researchers reported in Gastroenterology.
“We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection,” wrote Aatur D. Singhi, MD, PhD, of the University of Pittsburgh and associates.
The most common genomic mutations in pancreatic ductal adenocarcinoma (PDAC) involve KRAS, TP53, CDKN2A, and SMAD4, none of which can be treated by currently approved targeted agents. But PDACs are genomically very heterogeneous and contain low levels (less than 5%) of many other mutations, the researchers noted. In small studies, these low-prevalence mutations included kinase gene amplifications and rearrangements, which may be useful as treatment targets or predictive biomarkers of response.
To further characterize PDAC mutations and their relative penetrance, the researchers performed targeted genomic profile analyses of 3,594 PDAC tumor specimens from an international cohort. The tests included capture-based targeted genomic profiling of up to 315 cancer-linked genes and the intron regions of 28 genes that are rearranged in cancer cells. The researchers classified genomic alterations based on published signaling pathways, including receptor tyrosine kinase/ras/mitogen-activated protein kinase (RTK/ras/MAPK) activation, DNA damage repair, cell cycle control, transforming growth factor beta signaling, histone modification, switching/sucrose nonfermenting complex, phosphoinositide 3-kinase/mammalian target of rapamycin signaling, Wnt/beta-catenin pathway, RNA splicing, Notch pathway, angiogenesis, and hedgehog signaling. In addition, they analyzed tumor mutation burden in 1,021 samples and microsatellite instability status in 2,563 samples.
In all, the samples contained 19,120 genomic alterations of 317 genes. A total of 608 (17%) specimens harbored mutations considered actionable targets. These involved either the RTK/ras/MAPK signaling or DNA damage repair pathways. As expected, KRAS mutations were most common, but their penetrance (88%) was lower than in prior studies. This might be because the current study covered both resectable and nonresectable PDACs, while past studies tended to focus on resected PDACs only, the researchers said. Importantly, the 12% of KRAS wild-type PDACs often harbored other potentially targetable alterations of genes in the RTK/ras/MAPK pathway, such as kinase fusion, amplification, missense mutations, and intragenic-in-frame deletions.
A total of 81% of samples contained alterations of TP53 or other genes involved in DNA damage repair. Reflecting prior studies, the penetrance of individual DNA damage repair mutations was low – usually less than 5%. Most germline mutations involved the BRCA-FANC DNA repair pathway, and these may be targetable with agents such as poly (ADP-ribose) polymerase inhibitors and DNA strand-damaging, platinum-based cytotoxic regimens, the investigators wrote.
Among 3,117 samples with clinicopathologic data, 51% were from the primary tumor and the rest were from distal metastases of the liver, lung, nonregional lymph nodes, peritoneum, omentum, and other sites. Not surprisingly, BRCA1 and BRCA2 mutations were more common in younger patients, but KRAS, SMAD4, DNMT3A, and AP mutations were more common in older patients, and mutational frequencies also varied by sex, primary versus metastatic tumor status, and site of metastasis.
“The complex genomic heterogeneity in otherwise histologically similar PDACs suggests a one-size-fits-all approach to treating patients will not be successful,” they concluded. “Targeted genomic profiling of known genomic alterations across multiple tumor types highlights potentially targetable and predictive biomarkers for treatment in a significant subset of PDACs.”
Funders included the Pancreatic Cancer Action Network, the National Pancreas Foundation, and the Sky Foundation. Dr. Singhi and two coinvestigators reported receiving honoraria from Foundation Medicine, and seven other coinvestigators reported employment by and stock ownership in Foundation Medicine. No other disclosures were reported.
SOURCE: Singhi AD et al. Gastroenterology. 2019 Mar 2. doi: 10.1053/j.gastro.2019.02.03.