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Refining molecular classification to improve treatments for patients with endometrial carcinoma

Molecular testing has allowed researchers to understand that not all cancers are the same—even if they grow in the same part of the body or look similar under a microscope. This is the case with endometrial cancers, where molecular features can be used to identify four prognostic subgroups. Pragmatic molecular classification tools, assessing key mutations or the presence or absence of specific proteins, were developed by BC surgeon-scientist Dr. Jessica McAlpine and her Vancouver-based team in parallel with a team in the Netherlands and, subsequently, adopted by the World Health Organization as standard of care in pathology reporting. Clinical guidelines integrate these features into risk stratification and treatment recommendations, providing a new framework for both research and day-to-day endometrial cancer management.  

“Over the past two years, there has been a sea change in the clinical management of endometrial cancers driven by the rise of molecular classification,” says the professor and co-division head of gynecology oncology at the University of British Columbia, and director of the OVCARE tissue bank at BC Cancer and Vancouver General Hospital. “But if we want this to have a more profound impact on patient outcomes, we need to address the remaining deficiencies and critical knowledge gaps that exist.”

What are the gaps? Molecular testing isn’t available to everyone, certain subtypes continue to be misunderstood, and the most aggressive subtypes have yet to receive effective therapies.  Dr. McAlpine and her team of immunologists, surgeons/clinicians, pathologists, scientists and bioinformaticians will aim to address these deficiencies with their new $2.2M in funding over four years as first-time recipients of a 2022 Terry Fox New Frontiers Program Project Grant (PPG).

Their PPG  -- one of two new awards this year -- will have three major projects, addressing important areas of this disease:

  • Project 1 will develop a clinical triage protocol to ensure “that every component of molecular classification is available to every woman in BC through a one-step DNA-based classifier.” This project will also assess artificial intelligence interpretation of histomorphological images as a tool to augment molecular classification and predict outcomes and better personalize treatments
  • Project 2 will seek to understand more about “outlier” endometrial cancer cases (outliers by appearance, molecular features or clinical outcomes) that do not fall into established subtypes to better understand what drives them and how to treat patients that fall into this group.
  • Project 3 aims to discover new and better treatments for a molecular subtype called p53 abnormal, the most aggressive molecular subset of endometrial cancer and responsible for more than half of deaths from this disease. McAlpine explains: “We’ve elucidated specific pathways within p53 abnormal endometrial cancers that we think can be targeted and are working to define biomarkers for treatment selection, as well as assessing efficacy of treatment in preclinical models.”’  

As a surgeon who treats patients with endometrial cancer daily, Dr. McAlpine knows that bridging these gaps in knowledge is the only way to accelerate discoveries that will help make precision medicine a reality for more patients with endometrial cancer.

“What gets me up and drives me every day is not just the tremendously rewarding experience of working with patients who are going through this challenging and very vulnerable cancer journey, but also, through our research, trying to change the endometrial cancer landscape in a way that makes an immediate or near-immediate difference for patients during the next three to five years,” she says. “I know our entire TFRI team feels the same. We are doing this for patients and their families, to improve things today and in the future."