Pancreatic Cancer … Where do we stand?

By Joan Miguel Romero

It was this year’s special topic in the Canadian Cancer Society’s Annual statistics report. It continues to have the lowest overall survival of all cancers, and its incidence is rising. It is projected to be the fourth leading cause of cancer death in Canada in both males and females by 2020. It has taken the lives of many including Steve Jobs, Luciano Pavarotti, Alan Rickman, and Patrick Swayze and despite an urgent need for improved detection methods and treatment, there is a lack of awareness for it. Do you know which disease I am talking about? I’m talking about Pancreatic Cancer.

Pancreatic cancer continues to have the lowest 5 year age-standardized net survival of all cancers, with approximately only 7 percent of patients surviving more than five years¹. In fact, only half of patients diagnosed with pancreatic cancer, the majority being pancreatic ductal adenocarcinoma, live past four months¹¹. Currently, the only curative treatment option is surgical removal of the tumour, but unfortunately 60% of patients are diagnosed with advanced disease, often making them ineligible for surgery¹. Despite ongoing research efforts, detection, management, and prevention of this disease hasn’t improved compared to lung, breast, colorectal, and prostate cancers¹ and the survival rate has minimally changed in over 50 years ².

So what do we know about pancreatic cancer? It is often asymptomatic, leading to advanced-stage disease at time of diagnosis¹. Of the few symptoms that may present, nausea and deep upper belly pain are described, while late stage signs include general weakness and weight loss³. A number of environmental risk factors, which can be monitored through life style choices, often contribute to the disease as well. Excess body weight and tobacco products are well-documented factors that correlate with increased risk. In Canada, approximately 7% and 17% of pancreatic cancer cases are attributed to excessive body weight and tobacco products, respectively¹. As with other cancers, decreased consumption of red meats and increased intake of nutrients from fruits and vegetables may potentially decrease risk of developing pancreatic cancer¹.

Progress in research has increased our understanding of the genetic and molecular changes that drive this disease. We know that there are four main driver gene mutations associated with the development of this disease: KRAS2, CDKN2A, TP53, and SMAD4³. KRAS2 is an oncogene, meaning it is responsible for helping the cells divide and proliferate, which cancer cells take advantage of. The last three, on the other hand, are tumour suppressors, meaning they are responsible for making sure cells are normal and healthy before they divide. In the past few years, several groups have worked to divide pancreatic cancers into subtypes based on common genetic changes^2,4–6. This has been instrumental in identifying which tumours may be more aggressive than others.

A recent advancement in oncology has been the emergence of immunotherapies, where our own immune system is given a “kick” to help fight of cancer cells. While pancreatic cancer is notoriously unresponsive to some of the more common immunotherapies, this month Nature Letters published a paper identifying unique properties of long-term survivors of pancreatic cancer. Balachandran et al. found patients that enigmatically lived longer with pancreatic cancer had increased neoantigens, or ‘odd’ molecules, and CD8⁺ T cell infiltrates (immune cells that can detect these “odd” molecules)⁷. What exactly does this mean? Simply put, since tumours carry many mutations in their DNA, they also produce mutated, or “odd”, molecules. It might surprise some of you to know that our immune system actually has cells that can kill tumors. This includes CD8⁺ T cells. These cells work by “seeing” these mutated molecules, termed neoantigens. So, having more neoantigens, as well as more of the tumour-killing cells which recognize them, may suggest why these patients may live longer. Indeed, the concerted efforts of many researchers around the world are elucidating the mechanisms of pancreatic cancer and will help bring new treatment options and care for patients suffering from this disease.

By living well, eating healthy and staying active, we can reduce our risks for pancreatic cancer, as well many other cancers and diseases.  Furthermore, knowing the early signs can help with detection of the disease at its earliest stages, providing to more treatment options to patients. And as we’ve seen, there are many dedicated researchers hard at work, trying to understand the fundamental processes of this illness and developing new therapies to help patients. So, let’s not give up hope. Pancreatic cancer awareness month may soon be over, but the fight isn’t.

References:

1. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2017. Can. Cancer Soc. 1–141 (2017). doi:0835-2976
2. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).
3. Hidalgo, M. Pancreatic cancer. N. Engl. J. Med. 362, 1605–1617 (2010).
4. Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–3 (2011).
5. Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).
6. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).
7. Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).