Personalized prostate cancer treatment goes beyond Gleason scores


Researchers are shifting their focus to prostate tumor genomic analysis to identify the best treatment among radiation, surgery, or other therapy.

These medical scientists are working to develop strategies for treating prostate tumors that are tailored to individual patients, as is currently done for many women with breast cancer. Fresh advances in the understanding of prostate cancer suggest that some men with a high-risk form of the disease might benefit from more aggressive treatment.

Other men may benefit from less treatment. For instance, radiation plus hormone therapy, also called androgen-deprivation therapy, is a common strategy to kill prostate tumors. But a recent study from researchers at Memorial Sloan-Kettering Cancer Center suggests that analyzing a tumor's DNA may identify patients who would do just as well with radiation alone. If borne out in further research, some men may be able to skip hormone therapy, avoiding side effects that include loss of libido and heart disease.

The developments come amid changes in the way many types of cancer are identified and treated. The changes are being driven in part by the use of genomic information that defines tumors by their underlying biology and provides clues about drivers of the disease not available by conventional exams.

Researchers say, for instance, that several new genomic prostate-cancer tests can help separate high-risk tumors from those at low or intermediate risk, offering information to doctors and patients to guide treatment choices.

Most prostate cancer cases are low-risk forms of the disease that will have little effect on their lives or longevity. In these cases, a big concern is that overtreating the cancer puts these men at unnecessary risk for impotence, incontinence and other complications.

About 20% of diagnosed men are considered at high risk for having their cancers spread beyond the prostate gland based on a measure called the Gleason score and other factors. For some men with an aggressive form of the disease, the 10-year-survival rate is well below 50%. "We may not be treating them aggressively enough," says William Polkinghorn, a radiation oncologist at Memorial Sloan-Kettering, in New York.

Some 95% of men who die of the disease are initially diagnosed with cancer that is confined to the prostate region, says Philip Kantoff, director of the Lank Center for genitourinary oncology at the Harvard-affiliated Dana-Farber Cancer Institute, in Boston. Finding ways to "cure" such patients is "mission central," he says. Once cancer spreads beyond the prostate—typically to the bone—it is considered incurable.

The current standard of care for high-risk prostate cancer is either surgery to remove the cancerous gland or radiation plus hormone therapy to kill the tumor. Some men get radiation after surgery, but generally the two approaches aren't given together.

By comparison, women with high-risk breast cancer, which like prostate cancer is also typically fueled by sex hormones, typically get a combination of surgery, radiation and drugs. Medicines are tailored to patients based on whether the hormones estrogen and progesterone or a gene called HER2 is fueling the tumor.

Aggressive treatment of these women has resulted in improved survival and relapse rates, says Charles Sawyers, head of the human oncology and pathogenesis program at Memorial Sloan-Kettering. Whether a similar approach would improve survival for high-risk prostate cancer isn't certain but it is "a conversation that needs to be had in a more vigorous way," he says.

There is some evidence it could work. Research from clinical trials, for instance, suggests that giving radiation soon after surgery increases the time a patient lives without the disease coming back, says Adam Dicker, head of radiation oncology at Jefferson Medical College of Jefferson University, in Philadelphia.

But there have been few studies looking at the effect of combining treatments. It can take 10 to 15 years to complete a trial testing a multipronged strategy versus a single-treatment approach.

Genetic tests have recently become available that examine tumors for molecular signatures that predict whether a tumor is high- or low-risk and can help doctors make treatment decisions.

A test marketed by San Diego company GenomeDx Biosciences Inc. yields a molecular profile that can indicate, for instance, whether a man who undergoes prostate surgery to remove the tumor would also benefit from radiation treatment, says Doug Golginow, the company's chief executive.

It "doesn't tell you if a specific chemotherapy" will work against the tumor, but "it sorts out a lot of confusion by telling you whether you have the kind of disease that's going to kill you or not kill you," he says.

Genomic Health Inc. and Myriad Genetics Inc., sell tests that, for instance, can help distinguish between high- and low-risk prostate cancers, possibly enabling men to delay or forgo aggressive treatment.

Dr. Polkinghorn's research at Sloan-Kettering yielded another genetic signature that could tell men when they need less therapy. He led a recent study that showed androgen's role in prostate cancer goes beyond providing fuel for the tumor's growth; the male sex hormone also activates androgen receptors that turn on genes which repair damaged DNA. The finding is important because radiation kills tumor cells by breaking DNA. It also explains a two-decade-old mystery over why combining radiation with anti-androgen drugs is significantly more effective against high-risk cancer than radiation alone.

Depriving the tumor of androgen "takes the sunscreen off the prostate cancer cell and makes it more sensitive to radiation," Dr. Polkinghorn says. The report was published in November in the journal Cancer Discovery.

The analysis revealed that levels of androgen-receptor activity vary widely between patients. This suggests that patients with high androgen activity may benefit from hormone therapy while those with low activity levels may gain little from it and could forgo the treatment

The researchers plan to validate the result by testing it on a database of prostate-tumor specimens gathered from a variety of clinical trials where the outcomes of the patients are known.

Dr. Polkinghorn now runs a clinic for high-risk prostate-cancer patients. He and his colleagues are developing a protocol to test how well such patients respond to more aggressive therapy.

Howard Bellin, a 77-year-old recently retired plastic surgeon who had surgery to remove his cancerous prostate in October, is being treated with the approach. The conventional strategy, Dr. Bellin says, is for doctors to wait after surgery to see if the tumor comes back and then "go after it with bigger guns" or hormone therapy. He says he is being treated now with two hormone drugs and radiation, hoping that a cure lies in "treating it with your big guns right away."


Source: Wall Street Journal:

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