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Study puts spotlight on FDA’s accelerated approval of cancer drugs

Ten drugs given accelerated approval by the FDA remained recommended and in-market even if later found not to increase patient survival compared to standard of care

During the HIV epidemic of the 1990s, there were few drugs to combat the virus. With more-promising drugs in testing, pressure grew on the U.S. Food and Drug Administration (FDA) to speed their approval to get them to patients in desperate need. In response, an accelerated approval pathway was developed that allowed new drugs to be approved based on early evidence of benefit. This practice eventually grew to include cancer drugs, which now make up most of the drugs granted accelerated approval. Now, a study recently published in the British Medical Journal has found that in the end, many cancer drugs with accelerated approval have not proven to be of benefit to patients but continue to be used in the clinic.  

“The entire premise of accelerated approval is that a drug is allowed to enter the market under the condition that confirmatory studies are conducted within a reasonable amount of time and that they look at key clinical endpoints like overall survival and quality of life,” explains Dr. Bishal Gyawali, co-author of the study and Associate Professor at Queen’s University and OICR Clinician-Scientist. “However, some studies are delayed by years and often continue to use less-robust surrogate endpoints as evidence of benefit. In addition, even when no improvement in primary clinical endpoints is shown, the FDA can be slow to withdraw its approval and clinical guidelines do not always match the available evidence.”

To grasp the scale of this problem, Gyawali and his collaborators scanned the FDA database for all cancer drugs that had received accelerated approval between the creation of the pathway in 1992 and December 2020. Their analysis found that 10 cancer drugs failed to demonstrate clinical benefit in a combined 18 indications in confirmatory trials, all of which used overall survival as their primary endpoint and compared those drugs against the standard of care. However, a third of these indications for these drugs were allowed to remain on-label for an average of four years. The researchers also found that in most cases, even after a drug’s approval for a given indication had been withdrawn or revoked by the FDA, it continued to be strongly recommended in the National Comprehensive Cancer Network (NCCN) clinical guidelines.

Gyawali theorizes that a number of factors have led to issues with the accelerated approval pathway. He says it is a complex problem but highlights that the FDA faces immense pressure from pharmaceutical companies, patient advocacy groups and physicians to provide wider access to the latest drugs. Conflicts of interest may also be at play, given what Gyawali describes as a “revolving door” between officials at the FDA and the pharmaceutical industry.

“Accelerated approval is a fantastic pathway in theory, but how has it become broken, against the benefit of patients? In many cases it is not fulfilling the compromise between speed and evidence as was intended,” says Gyawali. “It is very understandable that patients want access to the latest drugs, but would patients want these drugs if they knew they were of no benefit? Not acting on the evidence is doing them a great disservice at an immense economic cost, given that in the U.S. Medicare must pay for drugs that are recommended in NCCN guidelines.”

NCCN guidelines are used globally, including in Canada, but Canada’s system of determining drug approval and funding has so far prevented the issues seen with accelerated approval in the U.S. “In Canada we have a two-step process with Health Canada approving drugs and a separate body (CADTH) deciding if they should be publicly funded,” he explains. “There are calls by some to combine the Canadian decision-making pathway into one so that any newly approved drug is automatically funded, but I think we need to treat the U.S. experience as a cautionary tale. Of the 18 indications that we highlight in our paper, most are not publicly funded in Canada. This demonstrates that our current system is working well, although there is always room to improve.”

Another aspect to improving decision-making to select the most effective new agents is robust quality-of-life assessments in clinical trials as well as real-world data through patient-reported outcome measures in addition to the clinical efficacy of new drugs. These factors need to be increasingly balanced into the whole equation, together with ‘toxicities’, both physical and financial.

Gyawali acknowledges that the problems with the FDA’s accelerated approval pathway are complex but says that there are avenues to improve the situation. “Really it all comes down to education. If we can train the next generation of oncologists to think differently about drugs and policy, they can become a force to push for improvements in the system and the type of information that is being used to inform treatment decisions,” he says.

