Distinct Mutational Signatures Correlate With Increased Immune Activity in Pancreatic Cancer

MedicalResearch.com Interview with
Dr. Ashton A. Connor, MD
PanCuRx Translational Research Initiative,
Ontario Institute for Cancer Research
Dr. Steven Gallinger MD, MSC
Division of General Surgery
Toronto General Hospital
Toronto, ON

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The etiology of pancreatic ductal adenocarcinoma (i.e. “pancreatic cancer”) and the relationship between the tumour and its characteristic dense, encroaching stroma are still poorly understood.

Using whole genome sequencing in two large cohorts, we show that there are four fundamental mutational processes that give rise to pancreatic cancer.
With expression data, we also show that the interaction between the tumour and the surrounding stroma varies with the type of mutational process found in the tumour. Specifically, tumours with defective DNA repair, either homologous recombination or mismatch repair deficiency, elicited strong anti-tumour immune responses, likely due to the relatively high numbers of neoantigens in these tumours.

Individually, these concepts have been studied in other cancer types, but we are first to apply either of these to pancreatic cancer, and we also the first to integrate these two aspects of cancer biology for any tumour, to our knowledge.

MedicalResearch.com: What should readers take away from your report?

Response: Our results will hopefully be of interest to both the scientific and clinical communities.

Most of all, I hope that the scientific community is interested in the heterogeneity of the tumour-stroma interaction, which merits further study. There are certainly additional tumoural and stromal factors that impact on this relationship, which may be exploitable in rational drug trials.

The clinical community should note most of all that one of our pancreatic cancer cases with Lynch syndrome had a good response to immunotherapy, as we predicted from our pre-treatment sequencing data. Immunotherapy has been tried in small numbers of pancreatic cancer patients without biomarker guidance and without encouraging results. This study should demonstrate that in carefully selected patients, which we estimate at ~10% of all pancreas cancers, there is the potential for effective immunotherapy. That obviously depends on other factors beyond the tumour-stroma interaction, and further translational research will advance this field.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: There are many avenues for future research based on this study.
Clinically, the most obvious is whether tumour sequencing can identify biomarkers that can potentially impact patient care in real time. We’ve started a clinical trial for patients with metastatic pancreatic cancer at the Princess Margaret Cancer Centre. We are performing whole genome and transcriptome sequencing of biopsies taken at the time of diagnosis, and returning the analyzed data to the treating oncologists within 8 weeks, in time to inform second-line therapies. Much of the interpretation of that data is driven by our findings in this paper on resected disease.

Translationally, we need readily accessible tests to stratify tumours in to the mutational groups identified in this study. We showed that mismatch repair immunohistochemistry accurately identifies the pancreatic cancers with microsatellite instability. However, our study and others have suggested that homologous recombination deficiency is also an important biomarker in selecting systemic therapies, and there is currently no comparable test for this which can be applied to patient samples. A straightforward assay for homologous recombination deficiency would be real received by clinical labs.
Scientifically, even though we know the mutational processes giving rise to pancreatic cancer, we still do not know the specific genes or pathways responsible for many of those processes. There is much more work to be done on that front.

MedicalResearch.com: Is there anything else you would like to add?
Response: I must strongly emphasize that this project could not have been completed without large, collaborative, multi-disciplinary consortia that agreed at their outset to openly share their data.

As Bertrand Russell noted, the pace of science slows as the time required to make a discovery lengthens. It is no longer possible for scientists and clinicians to advance cancer research and oncology care in silos. This study should hopefully stand out as a good example of what can be accomplished with transparent collegiality. This should encourage other groups, particularly clinical trials, to make their data freely available to the greater scientific community.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.


Connor AA, Denroche RE, Jang GH, Timms L, Kalimuthu SN, Selander I, McPherson T, Wilson GW, Chan-Seng-Yue MA, Borozan I, Ferretti V, Grant RC, Lungu IM, Costello E, Greenhalf W, Palmer D, Ghaneh P, Neoptolemos JP, Buchler M, Petersen G, Thayer S, Hollingsworth MA, Sherker A, Durocher D, Dhani N, Hedley D, Serra S, Pollett A, Roehrl MHA, Bavi P, Bartlett JMS, Cleary S, Wilson JM, Alexandrov LB, Moore M, Wouters BG, McPherson JD, Notta F, Stein LD, Gallinger S. Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. JAMA Oncol. Published online October 20, 2016. doi:10.1001/jamaoncol.2016.3916

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