New Clues to Pancreatic Cancer Subtypes' Unique Vulnerabilities

Pancreatic cancer anatomy concept , malignant tumor of pancreas: © Лилия Захарчук - stock.adobe.com

Pancreatic cancer remains one of the deadliest types, but research in this field is advancing. One area of interest is identifying differences between the subtypes of pancreatic cancer: pancreatic ductal adenocarcinoma (PDAC), the most common form, and the less common pancreatic adenosquamous carcinoma (PASC) and pancreatic squamous cell carcinoma (PSCC).

Investigators including Pat Gulhati, MD, PhD, assistant professor at the Rutgers Robert Wood Johnson Medical School, sought to identify differences in the genetics, immune landscape, and signaling pathways of these cancer subtypes. The findings were presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

PASC showed distinct genetic alterations compared to PDAC, including higher mutation rates in specific genes and amplifications of others. PASC also displayed increased expression of PD-L1 and immune-related genes, suggesting a potential for targeting it with immunotherapy. There was also a higher infiltration of CD4-positive T cells in PASC, indicating a more active immune response. Moreover, PASC had lower activity of the MAP kinase pathway compared with PDAC, potentially offering alternative therapeutic targets.¹

While no significant difference in overall survival was observed between PASC and PDAC, patients with PASC had better prognoses than patients with PSCC.

As the largest molecular analysis of PASC to date, this study provided valuable insights into this cancer subtype. However, further research is needed to translate these findings into improved clinical outcomes for patients.

In an interview with Targeted Oncology^TM, Gulhati discussed the treatment landscape of pancreatic cancer, the study’s findings, and the implications.

Pat Gulhati, MD

Targeted Oncology: What is the current treatment landscape of pancreatic cancer?

Gulhati: Pancreatic cancer is one of the most lethal cancers. This is partly due to the fact that many patients with pancreatic cancer are diagnosed at an advanced stage. Most patients that we as medical oncologists see in the clinic already have metastatic disease. There are currently no screening guidelines for this disease in patients who are at average risk.

As far as treatment goes, the majority of patients with advanced disease are treated with cytotoxic chemotherapy. There [are] 2 different types of first-line chemotherapy regimens. One is called FOLFIRINOX [leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, oxaliplatin]. The other is called gemcitabine/abraxane. We use various criteria to determine which of these treatment regimens to use in patients. Usually, 1 of these regimens is used in the first-line and in most cases, the second-line is the other regimen or a variant thereof.

There is another regimen that includes [nanoliposomal irinotecan (Onivyde)], which is also approved for use in pancreatic cancer. Furthermore, there is a subset of patients who may have underlying mutations in the BRCA gene or other DNA damage repair genes. For these patients, there is utility for [poly-ADP ribose polymerase (PARP)] inhibitors, which are a class of targeted therapies. We evaluate every single patient with pancreatic cancer for targetable alterations using next-generation sequencing. These can include alterations such as KRAS G12C, NTRK, RET fusions, among others; and all of these are now targetable with new drugs. These are some of the ways we try to treat pancreatic cancer in the clinic currently.

What is important in pancreatic cancer is that we need to improve our tools available for treating this disease. Clinical trials are an important way to improve our knowledge and treatment of pancreatic cancer. We and other institutions have many clinical trials ongoing for pancreatic cancer patients, so I always encourage patients to consider exploring and participating in these trials.

Can you summarize your abstract from ASCO GI and the goal of the analysis?

We looked at a subtype of pancreatic cancer called pancreatic adenosquamous cancer and compared pancreatic adenosquamous tumors and pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma is the most common subtype of pancreatic cancer that we see in the clinic. If there are differences, then it is going to be important to develop different methods of treating pancreatic adenosquamous cancer vs pancreatic ductal adenocarcinoma in the future.

Can you summarize your findings?

There were 3 major takeaways from this abstract. I want to emphasize that these are preliminary findings, and we are trying to validate these in a larger cohort now. The first finding is that we identified several genes which had higher mutation rates in pancreatic adenosquamous cancers compared with pancreatic ductal adenocarcinoma. Some of these genes included CDKN1B, SF3B1, PTEN, [and] BCL9. There were amplifications in AKT2, which were higher, and also ROS1 fusions, which were higher in pancreatic adenosquamous cancers.

The second finding is that there were several genes in the YAP signaling pathway, which were differentially expressed between pancreatic adenosquamous cancers and pancreatic ductal adenocarcinoma. This is an important pathway, and there are drugs in development targeting that YAP signaling pathway. It will be interesting to see the efficacy of these drugs in pancreatic cancer down the road.

The third interesting finding is that there was higher expression of PD-L1, and a trend towards higher rates of [microsatellite instability]-high and [tumor mutational burden]-high in pancreatic adenosquamous cancer. There were higher numbers of CD4-positive T cells in pancreatic adenosquamous tumors, and there was a higher interferon gamma signature compared with pancreatic ductal adenocarcinoma. Taken together, this raises the question whether there may be a role for immunotherapy in this subtype of pancreatic cancer. This is a question that would be best answered using prospective clinical trials, however this is difficult given the rare nature of pancreatic adenosquamous tumors.

Are there any takeaways for community oncologists?

It is important to do next-generation sequencing in every single pancreatic cancer patient, regardless of whether it is pancreatic adenosquamous cancer or pancreatic ductal adenocarcinoma, because this is how we find new and personalized ways to treat their cancer other than chemotherapy. It is also important to do germline testing in all pancreatic cancer patients. From a chemotherapy standpoint, we do not have any key takeaways from this study yet. The data are preliminary, and we are looking at a larger cohort of patients with this disease, to validate our findings.

REFERENCE:

1. Kania B, Baca Y, Riedlinger G, et al. Genomics and transcriptomics of pancreatic adenosquamous carcinoma. J Clin Oncol. 2024; 42 (suppl 3)abstr 691. doi: 10.1200/JCO.2024.42.3_suppl.691