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Mutations May Help Target Pancreatic Cancer Tx

Genomic sequencing of pancreatic ductal adenocarcinomas (PDACs) found that 17% contained alterations that might make tumor cells susceptible to anti-cancer agents proven effective in other tumors – and perhaps serve as predictive markers of treatment, according to a large real-time molecular study of tumor specimens from several countries.

“We identified alterations that we didn’t know much about with respect to pancreatic cancer. And in a certain subset, we also found interesting genomic alterations that might confer susceptibility to therapies not known to be associated with pancreatic cancer,” the study’s lead author, Aatur D. Singhi, MD, PhD, of the University of Pittsburgh Medical Center Presbyterian Hospital, told MedPage Today. These included NTRAK1 fusions, which have been noted in thyroid, colon, and lung cancers, as well as BRAF deletions, which occur in melanoma.

Reporting in Gastroenterology, Singhi and associates noted that while precision medicine based on genomic profiling has become a treatment reality for some malignancies, identifying targets for therapy in PDAC has been more than challenging. Yet PDAC is the third, and soon to become second, highest cause of cancer mortality in Western countries, with a 5-year survival rate of less than 9%.

While surgery offers the only potential cure, fewer than 20% of patients present with operable disease, and even operable patients commonly relapse. Median survival is roughly 28 months even with modern adjuvant therapies. “Although exceptional responses to chemotherapy are anecdotally reported, there remains an urgent need to optimize patient selection for current treatment options and identify novel therapeutic strategies,” the researchers wrote.

Their study analyzed an international sample of 3,594 PDACs from patients in active treatment. The majority were ages 50 or older, and most were male. Countries supplying specimens included the U.S., Europe, Africa, and China.

The team used a targeted sequencing panel to identify genomic alterations known to be clinically relevant in multiple tumor types – that is, targetable by anticancer drugs currently available on the market or in registered clinical trials. These mutations included those potentially actionable via kinase inhibitors such as alterations in KRAS, MAP2K4, and BRAF, or via platinum-based regimens such as BRCA1/2, CHEK2, and PARP.

A total of 19,120 genomic alterations were identified in 317 genes, with KRAS, TP53, CDKN2A, and SMAD4 the most frequent mutations. KRAS mutations occurred in 88% of samples. Among PDACs with no KRAS mutations, there were alterations in genes whose products lie in the mitogen-activated protein kinase signaling pathway and are candidate actionable targets (n=132; 4%).

In addition, there were gene fusions (n=51), gene amplifications (n=35), genes with missense mutations (n=30), and genes that contain internal deletions (n=16). Also identified were germline alterations in the BRCA-FANC gene family.

Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14%. Among PDACs evaluated for microsatellite instability (MSI, n=2563) and tumor mutational burden (TMB, n=1021), MSI-high (H) and/or TMBH phenotypes were detected in 0.5% of samples.

The study also evaluated primary versus distant metastatic tumors from biopsies and surgical specimens and identified several candidate genes involved in the malignant transformation of precursor intraductal papillary mucinous neoplasms. These may prove useful in the future as diagnostic biomarkers for early detection of PDAC.

The ongoing real-time analysis has since profiled almost 5,000 patients, Singh noted. “Our next aim is to delve deeper into geographical differences in alterations and to look at response to therapy,” he added. In the meantime, the study provides a compendium of genomic alterations that may help guide future treatment.

Asked for his perspective, Michael J. Pishvaihan, MD, PhD, of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., who was not involved in the research, said the findings are consistent with other recent studies “showing that a not negligible percentage – 17% to 25% – of pancreatic cancer patients harbor mutations that could be targeted by therapies not typically used for this cancer.”

“The results confirm that we should be looking at the genomic profiles of virtually all pancreatic cancer patients,” he added. Moreover, clinical trials should now be designed to make promising therapies available to PDAC patients. “We need to recognize that these patients do have treatment options that can benefit them, and the benefit can be significant and measured in years not months,” he said.

Pishvaihan and colleagues recently identified two metastatic PDAC patients with NTRK1 fusions who had partial responses to the selective tyrosine kinase inhibitor entrectinib.

Study limitations, Singhi and co-authors said, included the retrospective, observational design and potential selection bias. In addition, diagnostic resection material and autopsy review were not available in all cases, and independent review of the medical records, including imaging, could not be done for all patients. Moreover, in 4% of the cases, targeted genomic profiling was canceled owing to inadequate neoplastic cellularity, low-quality DNA, inability to create a sequencing library, insufficient mapped reads, or failure to attain adequate depth of coverage.

Another limitation was the study’s definition of actionable genomic alterations, including TMB-H phenotype, which was based on the aggregation of multiple studies that included some single case reports and other tumor types.

Singhi reported a financial relationship with Foundation Medicine; other co-authors including Greenbowe, Chung, Schrock, Miller, Stephens, Ross, and Ali are employees and stock owners in Foundation Medicine. Pishvaian is a consultant for the precision medicine company Perthera, Inc.