Pancreatic cancer patients may harbor treatable germline mutations

Last Updated: 2020-02-28

By Marilynn Larkin

NEW YORK (Reuters Health) - Germline mutations commonly found in individuals with pancreatic ductal adenocarcinoma (PDAC) may be treatable and should be identified as soon as possible, a comprehensive review suggests.

"Germline testing is now part of national guidelines and standard practice for a person with pancreas cancer," Dr. Eileen O'Reilly of Memorial Sloan Kettering Cancer Center in New York City told Reuters Health by email.

"This testing is best conducted by using a panel of genes, which includes 10-12 core genes that are associated with both pancreas cancer predisposition and some with treatment," she said. "The specific treatment applications include the use of olaparib as a recent U.S. Food and Drug Administration-approved maintenance treatment in the setting of germline BRCA-positive pancreas cancer, and the use of checkpoint inhibitor therapy for those who have mismatch repair deficiency (germline Lynch Syndrome)."

Such testing is also important for identifying a potential family who may be at risk for other cancers, she added.

Dr. O'Reilly and colleagues reviewed key studies that established the frequency and types of germline mutations in PDAC, and implications for family members, strategies for genetic counseling, and treatment options.

As reported in JAMA Oncology, pathogenic germline alterations (PGAs) are relatively common in individuals with PDAC, with a frequency of approximately 10%.

The most common PGAs are in BRCA1, BRCA2, and ATM, and more rarely, in PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53, among others, for an aggregate frequency of 3.8% to 9.7%.

Treatment implications, as Dr. O'Reilly noted, include the use of checkpoint inhibitor therapy for mismatch repair-deficient PDAC and the validation of poly-ADP (adenosine diphosphate)-ribose polymerase inhibitor (PARPi) therapy as a maintenance strategy in platinum-sensitive PDAC.

The authors state, "With increasing evidence and slow improvement of outcomes, PDAC has entered the era of precision medicine...The studies included in this review used panels with varying numbers of genes, with the most consistent and commonly implicated PGAs in PDAC, irrespective of the risk profile of the individual, being BRCA1, BRCA2, PALB2, ATM, CDKN2A, MSH2, MSH6, MLH1, EPCAM, and TP53 given their potential for clinical actionability and importance to the individual and family."

"At a minimum," they suggest, "it is recommended that germline panels include these core genes, along with the inclusion of rare but important genes such as STK11, APC (OMIM 611731), PRSS1, and SPINK1 if warranted based on clinical features."

Dr. Sanjay Reddy, Assistant Professor, Department of Surgical Oncology at Fox Chase Cancer Center in Philadelphia, affirmed in an email to Reuters Health, "The era of precision medicine in pancreatic cancer is upon us."

"Historically," he said, "regimens consisting of gemcitabine or 5-fluorouracil have been the backbone of the disease. Choosing (the) chemotherapeutic option was often determined by factors not necessarily relevant to the tumor biology."

"Knowing that approximately 10% of PDAC patients will have some mutation, profiling of these tumors is important as early as possible," he said. "The more commonly known BRCA1 and 2 account for roughly 5% of the mutations, but the role for precision medicine is to potentially discover actionable mutations otherwise unknown, and to also identify family members who may also be at risk."

SOURCE: http://bit.ly/2TnnJvQ JAMA Oncology, online February 13, 2020.