First, for the future, we have something we’ve never had in the past: excellent imaging of the prostate. Thanks to multi-parametric MRI, doctors have an unprecedented look inside this difficult-to-access gland. It’s not as good as it needs to be yet, but it’s much better than it was – and it’s already better than ultrasound.
“If you think about breast cancer,” says Johns Hopkins urologic pathologist Angelo M. De Marzo, M.D., Ph.D., “you never make the diagnosis other than by sticking a needle into a lesion that somebody felt or saw. But in prostate cancer, most diagnoses are made by sticking a needle blindly, into something we can’t see or feel. Prostate cancer is the only cancer where you are systematically making the diagnosis in a blinded way. That’s not done with any other cancer: every other cancer, you can see or feel.”
No one wants unnecessary biopsies. They are painful, costly, and the risk of infection increases with each one. After an inconclusive biopsy the next step may be to do an MRI first, and then do another biopsy if it’s warranted.
Next, we need molecular tests, and some of those are already here.
Certain molecular markers can be used on prostate tissue samples to help predict “upgrading” – the presence of higher-grade cancer. For example:
PTEN is a type of gene whose job description is: “tumor suppressor.” It helps prevent the out-of-control cell growth that can lead to cancer. “It acts like the brakes on a car for cancer cells,” says De Marzo, whose laboratory has been studying this gene’s loss in prostate cancer for a decade. But cancer doesn’t like brakes; it wants to go fast. In about half of all lethal prostate tumors, PTEN is knocked out.
As you might expect, when this happens – think of a bunch of rowdy high school kids having a wild party when someone’s parents go out of town – cancer cells behave more aggressively. “The loss of PTEN leads to uncontrolled cancer cell growth and the prevention of cancer cell death,” says De Marzo. Normally, in the cycle of life of all cells, new cells are born and others die; this keeps the population in check. In cancer, cells stop dying. “PTEN is one of the few genes whose loss has been consistently associated with aggressive prostate cancer.”
PTEN loss is a powerful predictor of which prostate tumors are likely to recur or metastasize. In the past, it has been expensive and cumbersome for scientists to try to measure this. Now, thanks to a novel antibody that was tested and validated extensively by De Marzo’s laboratory, this may soon change. The new test, called a PTEN IHC test, is less expensive, faster, and much easier for pathologists to interpret.
It will be available for widespread routine use soon. In studies led by De Marzo’s colleague at Johns Hopkins, pathologist Tamara Lotan, M.D., scientists discovered a strong correlation between the loss of PTEN and the signs of aggressive prostate cancer. In other research, Lotan, De Marzo, and colleagues found that PTEN loss correlated with faster recurrences after radical prostatectomy.
Lotan, along with De Marzo and Hopkins pathologist Jonathan Epstein, has found that the PTEN test can help identify an important subtype of non-invasive tumor called intraductal carcinoma of the prostate. Intraductal cancers spread within in ducts within the prostate and don’t venture outside the gland, but they keep bad company: They are linked to highly aggressive and often deadly invasive prostate cancers. Intraductal cancers are often difficult for pathologists to diagnose under the microscope, but Lotan has shown that these tumors have almost always lost PTEN, and this finding may help pathologists “better recognize these tumors and identify men who are at risk for developing metastases and lethal prostate cancer.”
Also using the new assay, De Marzo and colleagues have established a timetable of what happens in many prostate cancers on the genetic level — key molecular changes that can pinpoint precisely how prostate cancer develops and progresses to become a lethal disease. “We showed that PTEN loss happens after the fusion of two genes, TMPRSS2 and ERG,” says De Marzo. (This fusion occurs in about half of all prostate cancers in Caucasian men, but is not as common in men of African ancestry.)
The Hopkins scientists hope that the test for PTEN loss will become an important part of the diagnostic arsenal. Say a needle biopsy shows that a man apparently has low-risk. Does he need treatment right away? When PTEN loss is present in low-grade prostate cancer, it strongly indicates that higher-grade cancer is lurking nearby. Men whose prostate biopsies show loss of PTEN are “significantly more likely to harbor tumors at radical prostatectomy that are higher-grade than those without a loss of PTEN,” says De Marzo.
In the future, the PTEN test may help identify men who could benefit from specially targeted drugs to metastatic prostate tumors. “Putting together all of these findings,” says De Marzo, “it is clear that there is compelling clinical evidence that PTEN loss is associated with aggressive prostate cancer. But this is also paving the way for the ultimate widespread use of the PTEN IHC test in the clinic for men with low– to intermediate-risk prostate cancer.”
Other genetic tests: Prostate cancer lags behind breast cancer in the widespread use of genetic tests – and more importantly, in treatment that’s based on those findings. For example, a test called Oncotype DX, for women with lymph node-negative, estrogen receptor-positive breast cancer, can tell which women can safely avoid chemotherapy. “That’s why it got paid for by Medicare, why it’s worth doing, and why most oncologists for women in that setting are going to use this test,” says De Marzo. “Chemo can be highly toxic and expensive, and nobody wants it who doesn’t need it. If a test could save you chemotherapy, it would be a no-brainer to start using it routinely. It would probably save money, in addition to improving the outcome for the patient. If you could take a test and know that you have cancer that is not going to be aggressive, wouldn’t you want to do it? We aren’t quite there yet,” but he believes such tests are coming.
Another trend: Surgery on more aggressive disease. It used to be that surgeons wouldn’t operate if they thought a man had more aggressive disease – Gleason 9 or 10 – or cancer that had escaped from the prostate and moved into a lymph node. But some surgeons did by accident, not knowing until the prostate specimen had been sent to pathology just how aggressive the cancer was. But something unexpected happened with those men. “It looks like it benefits them,” says De Marzo. “do well. We didn’t expect them to do well.” He suspects that in a few years, studies will have shown that it is a good idea to operate on these men.
Why is this? It seems that just removing the vast majority of the tumor – even if there is some left behind – causes the cancer to take a huge hit. It’s still there, but it can take years for the cancer to recover its momentum. “There is precedent for this in other cancers,” says De Marzo. For example, ovarian cancer is often diagnosed after it has spread throughout the abdomen, “but it’s very clear that if you get as much as you can out of the abdomen, those women do better.” This is “debulking” the cancer. It can prolong life, and many surgeons may decide it’s worth doing in prostate cancer.