Genetic Testing Essential to Advancing Pancreatic Cancer Paradigm

Margaret A. Tempero, MD

Although pancreatic cancer has not seen the rapid emergence of new agents occurring in other oncology fields, more widespread utilization of genetic testing may offer investigators a leg up in the fight against the disease, said Margaret A. Tempero, MD.

Arguably the biggest advancement made in recent years has been with the introduction of FOLFIRINOX in the adjuvant setting. Findings from the PRODIGE 24/CCTG PA.6 trial showed that the median overall survival (OS) in patients treated with modified FOLFIRINOX (mFOLFIRINOX) was 54.4 months versus 35.0 months with gemcitabine, translating to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; P = .003). Median disease-free survival (DFS) was 21.6 months versus 12.8 months, also in favor of mFOLFIRINOX. Moreover, the 3-year DFS rates were 39.7% versus 21.4% with mFOLFIRINOX versus gemcitabine, respectively, according to data presented at the 2018 ASCO Annual Meeting.

Beyond this success, a better understanding of an individual’s molecular markup is helping drive treatment decisions in this space, said Tempero, director of the Pancreas Center and the Rombauer Family Distinguished Professor in Pancreas Cancer Clinical and Translational Science at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. By performing genetic testing in every patient, investigators can detect potentially targetable alterations.

OncLive: What are the recent advances made in the treatment of patients with pancreatic cancer?

What were some of the encouraging data seen with FOLFIRINOX in this patient population?

What are the risks associated with FOLFIRINOX?

What other updates have we had in this space?

In an interview with OncLive, Tempero discussed the impact of FOLFIRINOX in the treatment of patients with metastatic pancreatic cancer and shed light on the importance of molecular profiling in the space.Tempero: The main recent advance has been the introduction of another adjuvant therapy that really seems to make a big leap in DFS and, we think, OS. That's FOLFIRINOX, which was introduced at the 2018 ASCO Annual Meeting and was immediately incorporated into the National Comprehensive Cancer Network guidelines. It would appear that using FOLFIRINOX as an adjuvant therapy following surgery would provide patients with a big advantage and increase their chance for a cure. That's obviously the most important goal you have when treating this disease.The survival data from the adjuvant FOLFIRINOX trial are still immature; it's going to mature over time, but it looks like we may be seeing a 40% OS, which is pretty much double what we've had in the past. It does seem to be a striking improvement.FOLFIRINOX is a pretty tough regimen for patients to handle. It causes myelosuppression, neuropathy, diarrhea, and several other symptoms like fatigue. These patients have just gone through a major surgery like a Whipple procedure. Therefore, that has been one of the issues: trying to strike the right balance between effective therapy and tolerable therapy. Not all patients are candidates for this treatment.We haven't had many new treatment options introduced, but we have had more direction regarding the importance of germline testing in patients. We have found that about half of the patients who carry a deleterious mutation, which puts them at risk for pancreatic cancer, actually don't have a family history—which would make you think you should do germline testing. Now that we understand this, we are making a strong recommendation that germline testing be considered for every patient. We are finding that many of the mutations that these patients carry have therapeutic implications. Not only do you find information that can very informative for their families in general, but you can also help the therapeutic direction.

Is there any ongoing work that you think has promise?

For instance, patients who have germline mutations in the DNA repair pathways are much more likely to respond well to a DNA-damaging agent. This may help you select something like FOLFIRINOX versus the other frontline option, which is gemcitabine and paclitaxel.There is a study in patients with BRCA1/2 mutations. [These mutations] are not that uncommon; about 5% of patients have a BRCA1/2 mutation. This is called the POLO trial, this was an AstraZeneca trial in which patients were treated optimally with FOLFIRINOX and then randomized to receive either placebo or olaparib (Lynparza), a PARP inhibitor.

Looking ahead, where do you see the field shifting?

Could you speak to the importance of molecular profiling?

We are hopeful that olaparib will help prolong duration of remission after initial chemotherapy. There was a similar trial in patients with BRCA-positive ovarian cancer that was reported at the 2018 ESMO Congress. This was an extremely positive study, so we hope to see the same success in pancreatic cancer.One of the biggest focuses that we have is figuring out how to make immunotherapy work. We are seeing glimmers of activity in select trials. If we can just figure out the biology of this and determine what we need to address to break through the immune barrier, that's where we are hoping to see success. There are interesting drugs in clinical trials working on mechanisms we haven't previously tackled, such as mitochondrial function. However, it will be quite a while before we see the results from those trials.We've just recently had another drug approved across all tumor types: larotrectinib (Vitrakvi); it's an NTRK inhibitor. You aren't going to find these mutations unless you look. You don't need to order one test at a time, you can get a whole battery of genes analyzed and you can have the microsatellite status identified to see if pembrolizumab (Keytruda) is an option. Increasingly, [molecular profiling] is becoming more important to us, especially if we have limited therapeutic options, as we do in pancreatic cancer. Our entire community is getting more favorably predisposed to doing somatic molecular profiling as much as possible.

Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. UNICANCER GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol. 2018;36(suppl 18; abstr LBA4001). doi: 10.1200/JCO.2018.36.18_suppl.LBA4001.