Pancreatic cancer has a five-year survival rate of less than 9%, and for late-stage patients, existing chemotherapies can only extend survival for a few months. Researchers at the University of Pittsburgh Medical Center (UPMC) and University of Pittsburgh School of Medicine now report the results of what they claim is the largest genomic profiling study of pancreatic ductal adenocarcinomas (PDAC) carried out to date, which has identified genomic signatures that may predict which tumors might be susceptible to chemotherapy. The study, reported today in Gastroenterology, also found evidence for heritable genes—including some BRCA genes that are also linked with breast cancer—which may predispose families to pancreatic cancer, and identified genetic alterations that may be used as early biomarkers of disease.
“People have been looking for such markers for a long time, and our study shows that it’s possible to break pancreatic cancer patients into different treatment buckets,” said Nathan Bahary, MD, PhD, oncologist at UPMC Hillman Cancer Center and associate professor of medicine at the University of Pittsburgh School of Medicine, and is senior author of the team’s published paper, which is titled, “Real-time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations that Might be Targeted with Existing Drugs or Used as Biomarkers.”
PDAC is the third leading cause of cancer death in Western countries. Surgery could potentially be curative, but the disease is often diagnosed relatively late, by which time less than 20% of patients will have operable disease, the authors noted. Relapse is also common among patients for whom surgery is feasible, and median survival is just 28 months with the most modern treatments. “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 team further wrote.
Genomic profiling has identified potential therapeutic targets for some types of cancer, and for lung and breast tumors, for example, it is possible to match targeted therapy to genomic profiles. Ideally, doctors would similarly be able to target chemotherapy treatment to PDAC tumors on the basis of their genetic background. “The complex genomic heterogeneity in otherwise histologically similar PDACs suggests a one-size-fits-all approach to treating patients will not be successful,” the team noted. “Hence, the allure of precision medicine.”
However, identifying targets for anticancer therapy in PDAC hasn’t been easy, partly because the major known mutated genes, KRAS, TP53, CDKN21, and SMAD4, can’t be targeted with existing drugs. Apart from these four known PDAC genes, pancreatic cancer is characterized by mutations in many different genes, and which are present at low-level frequencies. “The high genomic heterogeneity of PDAC partly explains the relatively slow progress in development of effective therapeutics, as patients in clinical trials are often tested in an “all-comers” design,” the authors further pointed out.
To try and more accurately identify genomic alterations that may represent new therapeutic targets or biomarkers for diagnostics, the team carried out targeted genomic profiling of a cohort of 3,594 PDACs, and evaluated primary and distant metastatic tumors from both biopsies and surgical resections. “We believe that this is the largest study in pancreatic cancer conducted using comprehensive genomic profiling to identify a broad set of genomic alterations, and ultimately, therapeutic targets, in this difficult-to-treat disease,” said co-author Siraj Ali, MD, PhD, senior director of clinical development at Foundation Medicine.
The results overall identified 19,120 genomic alterations in 317 genes. Although the most frequent genomic alterations involved KRAS, one “intriguing” finding, was that 12% of PDACs exhibited a normal KRAS gene, a higher proportion than indicated by previous studies. Additional genomic alterations occurred notably in TP53 (74% of tumors), CDKN2A (44%), SMAD4 (22%), CDKN2B (21%), ARID1A (8%), GATA6 (5%), and MYC (5%), as well as others.
“PDAC in older patients (≥50 years) were significantly more likely to harbor genomic alterations in KRAS, SMAD4, DNMT3A, and APC,” the researchers reported. “Conversely, BRCA2 and BRCA1 alterations were more commonly detected in PDAC from younger patients (<50 years).” A higher frequency of genomic alterations in KRAS, SMAD4, and CDKN2A were found in samples from female patients; while, PDAC in male patients more often exhibited alterations in GNAS, KDM6A, ATM, and SF3B1.” Also notable was the finding that while TP53 was the DNA repair gene most frequently affected in the 81% of samples that demonstrated changes to DNA damage repair, recurrent genomic alterations were also identified in BRCA2, ATM, BRCA1, and FACA.
“On the basis of previously reported actionable targets and predictive biomarkers, 608 of 3,594 (17%) PDACs were found to harbor alterations that are considered to be therapeutically relevant,” the team concluded. “Moreover, these genomic alterations can be subdivided into two categories: targetable alterations in the RTK/Ras/MAPK signaling and predictive biomarkers for treatment in the DNA damage repair pathway.”
In fact, most of the predictive treatment biomarkers were identified within the DNA damage repair pathway, and particularly the BRCA-FANC family of genes, which confers sensitivity to DNA strand-damaging platinum-based cytotoxic regimens (e.g., FOLFIRINOX) and PARP inhibition, the researchers further pointed out. “Consistent with prior reports, mutations involving individual genes within this DNA repair gene family were present at low-level frequencies (<5%), but collectively affected 14% of PDACs.”
The scientists acknowledged potential limitations of the study, which was also retrospective in design. “Our observational study was, however, able to demonstrate at least anecdotal evidence of clinical benefit by pairing known genomic alterations with specific anticancer therapy,” they concluded.
“Every pancreatic cancer is different, and performing molecular profiling of each patient’s tumor could help determine the best treatment options,” said lead author Aatur Singhi, MD, PhD, surgical pathologist at UPMC and assistant professor of pathology at the University of Pittsburgh School of Medicine. “Rather than blindly giving patients the same chemotherapy, we want to tailor a patient’s chemo to their tumor type. A one-size-fits-all approach isn’t going to work. Therefore, we would like to make molecular profiling standard-of-care for patients with pancreatic cancer.”
” … this study provides a compendium of known genomic alterations for PDAC that may serve as a clinical resource to guide future treatment for patients undergoing targeted genomic profiling,” the authors stated ” … the genomic characterization of IPMN-associated PDACs has identified several candidate genes involved in the malignant transformation of IPMNs [intraductal papillary mucinous neoplasms] and may represent diagnostic biomarkers for PDAC early detection strategies.”
