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SRI Magazine 2016

SRI Magazine 2016

"Bespoke" prostate cancer treatment

Genomics and imaging tools are cracking the tough nut of prostate cancer, exposing which patients are most likely to get worse, and where tumours might be concealed

“How do we diagnose prostate cancer more responsibly and avoid overdiagnosis?” Dr. Masoom Haider pauses, having arrived at this crucial question midway through the interview. “We’ve talked about screening, overdiagnosis and PSA [prostate-specific antigen test] not being recommended for a number of years now,” says Haider, a senior scientist at Sunnybrook Research Institute (SRI) and chief of medical imaging at Sunnybrook. “What’s a man supposed to do?”

Since 1994, the PSA test has been used to screen for prostate cancer. The test is based on PSA levels in the blood. In healthy men, these are very low, whereas men with prostate cancer typically have elevated PSA levels. High levels can also result from a noncancerous condition, like an enlarged or infected prostate, and cannot, by itself, distinguish between aggressive cancer, which needs immediate treatment, and slow-growing disease that can be left untreated. “If you screen for prostate cancer you lower the mortality [rate], but you also find a lot of cancer that is clinically insignificant,” says Dr. Laurence Klotz, a urologist at Sunnybrook and a researcher at SRI. “If you treat all those patients aggressively, screening is not palatable because you have so many patients who are overtreated.”

Aggressive treatment for prostate cancer involves radiation and surgery to remove the prostate. Both therapies can have side effects, most commonly, erectile dysfunction, loss of bladder control and problems with rectal function. These effects may be acceptable when the treatment is life saving, but in men for whom the disease poses no threat, they are unnecessary and harmful. Despite the risk of overtreatment, Klotz and Haider say there is value to PSA screening. They, along with other doctors and researchers, are trying to make screening practices more effective. Their work is shedding light on the biology of prostate cancer and how doctors can treat patients based on their individual risk.

In a sun-lit office tucked away in the research wing of Sunnybrook, Dr. Arun Seth is working to turn his scientific discoveries into prognostic tools to predict a patient’s prostate cancer risk and outcome. Seth is a senior scientist at SRI. He studies microRNAs, small molecules in the cell that help regulate gene function by controlling protein production. “There are some microRNAs known to either increase disease spread or contribute to development of prostate cancer,” says Seth. “[Then] there are some microRNAs that go the other way; they inhibit the progression of prostate cancer.”

Dr. Arun Seth

Dr. Arun Seth’s work on the biology of prostate cancer has led to the discovery of new biomarkers that predict disease recurrence.

Photo: Curtis Lantinga

In 2015, Seth and Dr. Robert Nam, an associate scientist at SRI and head of the genitourinary group at Sunnybrook’s Odette Cancer Centre, published a study on the role of microRNAs in predicting prostate cancer outcomes. They used tumour samples from 31 patients who had their prostates removed. Thirteen remained cancer free five years later, whereas cancer returned and metastasized in 18 men. The scientists compared tumour microRNA levels between these two groups and identified five microRNAs that were strongly associated with disease spread. In a cohort of 515 patients, abundance of these five microRNAs in the prostate tumour predicted the likelihood of metastasis and recurrence.

One microRNA, miR-301a, was the most accurate in predicting recurrence after surgery—miR-301a levels were significantly higher in prostate tumours that recurred than in tumours that did not come back. The researchers discovered that miR-301a promotes tumour formation and cancer growth, but they wondered: How does this small molecule make cancer cells grow faster and spread more widely?

To answer this question, the researchers grew prostate cancer cells in a Petri dish. They engineered one group of cells to make lots of miR-301a and compared them to cells with little or no miR-301a. Cells that overproduced the microRNA grew faster than those with low miR-301a. Fascinatingly, the high miR-301a levels caused the cells to morph from rounded blobs into long missiles—a sign of their increased mobility and invasiveness. Cells overproducing miR-301a also had much lower levels of a protein called p63, which suppresses tumour formation. The team showed miR-301a directly inhibits production of p63, which in turn sets off a cascade of events that leads to the cancer cells becoming more virile.

The researchers are now exploring whether miR-301a can be used for prognosis. “Since [miR-301a] predicted recurrence, we’re going to look in blood, serum and urine to see if we can detect miR-301a early enough that we can classify patients into different [risk] groups,” says Seth. Knowing a person’s risk profile could help patients and doctors choose between aggressive treatment like surgery and a conservative approach like active surveillance.

Klotz is considered by many to be the father of active surveillance. A self-described contrarian, he rides to work every day on his electric scooter, undeterred even by the lashing freezing rain of a late Canadian March. In the mid-1990s, Klotz and fellow Sunnybrook physicians Drs. Richard Choo and Cyril Danjoux came up with the idea of active surveillance to address a gap in care. With the approval of the PSA test, the number of prostate cancer diagnoses rose dramatically. In the U.S. and Canada nearly 95% of these patients were treated aggressively. On the other hand, the U.K. and Scandinavian countries adopted a “no treatment” approach, leading to the highest prostate cancer mortality rates in the world.

Dr. Arun Seth

Dr. Laurence Klotz is the co-creator of active surveillance, a strategy that has changed the treatment landscape for men with prostate cancer.

