Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype

Abstract

Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy. Archival or prospectively acquired FFPE samples and matched normal DNA from = 336 patients with pancreatic cancer were analyzed using a hybridization capture-based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results. The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy. .

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

“…Comprehensive genetic analysis is being pursued to identify mutational pathways for potential treatment options, and a recent study utilizing genomic sequencing identified therapeutically relevant (highly actionable) alterations in 27% of PDAC samples (5). These findings were consistent with several other publications, all of which have demonstrated findings of actionable targets in 17% to 48% of PDAC samples (6)(7)(8)(9)(10)(11). One commonality to these largescale next-generation sequencing efforts is the identification of mutational defects in the genes that regulate the DNA damage response and repair (DDR) system, found in 17% to 25% of PDACs.…”

“…Our literature search, capturing 5,234 pancreatic cancer patients overall, shows that the total prevalence of ATM mutations (germline or somatic) in PDAC is 6.4% (range, 1%-34%; refs. 5,6,8,9,11,25,[47][48][49][50][51][52][53][54][55][56][57]. Importantly, in one study that showed that nearly 10% of PDAC patients carried a germline ATM mutation, in 44% of these patients a somatic second hit was identified (58).…”

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild‐type BRCA pancreatic ductal adenocarcinoma

“…Treatment for advanced PDAC is evolving, and therapy refinement and patient selection are emerging realities in small subsets of patients with this disease . Increasing evidence indicates that germline BRCA + patients are one such important subgroup.…”

“…Treatment for advanced PDAC is evolving, and therapy refinement and patient selection are emerging realities in small subsets of patients with this disease. 16 Increasing evidence indicates that germline BRCA1 patients are one such important subgroup. We chose to evaluate in a prospective fashion the utility of platinum-based therapy combined with a PARPi in subgroups of patients with PDAC so that the concept of synthetic lethality could be evaluated and potentially exploited.…”

Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative

“…Standardof-care (SOC) treatments for metastatic pancreatic ductal adenocarcinoma (PDAC) include FOLFIRINOX (3) and gemcitabine with nab-paclitaxel (4); however, most patients do not respond to these regimens, and the median overall survival (OS) remains less than 1 year. In an effort to optimize therapy, molecular profiling has been used to group patients with PDA into therapeutically "actionable" molecular subgroups (5)(6)(7)(8)(9)(10)(11)(12). Targets have included homologous recombination repair (14%-17%; refs.…”