Cancer study surprises researchers

More women than expected benefit from amenorrhea

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It has long been understood that one of the reasons most premenopausal women benefited from chemotherapy drugs after breast cancer surgery was because the drugs stop menstruation for a time, suppressing their ovaries and the estrogen they produce.

That helped them fight the disease because 75 percent of women with breast cancer typically have estrogen receptor-positive (ER-positive) cancer cells in their tumors, which can grow in response to the estrogen.

As a result, it also has been thought that the 25 percent of women who have ER-negative cancer cells -- that don't react to the estrogen -- would not benefit from chemotherapy-induced amenorrhea, which is the absence of menstruation.

But a new nine-year study of 5,351 women with early-stage, node-positive breast cancer, to be published as the lead article today in the New England Journal of Medicine, with much of the research done by Pittsburgh doctors, has stunned researchers by finding that even women with ER-negative cancer cells benefit from amenorrhea.

"That was a surprise," said Charles E. Geyer Jr., one of the lead authors and a breast medical oncologist at Allegheny General Hospital. "We're spending a lot of time now trying to come up with hypotheses as to why."

Dr. Geyer is also the director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project, which conducted the study in collaboration with leading U.S. cancer centers and cooperative cancer research groups, including Allegheny General, the University of Pittsburgh Cancer Institute, and the University of Pittsburgh's Graduate School of Public Health.

The study's finding that amenorrhea in ER-negative women was associated with higher rates of survival and disease-free life was such a surprise that when they were first presented at a breast cancer symposium in San Antonio in December 2008, "a lot of people were skeptical of our findings," said Dr. Geyer. "They said we had to go back and test our tumor testing."

Double-checking those tests that classified all 2,245 premenopausal women in the study into ER-positive and ER-negative categories confirmed the findings.

Now experts in the field say the study's results will probably be the beginning of a whole new range of studies that, first, will try to duplicate the results, but also try to find out why this occurs.

"It was a very interesting finding that I didn't expect," said Nancy Davidson, director of the University of Pittsburgh's Cancer Institute, who was not involved in the study, but, like most in the field, was aware of it and eager to see its results. "Maybe it's something else going on with the ovaries. Maybe it's doing something else we don't understand."

The finding on amenorrhea was so out of the blue that it is getting more attention than the main objective of the study, testing which of three regimens of chemotherapy drugs was best for breast cancer patients.

The regimens involved different dosages and lengths of cycles for combinations of three of the most effective chemotherapy drugs in use today: doxorubicin, an anthracycline antibiotic that inhibits DNA replication in rapidly growing cancer cells; cyclophosphamide, a nitrogen mustard alkylating agent, which slows or stops cancer cell growth; and docetaxel, a taxane that prevents cancer cells from undergoing mitosis and growing.

One regimen, known as "sequential ACT" gave patients four cycles (or 12 weeks) of doxorubicin and cyclophosphamide at the same time, followed by four more cycles of docetaxel (for 24 weeks total for all three drugs); the second regimen, known as "concurrent ACT" gave patients four cycles of the three drugs at the same time for four cycles (or 12 weeks total); and the third regimen gave four cycles of just doxorubicin and docetaxel.

"The hope had been to find out if you could use less chemotherapy, because they're so toxic," said Priya Rastogi, one of the study's co-authors who is an assistant professor of medicine at the University of Pittsburgh Cancer Institute.

But the results were clear that the longer, heavier doses of the drugs worked better, with 83 percent of the women receiving the sequential ACT regimen surviving at the eight-year mark in the survey, compared to 79 percent for both concurrent ACT and the doxorubicin-docetaxel regimen.

"It seems they proved that. The differences in the regimen are quite conclusive," said Abenaa Brewster, a breast cancer researcher at the M.D. Anderson Cancer Center at the University of Texas, whose prior work on the topic was cited in this new study.

While many oncologists already follow that protocol, for some doctors this will verify that belief and could change how they administer drugs.

"Now we know that's the way we should be giving drugs," said Joseph P. Costantino, a University of Pittsburgh professor of biostatistics and director of the National Surgical Adjuvant Breast and Bowel Project's Biostatistics Center, which collected and analyzed the study's data.

After skin cancer, breast cancer is the No. 1 form of cancer in women, with about 180,000 new cases diagnosed each year in the United States. About 40,000 women die from breast cancer each year, second only to lung cancer.

A sobering statistic in the report noted that 803 of the 5,351 women who volunteered to take part died by study's end on Aug. 31, 2008, a fact the researchers said points to the women's courage and the ongoing motivation for more research.

"A big part of the credit for this study goes out to these women," said Dr. Rastogi. "You can't get this information without them."


Sean D. Hamill: shamill@post-gazette.com or 412-263-2579.


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