"The most important new findings we describe in this article are that letrozole treatment can improve the survival of women with node-positive disease and can reduce the chance that metastatic tumors will develop," says Paul E. Goss, MD, PhD, who led the investigation. At the study's outset, Goss was with the Princess Margaret Hospital in Toronto; he now is director of Breast Cancer Research at Massachusetts General Hospital Cancer Center.
Letrozole is one of a class of drugs called aromatase inhibitors that suppress the production of estrogen. Estogen stimulates the growth of breast tumors that express the estrogen receptor, and drugs that block the production or the action of the hormone are used in the treatment of those tumors. The most widely used estrogen-blocking drug is tamoxifen, which becomes ineffective after five years of treatment, probably because tumor cells become resistant to or even dependent on the drug.
The international study, called the MA.17 trial, was conducted through the National Cancer Institute of Canada and designed to test whether letrozole could reduce tumor recurrence and increase survival in postmenopausal breast cancer patients who had completed five years of tamoxifen treatment. More than 5,000 women were enrolled and randomly assigned to receive either letrozole or a placebo for an additional five years. The study was halted in October 2003 – four years after it began – when an interim data analysis showed that the tumors of women taking letrozole were significantly less likely recur. Those results were published in the November 6, 2003 New England Journal of Medicine.
The current report analyzes all the data compiled during the MA.17 trial and confirms that the risk of recurrence was almost 5 percent lower in those receiving letrozole than in the placebo group. Women receiving the drug also had a 39 percent reduction in the risk of metastasis. While overall survival differences between the two groups were not significant, among women whose tumors had spread to their lymph nodes and those who had received tamoxifen for more than five years, letrozole was associated with significantly better overall survival.
Although participants taking letrozole did have a greater incidence of osteoporosis, there was no significant difference in reported fractures. There was also no increased risk of cardiovascular problems, which Goss says is particularly noteable. "A recent trial comparing letrozole to tamoxifen found that letrozole might be associated with heart problems. But our study, the only placebo-controlled trial of an aromatase inhibitor, found no such association. A possible explanation of the earlier study was that tamoxifen may actually protect against cardiovascular disease, which our results support."
Goss adds that current and future studies will investigate two key questions about letrozole and other aromatase inhibitors – how long treatment should continue and whether the drugs also can benefit women who previously stopped taking tamoxifen or never took that drug. One trial that has already begun will continue following the women who received letrozole throughout the MA.17 trial and re-randomize them to receive either letrozole or a placebo for an additional five years. Another study will examine tumor samples from all MA.17 trial participants to search for molecular fingerprints that might identify who would most benefit from letrozole treatment.
Along with Goss, who is a professor of Medicine at Harvard Medical School, the co-authors of the JNCI study are James Ingle, MD, Mayo Clinic; Silvana Martino, DO, John Wayne Cancer Institute; Nicholas Robert, MD, Inova Fairfax Hospital, Falls Church, Virginia; Hyman Muss, MD, University of Vermont; Martine Piccart, MD, Institut Jules Bordet, Brussels; Monica Castiglione, MD, University of Bern; Dongsheng Tu, PhD, Lois Shepherd, MD, Michael Palmer, MSc, and Joseph Pater, MD, National Cancer Institute of Canada Clinical Trials Group; Kathleen Pritchard, MD, Toronto-Sunnybrook Regional Cancer Centre; Robert Livingston, MD, University of Washington; Nancy Davidson, MD, Johns Hopkins Hospital; Larry Norton, MD, Memorial Sloan-Kettering Cancer Center; Edith Perez, MD, Mayo Clinic, Florida; Jeffrey Abrams, MD, National Cancer Institute; and David Cameron, MD, Western General Hospital, Edinburgh. The study was supported by the Canadian Cancer Society, the National Cancer Institute of Canada, the U.S. National Cancer Institute, and Novartis Pharmaceuticals, which markets letrozole under the brand name Femara.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $450 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
Journal
JNCI Journal of the National Cancer Institute