Pan-Cancer Analysis of Advanced Patient Tumors Reveals Interactions Between Therapy and Genomic Landscapes
This week we profile a recent publication in Nature Cancer from Dr. Erin Pleasance, Emma
Titmuss, and Dr. Laura Williamson (all pictured below) in the laboratory of Dr. Marco Marra
(pictured above, centre) at Canada’s Michael Smith Genome Sciences Centre at BC Cancer.
Can you provide a brief overview of your lab’s current research focus?
The BC Cancer Personalized OncoGenomics (POG) Program, co-led by Dr. Marco Marra, Director of Canada’s Michael Smith Genome Sciences Centre at BC Cancer and BC Cancer Medical Oncologist Dr. Janessa Laskin, is a patient-centric research initiative, consisting of oncologists, pathologists and other clinical, research, and technical personnel, studying the impact of embedding whole genome and transcriptome analysis into the clinical care of B.C. patients with advanced cancers.
POG is a world-leading research program that is using intensive genomic data collection and analysis to identify and better understand the genomic alterations that drive cancer growth, metastasis, and the biological evolution and response to therapies. Integration of genomic, transcriptomic, clinical, and treatment data provides a rich dataset for the interrogation and understanding of correlates of treatment response and resistance.
Analysis of the data from the first 570 patients, published in Nature Cancer’s April issue and featured on its cover, has demonstrated the impacts of therapy on cancer genomes and the potential for precision oncology to provide more effective therapeutic options for advanced cancer patients.
What is the significance of the findings in this publication?
Tumour sequencing from large-scale cancer genomic profiling initiatives has transformed our understanding of the genomic events that drive cancers, but has thus far mostly focused on primary disease and often only captures a small fraction of the genome. This in-depth analysis of the first 570 POG patients provides a unique, comprehensive characterization of whole genomes and transcriptomes from pre-treated, advanced cancer patients.
The cohort was comprised of a diverse group of patients representing 25 different cancer types from 18 anatomical locations from patients with complex treatment histories, enabling researchers to look broadly at genetic alterations that occur across many different cancers. In addition to known resistance mechanisms, the authors identified novel genomic and transcriptomic alterations associated with prior therapy and resistance. For example, the POG team uncovered an increase in mutations associated with prior therapy and elevated tumour mutation burden in tumours from patients treated with DNA damaging chemotherapy, a clinically important biomarker for response to immunotherapy. Mutations associated with prior therapy were higher in patients treated for longer periods of time, suggesting cumulative exposure to prior DNA damaging therapies can profoundly influence mutation landscape of advanced cancer patients.
The authors also analyzed the immune microenvironment across the diverse cohort of mostly metastatic tumours and identified clusters of patients with similar immune landscapes, independent of tumour type. The authors found that tumour mutation burden and immune microenvironment independently predict response to immune checkpoint inhibition across cancer types, providing the basis for the launch of a clinical trial of atezolizumab in patients with predictive markers for therapeutic response based on DNA and RNA sequencing (CAPTIV-8).
What are the next steps for this research?
Patients enrolled in the POG program consent to have their genomic data anonymously shared with the broader scientific community, each patient thereby contributing to the advancement of knowledge for the benefit of cancer patients around the world. Data sharing is vitally important for cancer researchers to discover subtle genetic patterns that would be impossible to detect in one individual, revealing themselves only when data from hundreds of patients are combined and analyzed as a whole.
Moving forward, the POG team will continue to enroll patients to make a difference in the lives of individuals while simultaneously providing a high-quality dataset to the broader scientific community. Findings from the POG program will continue to reveal genomic markers of response to therapy and provide a basis for further clinical research such as the CAPTIV-8 study.
This work was funded by:
This work would not have been possible without the participation of BC Cancer patients and their families, the multidisciplinary POG team (more than 200 oncologists, scientists, technicians and coordinators), Canada’s Michael Smith Genome Science Centre at BC Cancer technical platforms, and the generous support of the BC Cancer Foundation and their donors. We acknowledge contributions from Genome BC and Genome Canada , the Canada Foundation for Innovation, including the CGEn platform, the BC Knowledge Development Fund, the Canadian Institutes of Health Research, and the University of British Columbia Investigator Program.