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  • Joan Miguel Romero

Pancreatic Cancer … Are we improving?

Introduction

November is pancreatic cancer awareness month. Pancreatic cancer continues to have the lowest 5-year overall survival rate of all cancers, with 8% of patients living longer than 10-years1. It is expected to be the third leading cause of cancer death, despite only being the 11th most common cancer2. This highlights its aggressive nature, with little change in mortality for the past few decades1. In 2017, we provided a broad overview of this disease, discussing the signs and symptoms, genetic changes, some exciting advances in research. We want to revisit this cancer and provide an update on recent findings in the past 5 years, discussing three important areas of pancreatic cancer research that have helped us understand this disease further and have paved the way for new and exciting treatment opportunities.


Genetics and pancreatic cancer

An important focus in pancreatic cancer now is genetic screening. The first part of this process includes obtaining a family history when a patient believed to have pancreatic cancer, to identify whether this cancer, or other associated cancers, runs in the family and may therefore have a hereditary component3. In fact, recent guidelines from the National Comprehensive Cancer Network, a not-for-profit organization that provides guidelines for cancer care, has now recommended genetic testing for any recent pancreatic cancer diagnosis5. This is because up to 10% of pancreatic cancers have a genetic link, including BRCA1 and BRCA2 mutations which may increase the chance of tumours being more susceptible to certain targeted therapies6. These findings have led to large, concerted efforts, including the Pancreatic Cancer Early Detection Consortium (PRECEDE) currently spanning 30 institutions in North America and Europe, to improve early detection and screening for patients with pancreatic cancer. These international efforts provide the necessary infrastructure to better improve collaboration and data transfer between institutions and provide hope for patients diagnosed with this disease.


KRAS inhibitors

KRAS is the most commonly mutated gene in pancreatic cancer, with up to 95% of pancreatic cancers arising from mutations in this gene7. KRAS is known as an oncogene, meaning it creates a protein that helps the cancer cells grow. Because of this, there has been a lot of effort in finding molecules that target and stop the function of the KRAS protein. A breakthrough in the oncology research community was an important paper demonstrating that a specific KRAS mutation, KRASG12C, could be blocked through a drug. This study, published in the New England Journal of Medicine (NEJM) in September of 2020, was a phase I clinical trial with 129 patients evaluating the safety of sotorasib, an inhibitor of KRASG12C. In addition to how safe the drug was, the researchers also wanted to see whether patients with this mutation had their tumours shrink following treatment. They found that in patients with non-small cell lung cancer, 88.1% of patients had either disappearance of their tumour, shrinkage, or no significant change in tumour size (stable disease). Similar results were seen in colorectal cancer (73.8%), and with other responses observed in rarer cancers, including pancreatic cancer8. Despite representing only 1.7% of KRAS mutations9 (the main KRAS mutation in pancreatic cancer is KRASG12D), the pharmacological targeting of KRASG12C has galvanized the pancreatic cancer community to continue finding ways of targeting its main cancer gene.


Immunotherapy in pancreatic cancer

Another exciting area of pancreatic cancer research is oncoimmunology. Oncoimmunology, the study of the role of the immune system in cancer, has led to the development of several important immunotherapies for the treatment of various cancers, including adoptive and chimeric antigen receptor T cell therapy, and immune-checkpoint inhibition10–12. The basis of oncoimmunology is the cancer-immunity cycle, a set of steps that must occur for a special type of cell, called cytotoxic T cells, to successfully target and destroy cancer cells. In recent years, key work has been done by several groups that target the different steps of this cycle. An important early step in this cycle is the activation, or “turning-on” of dendritic cells, which subsequently activate T cells. A group led by O’Hara and colleagues studied sotigalimab, an activator of a molecule called CD40 which activates dendritic cells, and found that the drug showed some effect against the cancer in this phase 1 study of untreated metastatic pancreatic cancer13. The second study focused on the interaction between T cells and cancer cells. Led by Yamamoto, the group found that an important molecule responsible for allowing immune cells to scan our body for sick or cancerous cells called major histocompatibility complex class I (MHC-I), was selectively removed from the cancer cell surface, essentially hiding the cancer cells from T cells14. Importantly, this process could be blocked by drugs in experimental models. Finally, a case report published in the NEJM in June 2022 by Leidner and his group showed a decrease in the size of tumours after a patient with metastatic pancreatic cancer was given engineered T cells that targeted KRASG12D on the cancer cells. Together, this work and that of many other scientists around the world are paving the way for new advances that help us better target, treat, and identify pancreatic cancer patients that can respond to immunotherapy.


Conclusions

As we round off 2022, there are still many areas of this disease that we do not completely understand. However, the work of countless groups and the increased collaboration in the pancreatic cancer research community has led to novel developments and that have advanced our understand of this disease and have continued to drive the research forward for patients suffering from this cancer. The continued efforts of the scientific and medical community will ensure that the fight against pancreatic cancer remains active, serving as inspiration and hope for patients suffering from this disease.




References

1. Canada S. Canadian Cancer Statistics 2021. Can Cancer Stat. Published online 2021:1-114.

2. Brenner DR, Poirier A, Woods RR, et al. Projected estimates of cancer in Canada in 2022. Cmaj. 2022;194(17):E601-E607. doi:10.1503/CMAJ.212097

3. Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology. 2022;163(2):386-402.e1. doi:10.1053/j.gastro.2022.03.056

4. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet. 2020;395(10242):2008-2020. doi:10.1016/s0140-6736(20)30974-0

5. NCCN. Pancreatic adenocarcinoma. NCCN Guidel. 2022;1.2022. doi:10.1097/01.JAA.0000718300.59420.6c

6. Connor AA, Gallinger S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat Rev Cancer. 2022;22(3):131-142. doi:10.1038/s41568-021-00418-1

7. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020;17(3):153-168. doi:10.1038/s41575-019-0245-4

8. Hong DS, Fakih MG, Strickler JH, et al. KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors . N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/nejmoa1917239

9. Li S, Balmain A, Counter CM. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer. 2018;18(12):767-777. doi:10.1038/s41568-018-0076-6

10. Morotti M, Albukhari A, Alsaadi A, et al. Promises and challenges of adoptive T-cell therapies for solid tumours. Br J Cancer. 2021;124(11):1759-1776. doi:10.1038/s41416-021-01353-6

11. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4). doi:10.1038/s41408-021-00459-7

12. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science (80- ). 2018;1355(March):1350-1355. doi:10.1126/science.aar4060

13. Hara MHO, Reilly EMO, Varadhachary G, et al. CD40 agonistic monoclonal antibody APX005M ( sotigalimab ) and chemotherapy , with or without nivolumab , for the treatment of metastatic pancreatic adenocarcinoma : an open-label , multicentre , phase 1b study. Lancet Oncol. 2021;22(January):118-131. doi:10.1016/S1470-2045(20)30532-5

14. Yamamoto K, Yano J, Venida A, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020;(August 2019). doi:10.1038/s41586-020-2229-5


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