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Researchers probe links between gender and cancer

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Thursday, December 08, 2005

By Amy Dockser Marcus, The Wall Street Journal

Medical researchers are starting to explore an intriguing prospect: that cancer behaves differently in men and women.

The new insight is opening promising new avenues of research into cancer incidence and treatment. It could hold clues to new ways to use certain medications -- perhaps in combination with other treatments, including hormones. And it could even help revive previously abandoned drugs that weren't broadly effective but may be shown to work better in men or women.

Much of the early work has centered on lung cancer, because that is where many of the early clues to gender differences have emerged. Cell Therapeutics Inc. of Seattle will announce Tuesday that it is launching a women-only clinical trial for lung-cancer patients to test the efficacy of its new drug, Xyotax. If the results are promising, they could lead to an unusual gender-specific drug approval for a cancer that affects both men and women.

In another era, the drug might have been doomed. It had shown no significant survival benefit in two previous trials. But amid burgeoning interest in gender differences, researchers went back and analyzed the results for men and women separately -- and they found that women taking the drug saw a significant survival advantage. Based on this data, the company decided to enroll 600 women in the new trial at a total of 170 centers in the U.S. and abroad. Preliminary results are expected in early 2007.

There have always been women-only or men-only trials for diseases like prostate and ovarian cancer, of course. But now growing numbers of cancer centers are devoting funds and research to exploring gender differences in cancers that affect everyone broadly. Scientists are increasingly exploring the genetic mutations that make some people more susceptible to cancer or responsive to treatment -- and they are finding tantalizing clues related to gender.

Research efforts by the University of Pittsburgh Cancer Institute, the University of California, Los Angeles, the University of Wisconsin and the Southwest Oncology Group, a research and clinical-trials consortium, are all exploring the gender issue in cancer. There are also a number of gender-based efforts outside of oncology. Researchers are interested in the reasons why heart disease kills more women than men, and why the majority of people who have autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and lupus are women. Last year, Cedars-Sinai Medical Center in Los Angeles set up a Women's Health Research Registry for investigators in all diseases, with the aim of registering 10,000 women over the next five years who are willing to participate in clinical trials. Over 300 women have registered so far.

Most of these efforts are focused on women -- in part because medical research has historically been more focused on men and doctors are playing catch-up. But the hope is that any knowledge gained about gender differences could have implications for both sexes. "If we can understand the biological differences between men and women in cancer, we can improve all cancer therapies because we can figure out how to target them more effectively," says Kathy S. Albain, who is chairwoman of the steering committee on the new Xyotax study and a professor of medicine at Loyola University Health System in Chicago. For instance, Xyotax is in a class of chemotherapy drugs called taxanes, and the Xyotax findings could have implications for how taxanes are used in breast, ovarian and prostate cancer.

Interest in gender differences comes at a time when survival rates for many cancers have improved. But in its most recent report on cancer trends involving the 15 most common cancers, the National Cancer Institute said that while overall cancer incidence remained stable for men, among women it went up slightly between 1987 and 2002.

The American Cancer Society estimates that 73,020 women will die this year of lung cancer, more than breast, ovarian and uterine cancer combined. According to the National Cancer Institute, the overall five-year survival rates for lung cancer for 1995-2001 was 15.3 percent, but women have higher survival rates than men. Women who get lung cancer are more likely to develop a particular form of the disease called adenocarcinoma. Women who never smoked are more likely to develop lung cancer than men who never smoked, perhaps due to hormonal, genetic or metabolic differences. But recently, a study presented at the annual gathering of the American College of Chest Physicians found that women with lung cancer had significantly better survival rates than men -- even when their disease could not be treated.

Edward Trimble, head of gynecological cancer therapies at the National Cancer Institute, expresses caution about the idea of women-only trials. "Differences in outcome seem to be more related to genetic abnormalities in the cancers than the gender of the patient," he says. He cites an example in lung cancer, when studies of Iressa, a targeted therapy for lung cancer, showed that patients with a particular genetic mutation appeared to be more responsive to the drug. Women with lung cancer who didn't smoke were found to be more likely to have this genetic mutation.

But Dr. Trimble cautions that men historically have smoked more, and smokers tend to get a kind of lung cancer that doesn't usually involve the mutation. As a result, men with lung cancer "have the greater preponderance of the smoking-associated lung cancer," he said. But the mutation may actually appear equally in men and women in the general population.

Dr. Albain, who is also chairwoman of the Committee on Special Populations at the Southwest Oncology Group, which is funded by the NCI, is working on a trial that opened in October and plans to enroll 720 men and women with lung cancer nationwide. It aims to determine what factors put women at a higher risk of getting lung cancer at an earlier age than men and often at lower doses of smoking, as well as what factors contribute to lung cancer in men and women who do not smoke. Dr. Albain said the group also plans to examine a number of previously conducted trials to see if gender differences emerge in any of the other major cancers.

At the University of Pittsburgh Cancer Institute, research is focusing on the issue of why women may be more susceptible to certain kinds of lung cancer than men. In a paper published in 2001, investigators at the university found a gene for a protein that seems to promote the growth of lung cancer. The gene is on the X chromosome, meaning that women have twice as many copies as men do. Earlier this year, the university, along with the University of Wisconsin, did a small women-only trial testing whether Iressa and Faslodex, an estrogen blocker used in some breast cancers, would improve survival. The data, while preliminary, were promising and Pittsburgh, along with the University of California, Los Angeles, is now enrolling 120 men and women to test Tarceva, another targeted therapy approved for lung cancer, and Faslodex. Data on the women will be analyzed separately to see if the combination works better in women than in men.

Jack W. Singer, chief medical officer of Cell Therapeutics, says the new Xyotax trial has its origins in two previous trials that the company conducted testing its drug in both male and female lung-cancer patients. No significant difference in overall survival was found in either trial. But when the results of the two trials were combined, women on Xyotax had a one-year survival rate of 40 percent versus 25 percent in the women who were on the standard therapies. There were no statistical differences among the men. Dr. Singer said that one of the reasons Xyotax may work better in women is that estrogen appears to play a role in the way the drug is metabolized.

The company, which is funding the approximately $30 million cost of the trial itself, expects to have preliminary results of the new trial by the beginning of 2007. "If the strategy works in lung cancer," says Dr. Singer, "it can be tested in other cancers as well."

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