“On the other side of the coin is patient advocacy groups. Some patient groups are also misled to believe that newer is always better. I speak to many patient groups to help them understand the nuances of such regulatory policies when it comes to cancer drugs. We need to make them allies in our efforts to improve the system so that it is of true benefit to patients.”

New AI tool enables analysis of millions of cells within minutes

Method eliminates the need for manual identification of cell types

Tumours are more than just a clump of cancer cells. Within them you will also find stroma cells connecting tissue, various immune cells, and other types. Understanding this cellular makeup is essential to many areas of cancer research, especially biomarker discovery. Recently, a team of Toronto-based researchers unveiled a new AI-based method of analyzing data from imaging mass cytometry (IMC) and other high parameter technologies used to determine a sample’s cellular profile. Their work is described in a recent article in the journal Cell Systems.

“One of the big questions in this field is how do you go from the raw data generated by highly multiplexed imaging such as IMC to actually determining the presence and abundance, or absence, of different cell types,” explains the study’s lead author Dr. Kieran Campbell, Investigator at Lunenfeld-Tanenbaum Research Institute and an OICR Affiliate researcher. “Right now, if you take a tissue section and run it through IMC there is quite a laborious, manual process of analyzing the resulting data that is open to subjectivity due to the need for human annotators to assign cell types.”

IMC provides a high-dimensional view of a tumour sample by mapping the expression of about 40 different proteins. Analysis of the data allows for single cells within a sample to be assigned to a type. To address the shortcomings of current methods of analysis Campbell and his collaborators created “Astir” (ASsignmenT of sIngle-cell pRoteomics) to automate the process of annotating cells, doing away with the need for human annotators and offering other advantages.

“Current methods of automation can only go as far as putting individual cells into groups and then it’s off to the human annotators to determine what the cells in those groups are. However, with Astir we can automate the assignment of cell types for each individual cell within a sample based on previously known biology,” explains Campbell. “Astir is also able to do this at great speed – in our study we showed that the system could assign a cell type to 800,000 cells in 15 minutes on a standard desktop computer.”

Campbell and his collaborators, which include Dr. Hartland Jackson, OICR Investigator, envision two primary uses for this new technology. In a discovery setting, researchers could use Astir to conduct an initial broad analysis of a dataset to get a high-level picture of the cellular makeup of their samples. In addition, with further development, the research group sees future clinical use for their invention to look for predictive or prognostic cell types within a single sample. “This tool is crucial for both our ability to analyze millions of cells from each clinical sample we investigate and within these samples identify rare cells that may play an important role in cancer development or progression,” explains Jackson.

“Infiltration of a tumour by immune cells is a prognostic indicator across many cancers, but to infer this from IMC currently requires a lot of manual analysis and expertise,” explains Campbell. “So this is really the first step towards automating that. We look forward to continuing development to include elements such as the spatial location of the cells within a sample with the goal of enabling new discoveries and ultimately helping patients.”

Clinical trial breaks new ground on using immunotherapy for more cancer types

Guided by blood samples, collaborative research team shows that patients’ tumour genomic and immune landscape predict response to a common immunotherapy

A Phase II clinical trial has shown that regular monitoring of circulating tumour DNA (ctDNA) in patients can be used to predict and assess the efficacy of the immunotherapy pembrolizumab. Building on that previous finding, a new study of the same patients’ tumours, co-led by Drs. Trevor Pugh and Lillian Siu, and recently published in Nature Communications, produced clinically significant findings that have bolstered understanding of how genomic and immune characteristics shape response to this therapy. The study, part of a clinical trial called INSPIRE at the Princess Margaret Cancer Centre (PM), was the first to test pembrolizumab across a range of metastatic cancers such as head and neck, breast and ovarian cancers and rare solid tumours.

“From previous research we knew that the level of ctDNA in the bloodstream is very strongly associated with response to this therapy – increases in ctDNA after treatment are predictive of poor outcomes,” explains Pugh, Director of Genomics and a Senior Investigator at OICR and a Senior Scientist at PM. “By looking at ctDNA and response to this immunotherapy across many different cancer types, we were able to get a better understanding of the underlying mechanisms – both immune and genomic – that determine how well this therapy works for an individual patient.”

