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  • Ruomeng Fang

Pancreatic Cancer - Part Two

Introduction

Pancreatic cancer is one of the most aggressive cancers. Despite significant increases in survival rates for other major cancer types, the 5-year survival rate for pancreatic cancer has remained low1. It is anticipated to become the second cancer-related cause of mortality in North America by 20302. Despite these grim statistics, important advances have been made that help researchers and doctors better understand the biology of pancreas cancer and identify the subtypes of patients that may respond better to chemotherapies. In this blog post, we will discuss two general classification systems of pancreatic cancer and summarize the different subtypes identified.


Histological subtypes of pancreatic cancer

In your body, the pancreas plays an important role in both the exocrine and endocrine system. As an exocrine organ, the pancreas can secrete digestive enzymes into the gut and help process the food you eat. As an endocrine organ, the pancreas can produce hormones such as insulin and glucagon that are helpful on controlling blood sugar levels. There are different histological types of pancreatic cancer, depending on what cells the cancer comes from and what the cells look like under a microscope. These can include pancreatic neuroendocrine tumours, adenosquamous carcinomas, colloid carcinomas, and medullary carcinomas. However, the main subtype is pancreatic ductal adenocarcinoma (PDAC). This pancreas cancer arises from the exocrine component of the pancreas. Identifying the histological subtype of pancreatic cancer is important, as some tend to be less aggressive than others. However, in addition to identifying the histological subtypes, researchers are now uncovering transcriptional subtypes using a technology called RNA sequencing, to further identify different subtypes. Given PDAC is the most aggressive and common subtype, we will now focus on the exciting work that is being done to uncover these subtypes in PDAC, which may predict aggressiveness and response to treatment.


Transcriptional subtypes of Pancreatic cancer

PDAC is a highly lethal malignancy that accounts for approximately 90% of all pancreatic cancer cases3. Because the majority of patients are diagnosed when the cancer has already spread, surgery is rarely offered at this stage. Therefore, chemotherapy becomes the most common treatment; however, only a portion of patients respond to chemotherapy. This has led to the emergence of clinical and basic research studies trying to identify different PDAC subtypes with prognostic and biological significance at genetic and molecular level.


In 2015, Moffitt and colleagues performed a type of genetic analysis and were able to classify PDAC tumors into two subtypes: “classical” and “basal-like”4. In simple terms, patients with classical PDAC tumors show improved response to chemotherapy; patients with basal-like PDAC tumors, which are molecularly similar to basal tumors in bladder and breast cancer, are chemotherapy-resistant and are usually associated to poorer prognoses. This has led other groups to further investigate this subtype to determine its prognostic capability. In addition, many groups have also made important contributions on helping identify other PDAC subtypes as well. Collisson and colleagues described a three-group classification based on the RNA analysis on clinical patient samples5, which they termed classical, exocrine-like, and quasi-mesenchymal. Bailey and colleagues further defined a four-group classification based on RNA expression profiles6. These subtypes were called squamous, immunogenic, pancreatic progenitor, and aberrantly differentiated endocrine exocrine (ADEX). Just like Moffitt and colleagues, these groups have shown similar prognostic and molecular significance, with potential implications in precision and targeted therapy. Moreover, further work has found overlap amongst subsets of these different classifications, confirming these subtypes as distinct entities7. Taken together, these exciting data are providing new avenues of research for pancreatic cancer with the ultimate goal of identifying patients that can respond to current and novel treatments.


Conclusions

Scientists are working to demystify cancer and discover more efficacious treatments. By validating these clinically meaningful PDAC subtypes, patients can receive the optimal chemotherapy regimens with feasible and faster techniques. Identifying patients responsive to current chemotherapies has the potential to improve the prognosis of patients diagnosed with this deadly disease, with potentially actionable results for patients in the near future.


References

[1] Siegel, Rebecca L., et al. “Cancer Statistics, 2022.” CA: A Cancer Journal for Clinicians, vol. 72, no. 1, 12 Jan. 2022, pp. 7–33., doi:10.3322/caac.21708.

[2] Rahib, Lola et al. “Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.” Cancer research vol. 74,11 (2014): 2913-21. doi:10.1158/0008-5472.CAN-14-0155

[3] Kleeff, Jorg, et al. "Pancreatic cancer." Nature reviews Disease primers 2.1 (2016): 1-22.

[4] Moffitt, Richard A., et al. "Virtual microdissection identifies distinct tumor-and stroma-specific subtypes of pancreatic ductal adenocarcinoma." Nature genetics 47.10 (2015): 1168-1178.

[5] Collisson, Eric A., et al. "Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy." Nature medicine 17.4 (2011): 500-503.

[6] Bailey, Peter, et al. "Genomic analyses identify molecular subtypes of pancreatic cancer." Nature 531.7592 (2016): 47-52.

[7] Raphael, Benjamin J., et al. "Integrated genomic characterization of pancreatic ductal adenocarcinoma." Cancer cell 32.2 (2017): 185-203.


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