“The question was, was there some middle ground?” says Klotz. He knew that, in most cases, prostate cancer is extremely slow growing. Together, the researchers devised a strategy for men with low PSA whose cancer was confined to a small area. Instead of undergoing radical treatment, these patients would be monitored with regular PSA tests and biopsies. If tests showed cancer progression, then they would be treated right away. And so active surveillance was born. “That seems, in retrospect, like such an obvious idea,” says Klotz. “[But] at the time, it was very controversial. Many of our opponents truly felt this would result in unnecessary deaths.”

Klotz enrolled the first patient in active surveillance in 1995. He has been recruiting and following patients ever since. In two reports published in 2015, Klotz analyzed the outcomes of 993 men on active surveillance, one-quarter of whom had been in the program for more than 10 years. Of these men, 27% quit to receive treatment when their PSA tests and biopsies showed their cancer was progressing. While there were 149 deaths during the follow-up period, only 15 were due to prostate cancer. Thirty patients developed metastatic disease, including the 15 that succumbed to prostate cancer. At 10 years, the probability of surviving cancer was 98%. At 15 years, the odds dropped slightly to 94%.

“One of the criticisms of our program was, ‘you guys are just reporting too early,’” says Klotz. Long-term studies like this one have helped convince even his toughest adversaries that active surveillance is a safe approach for men with low-risk prostate cancer. Today, active surveillance has been adopted all over the world, and Klotz is tackling other challenges. “The Achilles heel of this approach is about 25% of patients [on active surveillance] have high-grade cancer elsewhere in the prostate,” he says. A high-grade cancer is more likely to grow and spread faster than a low-grade one, but it’s often missed in the biopsy. This creates a false sense of security, leading patients and doctors to choose a conservative approach when more aggressive treatment is needed.

To address this problem, Klotz is working with Haider and Dr. Laurent Milot to improve detection of high-risk prostate cancers. The current technique for prostate biopsy relies on ultrasound imaging for guidance. An ultrasound scan locates the prostate, from which 12 biopsy samples are taken systematically by following a grid-like pattern. The samples are then sent to a pathologist for diagnosis and grading. “Ultrasound is a great tool to see the prostate, but it’s not so great to see the cancer,” says Milot, a radiologist and researcher at SRI. He compares the ultrasound-guided systematic biopsy to navigating without a map. With no idea of where the disease might be, chance determines whether one of the 12 biopsy needles will hit cancerous tissue.

Dr. Masoom Haider

Dr. Masoom Haider is integrating MRI into existing treatment strategies to make prostate cancer screening smarter and more effective.

Magnetic resonance imaging is changing that. A new method fuses MRI with traditional ultrasound-guided biopsies to create GPS-like navigation for radiologists. “[Magnetic resonance imaging] gives you two things: it tells you whether there’s a cancer, but also where it is,” says Haider.

Milot is the only radiologist at Sunnybrook—and one of a handful in Canada—with expertise in MRI-ultrasound fused targeted biopsy. He recently performed the procedure on a patient who travelled to Toronto from Newfoundland expressly to get it. With this new technique, patients first undergo an MR scan to pinpoint the cancer. Newly developed fusion systems merge the MR and ultrasound images to generate a live map of the prostate with an “X” marking the tumour. With map in hand, Milot is able to guide the biopsy needle directly to the target site and take three or four samples instead of the standard 12.

Sunnybrook was the first hospital in Ontario to have an MRI-ultrasound fusion biopsy system, and the first in the world to do a prospective study comparing the two biopsy methods. In this work, Haider, Klotz and Milot tested how well MRI-ultrasound fused targeted biopsy and systematic biopsy could detect high-grade prostate cancer in men on active surveillance. Out of 72 patients, high-grade cancer was detected in 10 patients using both methods. An additional seven patients were found to have high-grade cancer revealed only by targeted biopsy. The study showed MRI-ultrasound fused targeted biopsy was six times more likely to detect a high-grade cancer. “[This] was really the landmark work for us in terms of saying, ‘Yes, we can do it. Yes, it makes sense to do it,’” says Milot. Based on these results, MRI scans are now given to nearly all patients on active surveillance at Sunnybrook.

“There are some parts of the prostate that are hard to get to,” says Klotz. “That’s where we think most of these bad cancers are hiding. We think going forward with MRI we will find most, if not all, of them early enough that they’re still curable.” The researchers recently finished recruiting patients for a large trial in which men on active surveillance were randomly assigned to receive either MRI-ultrasound fused targeted biopsy or systematic biopsy. They believe that the results will change practice and establish a role for MRI in prostate cancer care. “We’ve had an incredible influence in an area of oncology that affects a huge number of patients,” says Klotz. “That’s been unbelievably rewarding for everyone here that’s been involved.”

Haider’s research is supported by the Cancer Imaging Network of Ontario and the Ontario Institute for Cancer Research. Klotz’s research is funded by the Canadian Institutes of Health Research and Prostate Cancer Canada. Seth’s research is supported by the Canadian Cancer Society Research Institute and Cancer Research Society. The Canada Foundation for Innovation and Ontario Ministry of Research and Innovation provided infrastructure support.