Scientists have shown for the first time that prostate cancer can be categorized into five distinct subtypes, each of which has a unique molecular signature that appears to predict how well a patient will do after surgery. The findings, published this week in the journal EBioMedicine, are being described as “game-changing” in the fight against prostate cancer.
Until somewhat recently, cancer was believed to be one disease. But as our understanding has grown over the last 20 years, so has our awareness of its complexity. We now know that there are hundreds of different types of cancer – and that each one differs in its biology, the genes that cause it and how it grows. This is why patients receive different treatments, and why survival varies between cancer types.
Moreover, research has also shown that one ‘type’ of cancer can be further broken down into distinct sub-types, each of which has its own molecular fingerprint and unique weak spots that can be targeted by various therapeutic agents. For example, a 2012 study by Cancer Research UK showed that ‘breast cancer’ is in fact 10 distinct diseases, all of which harbor diverse genetic mutations and respond differently to treatment.
While previous studies have tried to extend these advances to prostate cancer, this line of research has not resulted in a reliable method of categorizing sub-groups of the disease. With limited prognostic information to guide decision-making, treatment for prostate cancer remains an imprecise science
“The challenge in treating prostate cancer is that it can either behave like a pussycat – growing slowly and unlikely to cause problems in a man’s lifetime – or a tiger – spreading aggressively and requiring urgent treatment,” said Dr. Malcolm Mason, Cancer Research UK’s prostate cancer expert. “But at the moment we have no reliable way to distinguish them. This means that some men may get treatment they don’t need, causing unnecessary side effects, while others might benefit from more intensive treatment.”
Hoping to change this, Cancer Research UK scientists led by Dr. Alastair Lamb used a novel approach to study the genomic profiles and tumor characteristics of 259 men with prostate cancer. To get a better look at the differences between patients and the distinguishing features of their tumors, the researchers combined two different methods of subgroup stratification.
Five subgroup classification confirmed in two samples
The first step involved looking at tumor samples from 156 men who had undergone surgery in Cambridge to remove their prostate after being diagnosed with cancer to see if certain areas of DNA were deleted or repeated – so-called “copy-number alterations.” Next, in the same group of men, the researchers measured the levels of thousands of molecules called messenger RNAs (mRNAs) to obtain a marker of the activity levels of different genes in their tumor.
Then, they compared the two sets of results. Based on this analysis, the researchers identified an initial set of 1,000 genes where changes in the copy-number – that is, they were deleted or repeated – also corresponded with a change in gene activity (mRNA levels). They then narrowed this down to 100 genes with the greatest change compared with healthy samples and which seemed to be crucial to prostate cancer growth, and looked to see how their activities varied across the 156 men.
The team found that by using this group of 100 genes – or gene signature – prostate cancer patients who’d had surgery to remove their prostate could be divided into five distinct subgroups:
- One group had lots of DNA deletions and consequently low activity of certain genes
- Another had high amounts of DNA repetition which resulted in increased activity of specific genes.
- Two more groups had very few copy-number alterations, or changes in activity.
- The fifth and final group had some – but not too many – copy-number alterations.
To confirm their findings, the researchers performed the same analysis on another group of 103 men, who’d had surgery in Sweden. Supporting their initial results, they identified the same set of 100 genes in these men, and confirmed that they could also be divided into five groups based on this gene signature.
Genetic signatures have prognostic value
In the final and most important phase of the study, the team wanted to determine whether men with different gene signatures actually have different forms of prostate cancer. To find out, the researchers analyzed the men’s post-treatment outcomes to see if the cancer was more likely to come back in one group of men compared with another — and it was.
Among the Cambridge men, when the researchers compared the number in each group who’s cancer came back after surgery, they found that men in groups with greater numbers of gene changes were more likely to relapse, compared with patients who had fewer changes. The researchers checked their findings in the Swedish group – those with higher levels of genetic alterations were also more likely to relapse after surgery.
The approach utilized by the researchers also proved to be more effective at predicting the most aggressive cancers, compared with the widely-used prostate-specific antigen (PSA) test and Gleason grading system.
“For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses … in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts,” the researchers wrote. They said this information could be “used for early detection of aggressive cases in a clinical setting, and inform treatment decisions.”
Moving toward precision medicine
Prostate cancer is the most common non-skin cancer in American men and is the second leading cause of cancer death among white, African-American and Hispanic men in the U.S. According to projections from the American Cancer Society, an estimated 220,800 men will be diagnosed with prostate cancer this year, and more than 27,5o0 will die from the disease.
The new research represent a major advance for the field, with potentially paradigm-shifting implications for both scientific and clinical practices. Armed with the knowledge from these latest findings, scientists can now begin trying to tailor therapies to the unique molecular characteristics and vulnerabilities of each of the five subtypes. This knowledge can also help doctors offer more informed, accurate advice to patients about what treatment could work best for them. The approach has worked well in breast cancer and helped millions avoid the unnecessary cost, pain and time spent on treatments that are destined to fail.
“The next step is to confirm these results in bigger studies and drill down into the molecular ‘nuts and bolts’ of each specific prostate cancer type,” said Dr. Lamb. “By carrying out more research into how the different diseases behave we might be able to develop more effective ways to treat prostate cancer patients in the future, saving more lives.”
Such work is the backbone of President Obama’s precision medicine initiative announced in January, which aims to pioneer a new approach to how we treat disease by moving away from a “one-size-fits-all” approach to medicine to one that takes into account things like a person’s genetic makeup, or the genetic profile of a tumor.
“This research could be game-changing if the results hold up in larger clinical trials and could give us better information to guide each man’s treatment – even helping us to choose between treatments for men with aggressive cancers,” said Cancer Research UK’s Dr. Mason. “Ultimately this could mean more effective treatment for the men who need it, helping to save more lives and improve the quality of life for many thousands of men with prostate cancer.”