The research team’s pan-cancer approach (studying across cancer types) allowed them to discover that in non-responding patients, many different molecular mechanisms were at play. “It was quite striking to see that many of these tumours had their own unique way of evading immune response from the therapy,” says Pugh. “It shows the need to break out of the cancer type-specific mold and expand our investigations to include the immune cells that infiltrate tumours and play a role in patient outcomes.”

These important findings were the result of a successful multi-disciplinary and inter-institutional collaboration that brought together researchers and clinicians from several organizations and specialties. The OICR-PM Joint Genomics Program and the PM Tumour Immune Profiling and Cancer Genomics Programs, with support from industry partners Natera and Merck, worked together to discover the new biomarkers.

“This study is a perfect example of what you can accomplish by taking a team approach to science. We are indebted to the study team, our patients and their families for their support.” says Siu, a Senior Scientist and medical oncologist at PM and the BMO Chair in Precision Cancer Genomics. “Through INSPIRE, not only did we discover new biomarkers, we also laid the groundwork for new investigator-initiated trials so that we can continue to find even more ways predict response to immunotherapy.”

It is anticipated that the knowledge generated from this study will be incorporated into clinical genomics reports generated by the OICR-PM Joint Genomics Program by screening patients for biomarkers of response to pembrolizumab and other immunotherapies so that the patients most likely to benefit enroll in these trials.

“As someone who leads a clinical lab, this really excites me,” says Pugh. “By building this new knowledge into the workflow of our CAP-accredited lab we can provide patients with another potential treatment option and help enable this type of therapy for more types of cancer, as it has only been commonly used in lung cancer and melanoma, with notable success.”

The study found that there are some shared ‘immunogenomic’ traits that predict response to pembrolizumab. For example, women with breast and ovarian cancers generally had a poor response to the therapy, but those that did respond shared molecular characteristics with melanoma patients who had similar outcomes.

“The work of our multidisciplinary team is allowing us to explore new uses of immunotherapies and will help us deliver even more useful information to patients and their doctors,” says Pugh. “We are excited to continue our work on this less-invasive method of managing patient care and are planning more studies to enable increased use of ctDNA and genome sequencing in the clinic.”

Read more: Princess Margaret Cancer Centre researchers expand understanding of immunotherapy benefits (UHN newsroom)

This work was supported by the Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Terry Fox Research Institute, Gattuso-Slaight Personalized Cancer Fund, BMO Chair in Precision Cancer Genomics, Canada Research Chair in Translational Genomics, Canada Foundation for Innovation, Ontario Ministry of Research and Innovation, and Merck for the study drug.

Researchers uncover evolutionary forces at play in the aging of the blood system and identify people at increased risk of blood cancer

Discovery could provide early warning for blood malignancies, triggering proactive screening and enabling early treatment

Toronto – (August 17, 2021) As people age, mutations can build up in blood stem cells and their clones in a process known as age-related clonal hematopoiesis, or ARCH. ARCH can be a risk factor for acute myeloid leukemia (AML), a form of blood cancer. New research provides insight into why some with ARCH go on to develop AML and others don’t. These findings, recently published in Nature Communications, have the potential to significantly advance the early detection and treatment of AML by identifying those at high risk of the disease so they can be monitored more closely.

The study, co-led by Dr. Philip Awadalla, Senior Principal Investigator and Director, Computational Biology at the Ontario Institute for Cancer Research (OICR) and Dr. Quaid Morris, Member, Computational and Systems Biology, Memorial Sloan Kettering Cancer Center (MSK) and OICR Associate, shows how the interplay of positive, neutral and negative evolutionary selection acting on mutations in aging blood stem cells can lead to AML in some individuals with ARCH. They did so by illustrating how negative selection, or ‘purifying selection’, present in individuals who did not go on to develop a malignancy, prevents disease-related cells from coming to dominate the cell population. These discoveries allow for the differentiation between those with ARCH who are at increased risk of developing AML and those who are not.

