BRCA-mutant pancreatic cancer is associated with high tumor mutational burden (TMB) and higher PD-L1 expression


Gilbert Spizzo, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony F. Shields, Mohamed E. Salem, Francesca Battaglin , Wafik S. El-Deiry , Ryuma Tokunaga, Philip A. Philip6, John L. Marshall, Florian Kocher, Michael Hall, W. Michael Korn, Heinz-Josef Lenz and Andreas Seeber


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 one of the most common genetic mutations involved in familial pancreatic cancer. The optimal treatment regimen to use in BRCAmutant (BRCA-MT) pancreatic cancer has still to be established. Moreover, no data are available on association of BRCA-MT with immune-related biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI) or PD-L1 expression.


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). 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


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 difference remains 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).


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-MT pancreatic cancer.

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