Guiding Treatment Selection Through Molecular Testing in Metastatic Pancreatic Cancer

Filippo Pietrantonio, MD, National Cancer Institute of Milan, Italy, discusses the management of a patient with Lynch syndrome and microsatellite instability-high (MSI-H) metastatic pancreatic cancer to illustrate how molecular testing can inform treatment selection.

He reviews the patient’s treatment course, including preoperative FOLFIRINOX, surgery, and subsequent progression on gemcitabine plus nab-paclitaxel, followed by a durable response to pembrolizumab lasting more than 3 years. He also discusses the evidence supporting immunotherapy in MSI-H pancreatic cancer, the association between microsatellite instability and Lynch syndrome, and the importance of comprehensive genomic profiling and genetic counseling.

Transcript: 

Hi everyone, my name is Filippo Pietrantonio. I’m a GI medical oncologist at the National Cancer Institute of Milan in Italy. Today, I am presenting a clinical case of a 63-year-old male patient with a previous personal history of GI cancer. In particular, 25 years before, he had right-sided colon cancer, which was surgically treated, and then 10 years after, an adenocarcinoma in the left colon. This led to the diagnosis of Lynch syndrome due to the presence of MSH2 and MSH6 loss on immunohistochemistry.

In February 2022, so 10 years after, the patient showed a pancreatic mass and was unfortunately diagnosed with pancreatic cancer. The disease was potentially resectable, and CA 19-9 was within the normal range. The patient received neoadjuvant chemotherapy with the FOLFIRINOX regimen, with a very good response, and then underwent radical surgery.

Unfortunately, immediately after surgery, this patient developed hepatic metastases and subsequently received gemcitabine plus nab-paclitaxel as standard first-line therapy. Unfortunately, the disease progressed, with progressive disease as the best response.

Due to the presence of microsatellite instability confirmed with PCR, the patient received pembrolizumab according to the tumor-agnostic approval of this immunotherapeutic drug in patients with MSI-high solid tumors. What we saw during the treatment course with immunotherapy was a very good response, almost a complete response, with minimal radiological residual disease.

Now, after more than 3 years, treatment is still ongoing. It is well tolerated. The patient is fine, with no symptoms, and disease control is still ongoing.

This is very, very important because we must first highlight the importance of molecular testing in pancreatic cancer. There are several actionable alterations, including BRCA1 and BRCA2 and PALB2 mutations, germline alterations, microsatellite instability, and gene fusions. More recently, there are very frequent molecular alterations such as KRAS mutations, MTAP loss, etc.

Regarding microsatellite instability, it’s important to note that it is a very uncommon alteration in pancreatic cancer. It’s 1% or even less than 1% of all cases of PDAC. But it’s important because it’s a tumor-agnostic predictive biomarker of response and durable clinical benefit from the use of immunotherapy.

In particular, the use of pembrolizumab is supported by several studies, especially the KEYNOTE-158 study, which showed a promising response rate and survival with pembrolizumab in patients with pretreated MSI-high solid tumors. The results of this study led to the FDA’s tumor-agnostic approval of pembrolizumab in these patients. We know very well that this is related to the high tumor mutational burden associated with microsatellite instability.

Of course, in pancreatic cancer, there may be some histology-specific response features. In this study in particular, the response rate was lower, less than 20% compared with almost 50% of the overall study population. So the benefit in pancreatic cancer seemed to be lower. But we must also recall that the sample size of patients with pancreatic cancer in this study was very small, with just about 20 patients enrolled. This is also consistent with the rarity of microsatellite instability in pancreatic cancer.

The presence of microsatellite instability is highly associated with Lynch syndrome in pancreatic cancer and should trigger genetic counseling whenever microsatellite instability is detected.

Subsequent studies in the real world, such as the French international collaborative study led by Julien Taieb, showed that the use of immunotherapy is associated with durable clinical responses and benefit. We need to consider the use of immunotherapy in this patient population, especially in those who showed disease progression after at least one prior standard treatment line. 

I think we should test patients with pancreatic cancer, potentially with comprehensive genomic profiling. Nowadays, there are several targets. Microsatellite instability is potentially a very important biomarker, but we know that for the vast majority of patients with MSS disease, the most important biomarker is going to be KRAS, thanks to the results of KRAS inhibitors. 

Thank you very much for your kind attention. I am very happy to have shown this clinical case and shared our treatment decisions with you.