Benefit of chemotherapy in breast cancer depends on estrogen-receptor status

HOUSTON - When it comes to chemotherapy treatment for women whose breast cancer has spread to their lymph nodes, the estrogen status of their tumors matters, says a team of researchers in the April 12 issue of the Journal of the American Medical Association.

Analyzing data from three clinical trials with a total of 6,644 patients, they determined that chemotherapy works much better in breast cancer that is estrogen receptor-negative (ER-) than many people think, and conversely, doesn't work as well in estrogen receptor-positive (ER+) cancer as believed, says the study's lead author Donald Berry, Ph.D., chair of the Department of Biostatistics and Applied Mathematics at The University of Texas M. D. Anderson Cancer Center.

This conclusion will come as a surprise to many oncologists, Berry says. Women with "node-positive" breast cancer routinely are given chemotherapy, regardless of their tumor type. Women who have ER+ tumors are also given tamoxifen, a drug which inhibits estrogen use by the cancer cells.

"Our analysis shows that tamoxifen works very well for a number of years and taken as a group, there is little or no benefit of even the cumulative effects of modern improvements in chemotherapy for women with ER+ tumors," he says.

"All in all, this is good news because it shows that the benefit of chemotherapy for ER- tumors is surprisingly dramatic in the same way that tamoxifen's effect is substantial for ER+ tumors," Berry says.

The research team, which includes investigators from top cancer centers nationwide, studied outcomes from three large randomized clinical trials which tested the optimal use of chemotherapy in node-positive breast cancer. But none of these trials, all of which were conducted by the Cancer and Leukemia Group B and the U.S. Breast Intergroup, considered estrogen status or whether women had received tamoxifen, largely because the diagnostic importance of estrogen status for chemotherapy was not recognized at the time the trials were designed, Berry says.

Accumulated evidence indicates, however, that improvements in chemotherapy disproportionately benefit women with ER- tumors, Berry says; so the research team decided to statistically model the relative contribution of chemotherapy treatment given estrogen receptor status.

They found the absolute benefits due to chemotherapy were greater for patients with ER- tumors compared to those with ER+ tumors. Specifically, 22.8 percent more ER- patients were disease-free after five years if they received chemotherapy versus 7 percent of ER+ patients. The corresponding improvements for overall survival were 16.7 percent versus 4 percent.

The researchers also compared the different chemotherapy regimens tested in the trials, and found the latest chemotherapy combination studied - biweekly doxorubicin/cyclophosphamide plus paclitaxel - lowered the rate of recurrence and death in ER- patients by more than 50 percent, compared to the low-dose regimen used in the first study.

"This tells us that breast oncology has made enormous strides in treating patients with ER- tumors, a finding which contradicts the prevailing wisdom that with the development of tamoxifen and newer selective estrogen receptor modulator drugs, the benefits of medical science have been primarily focused on ER+ tumors," Berry says.

"It is true that tamoxifen changed the landscape for ER+ tumors, but the playing field has now been leveled somewhat given the fact that ER- tumors respond well to modern improvements in chemotherapy regimens," he says.

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The study was funded by the National Cancer Institute through its support of the national cooperative oncology groups: the Cancer and Leukemia Group B, the Southwest Oncology Group, the Eastern Cooperative Oncology Group, and the North Central Cancer Treatment Group.

Co-authors include Constantine Cirrincione with the Cancer and Leukemia Group B Statistical Center; I. Craig Henderson, M.D., from the University of California at San Francisco; Marc Citron, M.D., from Albert Einstein College of Medicine; Daniel Budman, M.D., North Shore University Hospital; Lori Goldstein, M.D., from Fox Chase Cancer Center; Silvana Martino, D.O., from the Los Angeles Clinic and Research Institute; Edith Perez, M.D., from the Mayo Clinic and Mayo Foundation; Hyman Muss, M.D., from the Vermont Cancer Center; Larry Norton, M.D. and Clifford Hudis, M.D., from Memorial Sloan-Kettering Cancer Center; and Eric Winer, from the Dana-Farber Cancer Institute.


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