 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #238)
J Clin Oncol 37, 2019 (suppl; abstr 4133)
Author(s): Andreas Seeber, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Mohamed E. Salem, Francesca Battaglin, Wafik S. El-Deiry, Ryuma Tokunaga, Philip Agop Philip, John Marshall, Florian Kocher, Michael J. Hall, Wolfgang Michael Korn, Heinz-Josef Lenz, Gilbert Spizzo; Department of Internal Medicine V (Hematology and Oncology), Innsbruck, Austria; USC Keck School of Medicine, Los Angeles, CA; Caris Life Sciences, Phoenix, AZ; West Virginia University Cancer Institute, Morgantown, WV; West Cancer Center, University of Tennessee, Germantown, TN; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA; Fox Chase Cancer Center, Providence, RI; Karmanos Cancer Institute, Detroit, MI; Georgetown University, Washington, DC; Department for Haematology and Oncology, Tyrolean Cancer Research Institute, Innsbruck Medical University, Innsbruck, Austria; Fox Chase Cancer Center, Philadelphia, PA; University of Southern California, Los Angeles, CA; Experimental Oncology, Tyrolean Cancer Research Institute, Innsbruck, Austria
Background: In the U.S. 56,000 Americans are expected to be diagnosed with pancreatic cancer in 2019. Prognosis in pancreatic cancer is poor. Therefore, new treatment strategies are urgently needed to improve survival. BRCA1 and BRCA2 mutations have been described to be the most common genetic mutations involved in familial pancreatic cancer. The optimal treatment regimen to use in BRCA-mutant pancreatic cancer has still to be established. Moreover, no data are available on association of BRCA mutation with immune-associated markerssuch as tumor mutational burden (TMB), microsatellite instability (MSI) or PD-L1 expression. Methods: Tumor samples of 2824 patients with pancreatic ductal adenocarcinoma were analyzed for BRCA mutation by NGS and for other genes (MiSeq on 47 genes, NextSeq on 592 genes) at Caris Life Sciences, Phoenix, AZ. TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. PD-L1 expression was evaluated using immunohistochemistry. Results: In 4.4% (N = 124) of all pancreatic adenocarcinoma samples BRCA mutations were detected. BRCA2 mutations were more common: 3.1% (N = 89) vs 1.1% BRCA1 mutations (N = 35). BRCA mutations were associated with younger age (BRCA1: 61 yrs for mutated vs. 64 for wild-type, p = 0.07; BRCA2: 61 yrs vs. 64, p = 0.002; both: p < 0.001). BRCA mutations were associated with higher MSI-H frequency (4.8% vs. 1.2%, p = 0.002), elevated PD-L1 expression (22% vs. 11%, p < 0.001) and higher TMB (mean 8.7 mut/MB vs. 6.5, p < 0.001); the differences remain significant in MSS tumors (p < 0.05). BRCA-mutant pancreatic carcinomas showed a significantly lower mutation frequencies in TP53 (59% vs 73%, p = 0.001), CKDN2A (13% vs 25%, p = 0.006), but higher frequencies in APC (6.5% vs 2.2%), KMT2A (1.9% vs 0.2%), AMER1 (1.9 vs 0.5%) and SETD2 (3.7% vs 0.4%) mutations (p < 0.05 for all comparisons). Conclusions:BRCA mutations are found in a significant subgroup of pancreatic ductal adenocarcinoma and these carcinomas are associated with an immunogenic tumor profile. These data suggest evaluating PARP inhibitors in combination with immunotherapy in patients with BRCA-mutant pancreatic adenocarcinoma especially in tumors that are MSS.