“We have shown that the constellation of evolutionary forces at play within hematopoietic stem cells can be a robust indicator of those who are at increased risk of blood cancers such as AML,” says Awadalla. “Being able to accurately classify patients based on risk can allow for more frequent and intensive screening for those with ARCH mutations with a concerning evolutionary signature.”

The research team computationally generated more than five million blood populations, trained a deep neural network model (a type of machine learning) to recognize different evolutionary dynamics and employed the model to analyze blood samples that had undergone deep genomic sequencing. These samples were from 92 individuals who went on to develop AML, and 385 who did not despite the presence of ARCH. The study is one of the first to use a single system of tools to capture the interaction of the multiple evolutionary forces at play in ARCH.

“The models we developed in this study can significantly increase the value of ARCH as a biomarker for blood malignancies,” says Morris. “Our team is looking forward to continuing to bolster our understanding of ARCH and seeing these advancements help patients.”

The researchers were able to show that these alternative evolutionary models were predictive of AML risk over time. Similarly, these tools were able to identify genes where mutations that are damaging to stem cells can accumulate.

“Our novel application of deep learning tools and population genetic models to genomic sequencing allowed us to classify the evolutionary interactions within a blood sample with a very high degree of accuracy,” says Kimberly Skead, first author and PhD Candidate in the Awadalla and Morris Labs at OICR, the Department of Molecular Genetics at the University of Toronto and the Vector Institute for Artificial Intelligence. “This level of resolution enabled us to understand how both positive and negative selection shape the aging blood system and to establish strong links to individual health outcomes, which bodes well for potential clinical use.”

“In the future, we can anticipate screening blood samples for early detection of disease and blood cancers. With these tools we can more proactively monitor people’s health. Early detection of cancer is critical with respect to prevention and effectiveness of treatment,” adds Awadalla.

This research was supported by the Government of Ontario through the Ontario Institute for Cancer Research and by the Ontario Ministry of Colleges and Universities to Awadalla, CIHR Frederick Banting and Charles Best Canada Graduate Scholarships (Masters and Doctoral) and Terrence Donnelly Centre Cecil Yip Award to Skead, and research grants from the Vector Institute for Artificial Intelligence to Skead. Awadalla is supported by a Natural Sciences and Engineering Research Council of Canada Award (RGPIN-2019-06813). Morris is supported by a Canadian Institute for Advanced Research (CIFAR) Artificial Intelligence Research Chair, the National Institutes of Health (P30 CA 008748) and core funding from Memorial Sloan Kettering Cancer Center. Genomic data generation was supported by the Canadian Data Integration Center (CDIC) with funds provided by the Government of Ontario and the Government of Canada through Genome Canada and Ontario Genomics (OGI-136).

Largest study of its kind informs treatment of breast cancer in men

Commonly used recurrence risk tests found to be useful for male patients

Breast cancer is usually thought of as a disease that affects women, but many are not aware that men can develop breast cancer as well. Two-hundred and forty men in Canada were diagnosed with the disease in 2020 and it is estimated that 2,650 men in the U.S. will be diagnosed this year. Given that only one per cent of breast cancers occur in men they have been largely left out of breast cancer research, including clinical trials, which makes clinical decision making more difficult for male breast cancer patients and their doctors.

“The biggest defining feature of a breast cancer, in both men and women, is the expression of the hormone estrogen receptor, with most breast cancers being estrogen receptor positive. Given the differences in hormonal chemistry between men and women, and that the vast majority of breast cancer research is on women, we decided to study if commonly used diagnostic tests were indeed useful for male patients,” explains Dr. Jane Bayani, Co-Director of OICR’s Diagnostic Development Program and Principal Research Scientist at OICR. “These tests are important as they help patients and clinicians decide on their approach to treatment.”

