UHN study validates new tool to predict risk of lung cancer spread to the brain

​(Toronto, Oct. 8, 2024) – In a study published today in Nature Medicine, University Health Network (UHN) researchers have identified specific DNA changes that can predict a patient's risk of cancer spreading to the brain, offering new approaches to managing patients and improving health outcomes.

The spread of cancer to the brain, known as brain metastasis, significantly reduces patient survival rates, with a median patient survival of only 10 months to 16 months. Unfortunately, brain metastases are common and make up the majority of brain tumours.

Predicting a patient's risk of developing a brain metastasis remains a major challenge. Typically, by the time brain metastases are detected, patients are already experiencing headaches or other neurological symptoms, and treatments such as surgery or radiotherapy, are mainly palliative. There has been an important need for molecular biomarkers of brain metastasis risk to improve outcomes for these patients. However, currently there is no reliable approach to do this used in clinical practice.

"The key here is that our model identifies which patients are at risk of developing brain metastasis early to allow them to be monitored closely and started on treatment as soon as possible," says Dr. Gelareh Zadeh, co-Director of UHN's Krembil Brain Institute, Senior Scientist at UHN's Princess Margaret Cancer Centre, Head of the Division of Neurosurgery at UHN's Sprott Department of Surgery, and senior author of the study.

A research team led by Dr. Zadeh examined modifications to DNA, specifically DNA methylation alterations, for the new purpose of predicting the risk of developing brain metastases from lung adenocarcinoma (LUAD). DNA methylation findings have been used for diagnosing and assessing the onset of other cancers, but had not yet been comprehensively evaluated for predicting brain metastases in patients with cancer. The team developed and validated a computational model to predict patients' brain metastasis risk based on the DNA methylation signals in their tumour.

The model determines whether a patient's risk for developing a brain metastasis within five years of their cancer diagnosis is high or low, and its accuracy was compared to that of traditional cancer stage-based prediction by clinicians. The team found that their model reliably predicted the development of brain metastases in LUAD patients and was considerably more accurate than the stage-based approach currently used in clinical practice (81 per cent compared to 65 per cent).

"We compiled an extensive DNA methylation dataset of 402 tumour tissue and plasma samples from 346 patients with LUAD, including those who did and did not develop brain metastases, in order to develop and validate our prediction tool," says Dr. Jeffrey Zuccato, a PhD candidate in Dr. Zadeh's lab, recent graduate from the Neurosurgery Residency Program at the University of Toronto, Skull-Base Neurosurgery Fellow at the University of Oklahoma Health Sciences Center, and lead author of the study. "Our tool predicts brain metastasis risk more accurately than what has been shown or used to-date, and with an accuracy high enough to ultimately move towards changing our strategies for caring for patients."

The researchers also identified DNA methylation alterations in patient plasma, and built an additional set of models that can be used for reliable liquid biopsy of brain metastases using blood samples, a non-invasive approach. They are now moving towards translating this work into clinical practice and working on approaches to use these tools in clinical decision-making to improve patient outcomes.

"Understanding an individual patient's risk has the potential to transform care by enabling us to tailor our management approach to improve patient survival and quality of life," explains Dr. Zadeh, who is also a professor in the Department of Surgery in the Temerty Faculty of Medicine at the University of Toronto.

"This is a really exciting development," adds Dr. Vikas Patil, scientific associate at UHN's Princess Margaret Cancer Centre and co-senior author of the study. "This methylation-based model gives us the opportunity to predict cancer spread and attempt to intervene early to try and prevent it, putting us in a better position to manage this challenging condition."

This work was supported by UHN Foundation, The Princess Margaret Cancer Foundation, the Krembil Foundation, the National Cancer Institute, National Institutes of Health, the Canadian Institutes of Health Research, the Canadian Cancer Society, Brain Canada, and the MacFeeters Hamilton Centre for Neuro-Oncology Research Fund.

About the Krembil Brain Institute

UHN's Krembil Brain Institute at Toronto Western Hospital is home to one of the world's largest and most innovative teams of physicians and scientists uniquely working hand-in-hand to prevent and confront problems of the brain and spine. One in three Canadians will experience a brain-related condition such as Parkinson's, Alzheimer's or epilepsy in their lifetime. Through state-of-the-art patient care and advanced research, we are working relentlessly to find new treatments and cures. www.uhn.ca/Krembil

About University Health Network (UHN)

UHN is Canada's No. 1 hospital and the world's No. 1 publicly funded hospital. With 10 sites and more than 20,000 TeamUHN members, UHN consists of Toronto General Hospital, Toronto Western Hospital, Princess Margaret Cancer Centre, Toronto Rehabilitation Institute, The Michener Institute of Education and West Park Healthcare Centre. As Canada's top research hospital, the scope of biomedical research and complexity of cases at UHN have made it a national and international source for discovery, education and patient care. UHN has the largest hospital-based research program in Canada, with major research in neurosciences, cardiology, transplantation, oncology, surgical innovation, infectious diseases, genomic medicine and rehabilitation medicine. UHN is a research hospital affiliated with the University of Toronto.www.uhn.ca