expert roundtables

Role of Genetics, Immunology, and Biomarkers in Metastatic Pancreatic Cancer

by Alok Khorana, MD, Philip A. Philip, MD, PhD, FRCP, Margaret A. Tempero, MD

Overview

Our featured experts in the field discuss the role of genetic complexity, immunologic parameters, and biomarkers in metastatic pancreatic cancer.

Q:

What role do genetic complexity, immunologic parameters, and biomarkers play in the diagnosis and management of advanced pancreatic cancer?

Alok Khorana, MD

Professor of Medicine
Director, Gastrointestinal Malignancies Program
Cleveland Clinic
Cleveland, OH

This is a rapidly changing field. According to current approval by the US Food and Drug Administration (FDA), there is only one biomarker that has been shown to be of some value in pancreatic cancer. That is the serum level of CA 19-9. It is not to be used as a screening test, but it is to be used to guide whether patients are responding to systemic therapy or not. For patients who have a high level of CA 19-9, their level starts to come down with systemic treatment, and that generally indicates a response to treatment. Those data are not to be taken in isolation but should be taken in the context of other studies including imaging and staging studies. CA 19-9 marker has been around for a long time, but more markers are recently being studied. The most important one being studied is probably microsatellite instability (MSI) testing, which indicates whether patients have DNA mismatch repair deficiency. This has become important because, in early June 2017, the FDA approved the use of pembrolizumab, which is a type of immunotherapeutic agent for the treatment of patients with advanced solid tumors, who have been through standard of care treatment, for the subset of those patients who have high MSI due to deficient DNA mismatch repair. The FDA approval is largely derived from studies in other solid tumors, such as metastatic rectal cancer and metastatic gastric cancer where MSI high status is associated with a strong response to pembrolizumab. The FDA approval was beyond just those types of cancers. In fact, it was cytodiagnostic, which is the first time that I know of that FDA has approved a drug without specifying the type of cancer, such as gastric or pancreatic cancer, but rather stating that if you have any solid tumor with MSI high status, and you have been through standard care treatment and have no satisfactory alternative treatment options, you should be getting immunotherapy with pembrolizumab. It is important to note that MSI high status exists only in a small minority of pancreatic cancer patients (approximately 5%). We have very limited data on response rates in this population, but they do appear to be as high as in other solid tumors (approximately 50%). That is an important biomarker that has just become immediately practically usable.

Margaret A. Tempero, MD

Director, Pancreas Center
Professor of Medicine
Division of Hematology and Oncology
UCSF
San Francisco, CA

I think that we are getting a bit closer to having some real options for small subsets of patients. The first that springs to mind are patients who have MSI tumors. These would largely be patients with Lynch syndrome, and in that syndrome you do see an excess of pancreatic cancer. That is an area where you would definitely want to consider at least at some point in the patient’s therapeutic journey the use of pembrolizumab. The second area is patients with GERM line mutations in the DNA repair pathways. These patients are exquisitely sensitive to platinum drugs, particularly cisplatin. Therefore, these patients can be very effectively treated with gemcitabine and cisplatin and perhaps we will learn in the future that they can also be treated with approved PARP inhibitors, such as is being done now in patients with ovarian cancer who carry these mutations. Those are the 2 areas where we have some real traction. We do occasionally see anaplastic lymphoma kinase (ALK) rearrangements and other mutations that are potentially actionable, and we do like to send tissue out for extensive genetic testing when we can do it. Unfortunately, in this patient population, the disease is a very hypocellular one, so we often don’t have a lot of material to work with. Many biopsies that are obtained for diagnostic reasons are not sufficient for more extensive genetic analysis. That is why there is such a great interest in this patient population in looking at cell-free DNA or other surrogates for tissue based assays.

“I think that we are getting a bit closer to having some real options for small subsets of patients.”

Margaret A. Tempero, MD

Philip A. Philip, MD, PhD, FRCP

Professor of Oncology and Internal Medicine
Vice President for Medical Affairs
Barbara Ann Karmanos Cancer Institute
Wayne State University School of Medicine
Detroit, MI

In this disease, we do not have the luxury of a driver mutation that we can easily target with a drug to get a good benefit except for the BRCA1 and BRCA2, the MSI high patients, and the very rare ALK mutations. I have experience with trying genomic profiling on patients, and the frequency of tumor samples that are hypocellular is higher than the other cancers that I have dealt with in the gastrointestinal tract. Certainly, that is a problem because some of these patients are diagnosed with a fine needle aspirate, although gastroenterologists in some places are now able to obtain larger samples that can be used for genomic profiling in addition to the diagnostic, which is the basic test performed on those samples. There are some patients who can benefit from treatments that may work (for example, the MSI high tumors with immune checkpoint inhibitors, the BRCA1 and BRCA2 mutations with platinum compounds, or poly ADP ribose polymerase [PARP inhibitors]). I feel that patients should be profiled using the multi-gene profiling, even if we are seeing a very small number of patients who benefit from it. This disease also has KRAS mutations. Almost 100% have KRAS mutations, but we don’t have a drug to target the KRAS mutations. We see tumor suppressor gene mutations frequently (for example, P16, P63, and others), but again it is difficult to find a treatment that can benefit those patients at the present time. Overall, doing genetic profiling can give us some help in managing the patients, but the proportion of patients adequately matched to a treatment is still less than 10%.


“Overall, doing genetic profiling can give us some help in managing the patients, but the proportion of patients adequately matched to a treatment is still less than 10%.”

Philip A. Philip, MD, PhD

References

Aroldi F, Zaniboni A. Immunotherapy for pancreatic cancer: present and future. Immunotherapy. 2017;9(7):607-616.

Loosen SH, Neumann UP, Trautwein C, et al. Current and future biomarkers for pancreatic adenocarcinoma. Tumour Biol. 2017;39(6):1010428317692231.

Pavlidis ET, Pavlidis TE. Current molecular and genetic aspects of pancreatic cancer, the role of metastasis associated proteins (MTA): a review. J Invest Surg. 2017:1-13. doi: 10.1080/08941939.2016.1269854. [Epub ahead of print].

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