This week we profile a recent publication in Clinical Cancer Research from Cameron Herberts (pictured, left), Dr. Simon Fu (centre), and Elie Ritch (right) in the laboratory of Dr. Alexander Wyatt (pictured, below) at the Vancouver Prostate Centre and BC Cancer.
Can you provide a brief overview of your lab’s current research focus?
The Wyatt laboratory aims to identify associations between molecular alterations in metastatic genitourinary cancers (e.g. prostate, bladder) and patient clinical outcomes. We hope that this will lead to better biomarkers for guiding therapy selection and improving patient quality of life and length of life. In particular, we leverage blood-based ‘liquid’ biopsies and we have previously shown that plasma circulating tumour DNA (ctDNA) is highly representative of metastatic lesions in prostate and bladder cancer, and that somatic alterations detected in ctDNA can help predict therapy resistance or response.
What is the significance of the findings in this publication?
A small proportion (3-5%) of metastatic prostate cancers have defects in DNA mismatch repair genes. These defects lead to a high tumour mutational burden (TMB), and characteristic microsatellite instability (MSI-high). It has been shown that metastatic prostate cancers with mismatch repair defects are likely to respond to immune checkpoint inhibition, a class of therapy that has little efficacy in unselected patients. Our latest paper, published in Clinical Cancer Research, demonstrates that mismatch repair defective metastatic prostate cancer can be identified and characterized using plasma ctDNA. Importantly, we show that it is not strictly necessary to identify the precise underlying defect (which can be very hard to detect), because the signature of high TMB and MSI can manifest at the genome-wide level, even in a liquid biopsy. In our study, we also explored the wider landscape of mismatch repair defective prostate cancer, and show that it is characterized by frequent tumour suppressor loss through compound heterozygous mutation, oncogene activation through hotspot mutation, and a rapidly evolving subclonal landscape. Indeed, among patients with multiple ctDNA samples and matched primary tumour tissue, we observed very high levels of spatial and temporal heterogeneity. Most of the patients we identified in our study had relatively poor clinical outcomes with standard of care therapy approaches, reinforcing the need to prioritize these patients for immune checkpoint inhibition in future.
What are the next steps for this research?
Since our research to date was retrospective, the next steps are to test the emergent hypotheses in prospective clinical trials. As such, we are performing the above ctDNA analysis on new samples generously donated by metastatic prostate cancer patients participating in a CCTG immunotherapy trial (clinical trial identifier: NCT02788773). We will also soon add an arm to our Canadian multi-centre phase II precision oncology trial (IND.234) where patients with mismatch repair defective etiology in their ctDNA will be treated with immune checkpoint inhibitors. Together we hope that these trials will help prove that ctDNA can be used as a biomarker to select patients most likely to respond to immune checkpoint inhibitors.
This work was funded by:
This study was generously supported by a Canadian Institutes of Health Research (CIHR) project grant, the Prostate Cancer Foundation (USA), and Prostate Cancer Canada.