The study, recently published in NPJ Breast Cancer, found that the most common tests for breast cancer reoccurrence risk can be used to guide clinical decision making for male breast cancer patients. It evaluated the prognostic value of these tests by emulating the risk classifications from commercial Prosigna, OncotypeDX and MammaPrint tests, as well as using a 95-gene signature developed and patented by the OICR Diagnostic Development team. They found that at a population level the tests performed similarly in men as they do in women.

To assess the performance of the tests, the team built a custom tool that targeted the same gene expressions used in the risk tests and analyzed 380 samples collected as part of the International Male Breast Cancer Program, a global research collaboration. The results from those samples were then compared to patient records to see how well they corresponded to real world outcomes. The study is believed to be the largest comparison of commercial and academic risk tests in male breast cancers.

“We were pleased that our results show that these tests have comparable clinical utility in men as they do in women, however there is still much work to be done to better understand breast cancer in men,” says Bayani. “We are interested in understanding the role of androgens and their hormonal impact on biological pathways of breast cancer in men so that we can begin to improve precision medicine for these patients. Together with our research partners we want to close the knowledge gap when it comes to male breast cancer.”

This study was funded by Breast Cancer Research Foundation (BCRF), the Susan G. Komen for the Cure Foundation and the Government of Ontario.

Microscopes and molecules: New OICR Investigator Dr. Rola Saleeb brings integrated approach to cancer pathology

Dr. Rola Saleeb, a pathologist and researcher at St. Michael’s Hospital, Unity Health in Toronto and the University of Toronto is the latest recipient of an OICR Investigator Award. Saleeb’s appointment as an OICR Clinician Scientist will allow her to undertake her innovative research while maintaining a clinical role. In this Q and A, Saleeb talks about how she hopes to improve the clinical practice of pathology through research, her career journey, and the positive impact of OICR’s past and current support.

What is the focus of your research and what sort of projects are you currently engaged in?

My two main areas of research are kidney cancer and molecular pathology – sometimes these interests are combined, sometimes not. I am working to develop ways to combine a kidney tumour’s morphology (the way it looks under the microscope) with its molecular or genetic makeup. Through this approach we can improve clinical care by better classifying tumours to provide more-accurate predictions of outcomes or response to therapy. I am also interested in molecular testing across cancer types and in increasing its use in the clinical setting by developing ways to overcome existing barriers.

How has your clinical role influenced your research?

As a genitourinary pathologist my job is to give clinicians such as medical oncologists, radiologists and urologists the information that they need to manage a patient’s tumour. In my day-to-day work I am examining kidney, bladder, urethral and prostate cancers under the microscope to determine the specific type and stage of cancer and to provide a prediction of its aggressiveness. But not everything can be foretold by the microscope, which is why I think it is important that we continue to improve our ability to integrate tumour biology into our work as pathologists. I want to be able to provide my clinical colleagues and patients with the most accurate and useful information I can.

What do you see as challenges to increasing the use of molecular pathology in the clinic?

Early in my clinical career I became interested in genetic testing as a research area because I saw that despite its value, blocks remained to it being an easily accessible and common tool to aid in the management of cancer. Genetic testing often involves expensive tools and large pieces of lab equipment that can strain existing, limited lab space. Another issue is that genetic testing for cancer usually requires multiple tests, taking up more pathologist time and other resources. Lastly, it can take weeks for some of these tests to be processed and results provided, reducing their clinical utility.

How does your research aim to find solutions to these issues?

My collaborators and I have set out to develop a quicker, more efficient and less resource intensive approach to genetic testing. We are doing this by combining the cutting-edge technologies of next-next generation sequencers and genome engineering techniques, an approach we believe could return results to clinicians and patients within days. We are selectively targeting parts of the DNA that we want to analyze, meaning we save time by not sequencing the entire genome. We have also streamlined the process by being able to test for multiple biomarkers in a tumour at the same time, eliminating the need for multiple, individual tests. By personalizing testing and using smaller and less expensive equipment we can bring this approach to hospitals big and small and make a real difference for patients.

