Hunting tailored care for advanced prostate cancer

By LAURAN NEERGAARD

WASHINGTON, 25 mar 2009 – Prostate cancer has been left behind in the race for personalized medicine but that may be changing: Doctors are starting to attempt gene-guided treatment for men with advanced disease.

It's an approach already offered in treating breast and certain other cancers. The new prostate work is a small initial step at catching up. And it targets the men in most dire need — those whose prostate cancer has spread to the bones or other parts of the body, and hormone treatment to slow its march has quit working.

These are the men who ultimately wind up dying of prostate cancer, some 28,000 a year.

"Prostate cancer has learned some tricks," says Dr. Phillip Febbo of Duke University Medical Center, who is unraveling how to decode those tricks to better direct therapy — by looking directly at the tumor's genetic signature.

The research is very preliminary but if a gene-guided method ultimately works it could ease what the American Cancer Society's Dr. Durado Brooks calls today's "shotgun approach" to advanced prostate cancer. Patients slog their way through a handful of medications in no particular order, changing course only after the cancer quits responding.

"This gives us a more scientifically reasoned, evidence-based approach to treating these men — hopefully. That's the theory," Brooks cautions.

Starting next month, Duke will recruit men for a study that will help determine their treatment.

Tumors carry a pattern of gene and protein activity that signal whether a cancer is more or less aggressive and whether it is susceptible to various treatments. Those signatures already have led to breast cancer tests that predict which tumors are more likely to return, helping patients decide whether to try or skip chemotherapy, for example. Everyone with advanced colon cancer is supposed to get a genetic test before trying one of two leading treatments, to see if their tumor will respond.

Yet even though prostate cancer hits as many men as breast cancer hits women, finding genetic signatures in prostate tumors has been a struggle. Men tend to get prostate biopsies early on, before the cancer has spread. Very few get one after their cancer worsens, when the tumor has evolved, leaving few advanced tumor samples for scientists to examine which genetic activity is most crucial, Febbo explains.

But that's slowly changing, and the result is a race to find genetic signatures that might predict a therapy's usefulness.

First up, the "androgen receptor." It's the male counterpart to the estrogen receptor that determines how strongly estrogen fuels breast cancer growth.

Hormone therapy to block testosterone production is a key prostate cancer treatment. But some cancers keep growing despite low testosterone levels, and researchers in the last few years have found that how tumor cells use their androgen receptor plays a major role. The cancer might make copies of its androgen receptor so a cell now has 10 instead of two, Febbo says, the better to suck in remaining testosterone. Or the receptors may become more sensitive, able to react to the tiniest bit of testosterone instead of usual levels. Prostate tumors sometimes even start making their own testosterone.

Febbo's team genetically profiled more than 100 samples of prostate cancer. A genetic signature separates which men with hormone-resistant advanced cancer still have a very active androgen receptor and which don't — something else, perhaps a gene named Src, is fueling their cancer, he reported this month in the Journal of Clinical Oncology.

Next month, Duke and other hospitals that are part of the Defense Department's Prostate Cancer Consortium will begin recruiting 60 such patients and custom-profile their cancer to decide treatment. Those with highly active androgen receptors will get nilutamide, a receptor blocker. Those whose androgen receptors aren't the problem will receive an experimental treatment, the leukemia drug dasatanib that's known to target prostate-related factors.

Also under way: Testing whether there's a genetic signature that says which men will respond best to a different drug, docetaxel. It's proven to increase survival in hormone-resistant advanced prostate cancer but only in a fraction of patients.

Separately, doctors are closely watching studies of an experimental drug named abiraterone that's supposed to target mutated androgen receptors.

It's way too soon to predict if any of these approaches will pan out. But the genetics rationale appeals to Tim Atkeson, a Denver lawyer whose prostate cancer already had spread to his bones when he was diagnosed at the unusually young age of 49.

Atkeson read up on studies presented at leading cancer meetings and, while systematically working through treatments for the hormone-resistant, he contacted Febbo about volunteering for the gene-guided study. At the very least, he hopes to spur science in case his sons or brothers ever face the same disease.

"I keep my fingers crossed that perhaps I'll be one of the lucky ones," says Atkeson, now 51.

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EDITOR's NOTE — Lauran Neergaard covers health and medical issues for The Associated Press in Washington.