Molecular features of primary and metastatic pancreatic ductal adenocarcinoma (PDAC) may provide clues to treatment response and additional targets for drug development, according to a study presented at the 2018 AACR Pancreatic Cancer: Advances in Science and Clinical Care conference in Boston, Massachusetts.1

“Our study characterizes novel molecular features that distinguish highly biologically concordant PDAC primaries and metastases, providing further insight into management,” the authors wrote.

Though some driver genes, mutational signatures, transcriptional subtypes, and other features have been identified in PDAC, how these features may influence disease progression to metastases has not yet been evaluated in a larger study. The aim of this study was to determine how such features change when PDAC progresses from a primary tumor to metastatic disease.

In the study, whole-genome and RNA sequencing were used to evaluate samples from 217 patients with primary PDAC and 101 patients with metastatic disease for cell cycle progression (CCP), hypoxia, and intertumoral heterogeneity (ITH). A subset of samples formed a “paired” cohort, in which both primary tumor and metastatic disease were available for the same patient. 

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Genomic and transcriptional features were similar between primary and metastatic disease. Sequential tumor suppressor gene inactivation was associated with increased CCP and was therefore higher in metastatic tumors. CCP was the only feature that predicted response to therapy.

Approximately half of the samples demonstrated hypoxia, regardless of primary or metastatic disease.

Improved survival was associated with lower ITH compared with higher ITH. Analysis of ITH demonstrated that the most conserved genetic aberrations between the primary tumor and metastatic disease were truncations, inversions, and translocations. The authors surmised that these may be potential targets for drug development.

Within the paired cohort, there was evidence of multiple PDAC in the same patient, as indicated by synchronous and metachronous disease, suggesting that intraparenchymal metastases occurred rather than the development of new primaries. The authors concluded that this demonstrates that “sequencing recurrences distinguishes relapses from new primaries and resolving a clinical conundrum not addressed by current AJCC [American Joint Committee on Cancer] staging.”

Reference

  1. Connor A, Denroche RE, Jang GH, et al. Comparison of primary and metastatic pancreatic cancer by integration of clinical, pathologic, genomic, and transcriptional features. Presententation at: AACR Pancreatic Cancer: Advances in Science and Clinical Care; Boston, Massachusetts: September 21-24, 2018. Abstract A016.