You were previously an OICR Transformative Pathology Fellow and received support from the Ontario Molecular Pathology Research Network (OMPRN). What has OICR’s support meant for your research and your career?

I applied to the Transformative Pathology Fellowship while doing my pathology residency and it really changed my entire career trajectory. It led to me pursuing a master’s degree and eventually a PhD and put me on the path towards clinical science and molecular pathology. The support from OMPRN was also key as it, along with the Fellowship, allowed me to publish some of my first research in the area and establish myself as a researcher.

You are now taking on a new role in the OICR community as a Clinician-Scientist. What excites you most about this position?

This is a really great opportunity because it allows me to do what I want to be doing and that is being an active pathologist and combining that with my efforts as a researcher. Having time set aside to be a scientist means that I will be able to really bring my experiences as a pathologist to bear and work to bridge the gap between research and the clinic. I am so thankful for the support and am excited to continue working alongside the amazing researchers of the OICR community.

Learning how to fly blind

New approach can detect cancer in different patients without the need for tumour biopsies.

Blood contains a vast array of components. In addition to blood cells, plasma and proteins, are free-floating pieces of DNA—some of which can originate from cancer cells and are known as circulating tumour DNA. Recent findings published in Clinical Cancer Research highlight a new approach to detect cancer in blood samples—opening up new possibilities for using blood-based tests to diagnose and monitor individuals with cancer.

The approach was developed by a multidisciplinary team that included researchers at the University Health Network, the University of Toronto and the Vector Institute. It was led by Drs. Scott Bratman and Daniel De Carvalho, Senior Scientists at the Princess Margaret Cancer Centre, and their graduate student Justin Burgener. OICR supported this research through funding provided to De Carvalho.

The strategy involved an integration of methods that analyzed different molecular features. The researchers performed in-depth sequencing on the free-floating DNA present in the blood to identify mutations specific to tumours. In addition to identifying these genetic features, the team measured modifications to that DNA—known as epigenetic changes—and analyzed the lengths of the DNA fragments, which provided rich multi-dimensional data. Also, to refine the data, DNA mutations and epigenetic changes found in white blood cells present in each sample, as well as blood from healthy individuals, were used to remove unwanted background noise.

“This integrated approach is unique and advances our ability to identify clinically relevant biomarkers for a wide variety of cancer types,” says Bratman.

The researchers chose to test the strategy in early stage squamous cell carcinoma, the most common type of head and neck cancer. Choosing this ‘localized’ type of cancer enabled the team to confirm that the blood test works for cancers that are located at single sites in the body, and before they begin to spread. It also verifies whether this test can be used when there are low amounts of free-floating DNA derived from tumours in the blood.

The researchers analyzed blood samples from 30 individuals with squamous cell carcinoma as well as blood samples from 20 healthy individuals. By comparing the rich sequence and epigenetic data between cancer and healthy samples, as well as with an existing sequence database known as The Cancer Genome Atlas, the researchers we were able to identify markers in the blood that could be used to predict clinical outcome and, potentially in the future, guide therapies.

“Doctors need better ways of detecting cancer and then monitoring treatment response without relying on tumour biopsies. Because our method can be applied across cancer types even when tumour tissue is not available for molecular analysis, it addresses a key limitation of current tests and provides new avenues for future research,” says De Carvalho.

This story was reposted with the permission of the Princess Margaret Cancer Centre. You can view the original post here.

This research was supported by the Gattuso-Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre; the Strategic Training in Transdisciplinary Radiation Science for the 21st Century (STARS21) training program; the Canadian Institutes of Health Research; the Ontario Institute for Cancer Research; the Province of Ontario; The Princess Margaret Cancer Foundation; the Conquer Cancer Foundation (American Society of Clinical Oncology); and the Princess Margaret Cancer Centre Head & Neck Translational Program, which is supported by philanthropic funds from the Wharton Family, Joe’s Team, Gordon Tozer and the Reed Fund. DD De Carvalho is a Tier 2 Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy.

