TORONTO – Canadian researchers have identified the genetic signature that explains why up to 30 per cent of men with potentially curable localized prostate cancer develop aggressive disease that spreads beyond the gland after treatment with surgery or radiation.
The discovery means doctors may be able to predict at an early stage whether a prostate tumour will become aggressive and potentially deadly, allowing for more personalized treatment from the moment a man is diagnosed, said co-principal investigator Dr. Robert Bristow, a clinician-scientist at Princess Margaret Cancer Centre in Toronto.
“We used specialized state-of-the-art DNA sequencing techniques to focus on the genetics of prostate cancers to better understand what is so different from one man’s disease to another man’s disease,” said Bristow.
“These genetic fingerprints had high accuracy in being able to discern those men who do well with surgery or radiotherapy and those men that already have early spread of their disease outside the prostate gland,” he said.
“This information gives us … important clues as to how to better treat one set of men versus the other to improve cure rates overall.”
To conduct the study, published online Monday in the journal Nature, Bristow, co-principal investigator Dr. Paul Boutros of the Ontario Institute for Cancer Research and collaborators at Laval University in Quebec genetically analyzed the tumours of 500 Canadian men in the general population with localized, non-inherited prostate cancer.
The men had been treated with either surgical removal of the prostate or radiation, and the researchers looked at the genetic underpinnings of their tumours to see if there was a correlation between those who responded well to treatment and those who did not.
“And that starts to give us a hint as to if the patient didn’t do well and had a different signature than a patient who did do well. We start to develop really the genetic fingerprint of aggressive disease,” Bristow said in an interview. “And if we can do that, those are the patients who need to have intensified therapy.
“They can’t just have radiotherapy or surgery alone,” he said, suggesting these patients would also be treated with some form of chemo or hormone therapy because their cancer had spread elsewhere in the body.
Prostate cancer is the most common malignancy among Canadian men and the third leading cause of male cancer deaths after lung and colorectal cancers. An estimated 21,600 men in Canada were diagnosed with prostate cancer in 2016, and about 4,000 died from the disease.
In a related study published Monday in Nature Communications, the Toronto researchers and collaborators at Monash University in Melbourne, Australia, were able to show through genetic analysis why prostate tumours linked to the inherited BRCA2 gene mutation turn lethal, killing half of affected patients within five years of diagnosis.
About two per cent of all men with prostate cancer have a BRCA2 mutation.
BRCA gene mutations also affect women, putting them at high risk for aggressive breast and ovarian cancers. Actress Angelina Jolie, who carries a BRCA1 mutation, underwent a double mastectomy and removal of her ovaries and Fallopian tubes in recent years in a bid to prevent development of the deadly cancers.
Bristow said researchers compared the genetic signatures of 14 men with BRCA2-linked prostate cancer to those among the 500 men in the first study to identify whether there were key differences.
They found that genetic changes in tumours from the 14 men matched those associated with the spread of cancer and resistance to hormone therapy in the larger group of patients.
“They were already activated before the patient ever saw hormone therapy, so they’re almost primed to be resistant to our current therapies, even before we start,” he said.
“So it’s no wonder that men who have surgery or radiotherapy for BRCA2-associated prostate cancers do poorly — because the pathways that are existent for resistant cancer are already turned on.”
Knowing this could perhaps allow doctors in the future to try more targeted therapies earlier in the treatment regimen that would provide better odds of a cure, the researchers say.
“This work really gives us a map to what is going on inside a prostate cancer cell and will become the scaffold on which precision therapy will be built,” Boutros said in a release.
Bristow said the team will next work on translating its findings into a diagnostic tool that can be used to better tailor treatments for prostate cancer patients worldwide, a step he predicts will take two to three years.