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IMPaCT Investigator Highlights (Text Version) - Dr. Lorelei Mucci

Title: Defining Gleason Grade as a Predictor of Lethal Prostate Cancer

Investigator: Lorelei Mucci, MPH, ScD, Harvard School of Public Health

My New Investigator Award was focused on looking at different molecular signatures of prostate cancer progression as well as clinical markers of prostate cancer progression, and specifically we focused on the Gleason grade, and trying to define the role that Gleason plays in lethal prostate cancer.

I work as an epidemiologist on two large studies of men from the United States. One is called the Physicians’ Health Study and the other is the Health Professionals Follow-up Study and these are large epidemiological studies of men. We’ve been following them since the 1980s and between these two studies more than 8,000 men have developed prostate cancer. So we’ve gone back within these studies and collected tumor tissue blocks for the men and we can have our pathologists look at their slides and assign a standard Gleason grading.

And then the third cohort that we included in this project is a cohort of men from Sweden. It’s a very interesting cohort because it’s men who initially underwent active surveillance when initially they were untreated and that’s quite an important cohort to have to look at things like Gleason grade as a predictor of lethal prostate cancer.

The first part of our project was focused on how well does Gleason score predict lethal prostate cancer. The way pathologists grade Gleason grading has changed substantially over time and you can see that here in this first figure, the pink line here refers to the original Gleason score, so when the men were originally diagnosed these men were diagnosed between 1982 and 2002. So quite a long time but you can see, and then the blue line refers to the Gleason grading from our standard pathology led by Dr. Massimo Loda, he’s been fundamental in reviewing all of our specimens to assign a standardized Gleason grading.

And you can see there’s been a shift in the way Gleason gets ascribed over time. And so what’s happened and this has been observed in other populations as well is that very few men now are diagnosed with Gleason 2 to 5 prostate cancer and that most of the cancers are Gleason 6, 7, and 8. So that’s one interesting change that’s happened.

And why this is really important actually is that in fact the—the way we’re grading Gleason grading now is a better predictor of—of prognosis and that’s so critical. If Gleason grading is being used for—by men and their—and their clinicians to make decisions about therapy, we want to make sure that the—the Gleason grading is the best information possible.

And then one other piece of information that we found which is quite interesting was that Gleason grading across the continuum predicts lethal prostate cancer. So as cancers get more poorly differentiated, men with Gleason 8 cancers had about a six times greater risk of dying of prostate cancer during follow-up compared to men with Gleason 3-plus—4 cancers. And then also men with 9 to 10 cancers were about 13 times more likely.

But in particular what was quite interesting was that among the men with Gleason 7 tumors, which is actually the majority of men with prostate cancer, we were able to really further discriminate outcomes for that group and that really depends on the proportion of the tumor that has a pattern 4 versus a pattern 3. And this was really a new finding that if a man had more Gleason 4 in his cancer than 3 then that carried a worse prognosis. So that—having that added information we think is very important clinically.

So in the second part of our project we brought in the gene expression profiling data and the idea was really can we understand which are the genes that are involved in why men get—some men get a poorly differentiated prostate cancer and others get a well-differentiated prostate cancer. And so we took the extremes of Gleason score. We looked at the men who had Gleason 6 cancers and we compared what their gene profiles looked like to the men who had the more poorly differentiated Gleason 4 plus 4 or higher cancers. And we found 157 genes that were that different between the two groups. And they’ve been involved in a number of pathways that are probably quite important for this tumor differentiation or the Gleason grade. So for example they are involved, the genes are involved in the metabolism of the tumor, so different types of metabolism may be important for different types of prostate cancer. We also found different genes that are related to the cell cycle and the way the—the tumor cell proliferates and so this has been quite interesting seeing what these genes are. And this type of information may be very helpful in preventing a man’s prostate cancer from progressing. It also may be very helpful in thinking about new therapies or using existing therapies for different subtypes of men with prostate cancer.

So what we did was then to take these 157 genes and then apply that to the men with the Gleason 7 tumors. The majority of prostate cancer have a Gleason 7 cancer and that’s where we need the most information to predict whether they’re going to have a good or a bad outcome. And so what we were able to do was to apply this—this signature to the group of men with the Gleason 7 tumors and in fact the signature really helped predict 10 or 20 years in the future who ended up having a good outcome and who died of their cancer. And so the more likely your tumor was to have this signature, the more likely those men progressed and died of their cancer.

And so we’re hopeful that signatures like this could be actually implemented in the clinic and help guide treatment decisions among men once they’re diagnosed with cancer.