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Optimizing Application of Genomic Analyses Critical to Advancing Pancreatic Cancer Care

Gina Columbus @ginacolumbusonc
Published: Wednesday, May 23, 2018

Diane M. Simeone, MD
Diane M. Simeone, MD
Molecular abnormalities, such as BRCA1/2, ATM, CHEK2, and microsatellite instability (MSI), are a handful of subtypes emerging in pancreatic cancer research, but the way these are identified and targeted with treatment still requires further investigation, said Diane M. Simeone, MD.

State of the Science Summit™ on Gastrointestinal Cancers, Simeone, who was also chair of the meeting, discussed the molecular complexities of pancreatic cancer, some of the commonly identified mutations, and ongoing clinical trial efforts that may be game changing for the field.

OncLive: What did you highlight in your presentation on pancreatic cancer?

Simeone: One of the points I wanted to make is that we need to make advances and do things a little differently than we have been to really change outcomes for the disease, which right now is a 9% 5-year survival rate. One of the missing pieces of the puzzle is actually how to best apply genomic analyses to pancreatic cancer. There actually has been a lot of activity, but how to actually best utilize that to help guide patient care has still been a “black box.” 

Then, the second portion of my talk was on germline genomics. We perhaps underappreciate the presence of germline mutations in pancreatic cancer and [we should do] more comprehensive germline analyses; every patient with pancreatic cancer should get a germline analysis. Then, we will have a much higher likelihood of identifying individuals who have the disease at an earlier stage, increase our resectability rates, and increase overall survival. 

What are some of these emerging subtypes?

We still haven’t sorted out all of the emerging subtypes, but there are a couple that have fallen out. There is a small percentage of patients with MSI. Those are only 1% of pancreatic cancers, but there are some data that suggest that 1% of patients may be a population that responds well to immuno-oncology drugs. Therefore, we want to make the case, based on the lethality of the disease, that we would want to test every patient with pancreatic cancer to see if they are MSI high. 

Secondly, there are mutations in the DNA damage-response signaling pathway [such as] BRCA 1/2, but there are others like ATM and CHET2. These are also genes that are found to be present in the germline of individuals with an increased risk of pancreatic cancer. What we know is that those patients actually respond a little bit differently than others with pancreatic cancer, and we want to be able to tailor their therapy with that knowledge. 

If we look at all the mismatch repair deficient (dMMR) pancreatic cancers, which can represent about 20% of patients, we are going to make the case that every patient with pancreatic cancer should have a germline and somatic mutational analysis. 

You mentioned that we might be underappreciating germline mutations. Why is that?

We have typically relied on family history. Do [patients] have other people in [their] family who have pancreatic cancer? Are there other people [in their family] with related cancers? But actually, we found that many patients with cancer [don’t have a] complete family history. In addition to that, we find that when we have done germline analyses of patients with sporadic pancreatic cancer without a family history, we have had about 10% to 12% of patients who actually have a germline mutation.

Even in genes that are associated with other specific cancers, we have found [individuals] who come in with a sporadic pancreatic cancer—for example…a mutation in the p16 gene, which is associated with melanoma. This individual had no family history of melanoma. What it leads us to realize is that we're just at the tip of the iceberg in realizing that, in some families who have these mutations, the tumors that evolve aren’t always what you think.

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