Unravelling the secrets of the non-coding cancer genome

For Dr. Jüri Reimand, tracking down the mutations that cause cancer is a little like archeology – you must sift through all the elements to understand the whole story. “While every cancer genome contains a small number of driver mutations responsible for cancer, a far larger number of functionally inactive ‘passenger’ mutations tell us about the evolution of the cancer genome and its exposures over time,” he says.

Reimand, a Principal Investigator in OICR’s Computational Biology Program, and his team, have created a new computational tool to characterize mutational frequencies and processes affecting classes of functional genomic elements.

“While it is well-established that mutation rates are highly variable in the cancer genome and among different types of cancer, there is a need for computational methods to systematically analyze genomic elements to pinpoint those that display distinct mutational patterns,” says Christian Lee, co-first author of the study and graduate student at OICR and Department of Medical Biophysics, University of Toronto.

In particular, the team focused on the non-coding, regulatory genome for clues about the origins of cancer and mutations. “Mutations in the genome are not distributed randomly, only a small minority of all mutations cause cancer, and our tool helps identify these mutations and understand why they occurred,” explains Reimand.

In a recently published paper and another preprint, the research group describes how they analyzed mutational processes acting on different resolutions of the cancer genome and their underlying causes, such as faulty DNA repair mechanisms and lifestyle factors such as tobacco use and sun exposure. “We know that some regulatory elements of the genome have more mutations, for example the elements controlling highly active genes, or others that are consistently utilized in many types of cells. This accumulated damage may affect critical elements of oncogenes and tumour suppressors, potentially making the cancer more aggressive as it evolves.” says Reimand. “For example, our research has refined the mutational processes that affect non-coding regions involved in the 3D structure of the cancer genome.”

The tightly bound, dynamic structure of the genome is controlled by a specific group of proteins.  For example, the binding sites of CTCF, the master regulator of chromatin architecture, is frequently mutated in several cancer types. Using their newly developed tool, Reimand and team show that this signal is driven by a subset of highly conserved CTCF binding sites shared across dozens of cell lines. Disruption of these regions can alter the underlying DNA conformation and genetic interactions, and thereby contribute to genomic instability and cancer.

On the other hand, megabase-scale (1 million nucleotides) DNA domains are subject to different mutational processes that correlate with the epigenomes of cancer cells, and as such, understanding regional changes in the DNA allows us to predict when and where the passenger mutations predominantly occurred during tumour evolution.

“To better understand the formation of these mutations we need to use computational tools to look at many elements of the genome at the same time. There is a constellation of factors behind the formation of cancer,” says Reimand. “Our tools will enable us to better characterize patient information such as clinical and pathology data as well as lifestyle factors. There is also an opportunity to better understand the processes in rare hereditary cancers by linking specific inherited genetic risk variants with mutational processes in cancer genomes.”

Reimand’s work builds on the Pan-Cancer Analysis on Whole Genomes project which analyzed the genomes of 2,500 patients to better understand the inner workings of the non-coding regions of the genome.

Functional and genetic determinants of mutation rate variability in regulatory elements of cancer genomes

Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin

New OICR Investigator aims to improve cancer treatment in Ontario and worldwide

Dr. Bishal Gyawali, based at Queen’s University, is an expert in global oncology, cancer policy, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, supportive care, and global oncology.

The emergence of new cancer therapies and improved methods to screen for and diagnose cancer have led to marked improvements in survival rates for cancer patients. However, survival rates do not tell the whole story – a patient’s quality of life can be just as important. That is why Dr. Bishal Gyawali is interested in taking a value-based approach to cancer care. Gyawali, a newly appointed OICR Investigator based at Queen’s University, is using evidence, education and communication to deliver his message to stakeholders in the cancer care system.

“Every society has a limited amount of resources that they can devote to cancer care. We need to be sure that we are using these resources wisely by selecting proven, high-value interventions that have evidence of improving the duration and quality of patients’ lives,” says Gyawali. “When we are making policy and clinical decisions about a new cancer drug, we need to be asking what the societal value is. For many of the new cancer drugs there isn’t strong evidence that they actual improve a patient’s survival or quality of life.”

