Germline Testing At Diagnosis Vital for Managing Pancreatic Cancers

Elena G. Chiorean, MD

Clinical trials for patients with pancreatic cancer have begun to offer an array of therapies that target certain mutations. There are also several FDA-approved targeted therapies for these patients. With all of these available options, Elena G. Chiorean, MD, stated that patients should undergo genetic testing at the time to diagnosis, during a presentation for the 17th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO 2020).

According to Chiorean, the key reason oncologists should perform genetic testing at the time of cancer diagnosis is to identify actionable mutations that are known to be present in up to 20% of patients. These mutations can include BRCA mutations, PALB2, KRAS, BRAF, and even microsatellite instability (MSI). There is also a subset of patients with pancreatic cancer who may also have NTRK fusions.

Pancreatic cancer has a treatment landscape that to-date is largely dependent on platinum-based chemotherapy and PARP inhibitors. However, for patients with MSI-high tumors, immune checkpoint inhibitors like pembrolizumab (Keytruda) appear to be promising. BRCA mutations have been shown to respond well to treatment with olaparib (Lynparza), and NTRK fusions have 2 FDA-approved agents as well, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi)

In an interview with Targeted Oncology following ISGIO 2020, Chiorean, oncologist, University of Washington Medical Center and Seattle Cancer Care Alliance, discussed universal genetic testing at the time of diagnosis for patients with pancreatic cancer, a topic she argued on during an ISGIO medical crossfire. She also explained the challenges with execute germline testing setting.

TARGETED ONCOLOGY: What is the current role of genetic testing in pancreatic cancer

Chiorean: The current role involves both germline testing, meaning blood testing for potentially predatory gene alterations, due to the impact that they have on prognosis, the potential treatment options, as well as screening. In addition, for people that have advanced disease, we recommend somatic tumor genetic profiling, which can help detect additional alterations, which are not at present, in the germline profile. The germline test applies to all patients regardless of cancer stage and the somatic tumor biopsy testing applies to those with advanced disease.

TARGETED ONCOLOGY: Can you explain the reason for you recommendation of genetic testing at the time of diagnosis in all patients with pancreatic cancer?

Chiorean: The reason being is that 15% to 20% of the time, patients may be found to harbor actionable mutations. For example, 1% of them may have something called MSI-high status, which means that immune therapies are a very good option in their treatment armamentarium. Another 5% to 10% of patients may have BRCA mutations or PALB2 mutations that pertain to very good results and prognosis on treatment with platinum-based chemotherapy, as well as with PARP inhibitors. Many other subsets, each in the order of 1% or less, may have access to clinical trials with targeted therapies that are not limited to KRAS G12C mutation, BRAF mutations, tumor mutation burden, and many others. I think that if possible, patients should be recommended to undergo genomic profiling on their tumors at the time of diagnosis, and everybody should have germline testing.

TARGETED ONCOLOGY: What are some ongoing challenges with implementing genetic testing in community clinics?

Chiorean: I believe the main challenge is the unavailability of genetic counselors to be able to discuss the implication of genetic testing with patients. In addition, for the tumor testing, I think that sometimes physicians may not recommend tumor testing due to the challenge of obtaining a biopsy, the cost of the profiling, and the fact that oftentimes that results are not actionable. It is only about 10% to 15% of the time that patients have actionable genetic mutations in the tumor. These mutations appear even less frequently in the blood. These are the challenges that we encounter today.

TARGETED ONCOLOGY: Which therapeutic agents are showing the most promise right now in pancreatic cancer?

Chiorean: The most promising agents are platinum-based chemotherapies and PARP inhibitors. For patients that have a germline BRCA1 or BRCA2 mutations as well as germline, PALB2 mutations. These by far have bean are well established and we have recent studies supporting the use of platinum chemotherapy for people that have DNA repair deficiencies, including a BRCA1, BRCA2, and PALB2.

In addition, the MSI-high patients benefit significantly from pembrolizumab or other immune checkpoint inhibitors. There is a small subset that may have a high tumor mutational burden of greater than 10 mutations per megabase of the DNA, and those patients also have benefitted from pembrolizumab. All of these agents are FDA-approved. For those that have BRCA mutations, olaparib is FDA-approved as maintenance therapy as long as the cancer doesn't grow for at least 4 months on platinum. We strongly recommend everybody to be tested for these alterations. A small subset of tumors have NTRK fusions, and we have 2 FDA-approved agents for patients with NRTK fusions which are entrectinib and larotrectinib. These agents confer response rate as high as 50% to 60%, and overall survival as high as 2 years for people with these alterations.

TARGETED ONCOLOGY: What is the key takeaway from you presentation and medical crossfire during ISGIO 2020?

Chiorean: I think the key take-home message is that there is a very significant advantage and benefit for patients to survive as long as possible if we know as much about them as we can, and that includes as much about their hereditary potential.

Based on an analysis of the several thousands of patients are performed in the Know Your Tumor Project sponsored by the Pancreatic Action Network, the overall survival in patients that had matched therapies based on their germline genetic profiling, patients had more than twice the overall survival compared with patients that either had the profiling done, but they did not have access to match therapy or the had no actionable genetic alteration.

The message I want to leave is that people with pancreas cancer may have longer lives and potentially better quality lives if they have genomic profiling and they’re identified to harbor genetic mutation and have access either to standard FDA-approved agents that target these alterations, or are enrolled in clinical trials appropriate for the genetic alterations that they may have.

TARGETED ONCOLOGY: What would you say to community oncologist treating patients with pancreatic cancer in their clinics?

Chiorean: I want to encourage our physicians that are in the community setting that while they may not have access to the clinical trials immediately, I think it would be still good to inform the patient of the availability of the genetic profiling such that the patient may decide for themselves whether they are willing to centers expertise to participate in clinical trials. The patients should be informed about the guidelines because these are national that should be pursued.