Gyawali, who is from Nepal, explains that he first became interested in this area of research working in Japan and then in the U.S. “Working in these high-income countries was eye-opening. I saw that yes, there were lots of resources, but a significant amount was being spent on things that were not helping patients,” says Gyawali.

To combat this issue, Gyawali has published several research articles to inform policy and has personally been involved in advocacy and policy works through his membership in committees and working groups of organizations such as the American Society for Clinical Oncology, the European Society for Clinical Oncology and the WHO-Essential Medicines List for Cancer Drugs with the ultimate goal to identify and reduce the use of unhelpful and low-value treatments and to educate physicians through these groups.

Gyawali is also trying to increase stakeholders’ understanding of clinical trial results. “My goal is to educate patients, clinicians and advocates about how to properly interpret the results of a clinical trial, so they have a clear picture of a drug’s potential benefits as well as its risks,” explains Gyawali. “Only when we truly understand what the data is telling us and how the trial was conducted can we best choose the right course of action.”

Making decisions about their treatment is just one of a number of challenges faced by cancer patients and their families. “There is a financial toxicity associated with cancer treatment,” says Gyawali. “Even though some of the costs of treatment may be covered by universal healthcare systems or private insurance, there are still many other financially damaging effects from cancer treatment. For example, the loss of wages, the costs of travel and parking as well as supportive care if needed. This added stress can have a significant negative impact on a patient’s quality of life. I want to help find ways to address these issues.”

Through his research, Gyawali wants to not only improve cancer care in Ontario, but worldwide, with a focus on low- and middle-income countries. “The global burden of cancer is immense and growing. Identifying interventions that are proven and affordable that can be deployed in these countries is essential to increasing equity in cancer care. There are lessons we can learn from low-and-middle-income countries for the benefit of Ontario and lessons Ontario can teach to the world as a leader in cancer care and research,” says Gyawali, a member of the Queen’s University Global Oncology Program.

Since coming to Ontario as a Clinical Fellow at Queen’s in 2019, Gyawali has gained an appreciation of the elements that make Ontario an ideal place to carry out this type of research. “Ontario has a world class community of researchers and some unique resources that have proven very beneficial to my research,” says Gyawali. “For example, the database maintained by ICES is an invaluable resource for finding evidence to support a value-based approach to care.”

Gyawali, who is now an Associate Professor in the Department of Medical Oncology at Queen’s is happy to be continuing his research in Ontario with the support of OICR. “This award from OICR helped me secure a faculty position at Queen’s and has allowed me to confidently plan my academic work. It also provided a sense of validation about my research and is great encouragement to continue,” says Gyawali. “It is fantastic that the Institute is supporting young researchers such as myself. I am excited to immerse myself in the OICR community and contribute to improved cancer policy and care in Ontario and worldwide.”

Dr. Geoffrey Fong receives prestigious O. Harold Warwick Prize from the Canadian Cancer Society

Dr. Geoffrey Fong, OICR Senior Investigator, has been selected as this year’s recipient of the O. Harold Warwick Prize from the Canadian Cancer Society. The Prize recognizes outstanding achievements in cancer control research. Fong has made exceptional contributions to the field of cancer control as the founder and Principal Investigator of the International Tobacco Control Evaluation Project (ITC Project). The ITC Project aims to evaluate the impact of tobacco control measures implemented through the WHO Framework Convention on Tobacco Control, the world’s first international health treaty. Fong’s research has demonstrated the effectiveness of measures such as plain packaging for cigarettes and bans on menthol in cigarettes. ITC Project findings have informed tobacco control efforts in Canada and in Ontario, for example, in support of smoke-free laws, including bans on smoking in cars with children. Fong’s work through the ITC Project has also made a significant impact internationally. The ITC Project covers 29 countries, inhabited by more than 50 per cent of the world’s population, 60 per cent of the world’s smokers and 70 per cent of the world’s tobacco users. Fong is also a Professor of Psychology at the University of Waterloo.

Read the announcement