An updated analysis from an international clinical trial of the drug letrozole was presented on June 8, 2004 at the American Society of Clinical Oncology annual meeting in New Orleans. With additional follow up now available to a median of 2.5 years, letrozole (Femara) was found to be effective in reducing local and distant recurrences of cancer, as well as new breast cancers, regardless of whether the patient's cancer had spread (node-positive) or had not spread (node-negative) to the lymph nodes at the time of diagnosis. The rate of distant breast cancer spread was reduced by 40 percent compared to placebo. Most importantly, with the additional followup available for this new analysis, letrozole now shows an improvement of 39 percent in overall survival for node-positive patients.
"Of equal interest to the good news on survival, additional follow up did not show any further increase in side effects related to bone fractures or heart," said Jeffrey Abrams, M.D., coordinator of the U.S. National Cancer Institute's Cooperative Group breast cancer treatment trials. "While a survival advantage has not yet appeared for patients with node-negative disease, their results do parallel those seen in node-positive tumors."
Follow up with women in this study will continue for another ten to fifteen years. Other studies are being planned or are in progress to examine the issue of when is the optimal time to switch women on tamoxifen to aromatase inhibitors, such as letrozole, and for how long these drugs could be administered.
A Canadian-led international clinical trial has found that post-menopausal survivors of early-stage breast cancer who took the drug letrozole after completing an initial five years of tamoxifen therapy had a significantly reduced risk of cancer recurrence compared to women taking a placebo. The results of the study appear in today's advance on-line edition of the New England Journal of Medicine.
The clinical trial has been halted early because of the positive results and researchers are notifying the 5,187 women worldwide who have participated in the study. Women on letrozole will continue taking the drug and those on the placebo can begin taking letrozole, if they wish.
"This very important advance in breast cancer treatment will improve the outlook for many thousands of women," said Andrew von Eschenbach, M.D., director of the National Cancer Institute which led the study in the United States. "This is one more example of the ability to interrupt the progression of a cancer using a drug that blocks a crucial metabolic pathway in the tumor cell."
Study researchers found that letrozole, when taken after five years of tamoxifen therapy, substantially increased the chance of remaining cancer free. In total, 132 women taking the placebo had their disease recur compared to 75 on letrozole. Overall, letrozole reduced the risk of recurrence by 43 percent, so that after four years of participating in the trial, 13 percent of the women on the placebo, but only seven percent, of those on letrozole had recurred. Deaths from breast cancer were also reduced. Seventeen women taking the placebo died of breast cancer compared to nine taking letrozole.
While tamoxifen is widely used to prevent breast cancer recurrence in post-menopausal women, it stops being effective after five years because, researchers believe, tumours become resistant to it.
"More than half of women who develop recurrent breast cancer do so more than five years after their original diagnosis," says Paul Goss, M.D., of Princess Margaret Hospital in Toronto. "For years, we have thought that we had reached the limit of what we could do to reduce the risk of recurrence with five years of tamoxifen. Our study ushers in a new era of hope by cutting these ongoing recurrences and deaths from breast cancer after tamoxifen by almost one half." Goss, a leading expert in novel hormone therapies for the treatment and prevention of breast cancer, conceived and chaired the international trial with letrozole.
A form of hormone therapy for the treatment of breast cancer, letrozole works by limiting the ability of an enzyme called aromatase to produce estrogen, a major growth stimulant in many breast cancers.
Mayo Clinic medical oncologist James Ingle, M.D., says, "Based on our findings, all post-menopausal women with hormone-receptor positive tumours completing about five years of tamoxifen should discuss taking letrozole with their doctors to reduce their risk of breast cancer recurrence." Ingle, from Rochester, Minn., led the research study in the United States.
With Canadian Cancer Society funding, the clinical trial was coordinated by the National Cancer Institute of Canada Clinical Trials Group at Queen's University, in partnership with the U.S. National Cancer Institute and its Clinical Trials Cooperative Groups. Novartis, which manufactures letrozole, also known as Femara®, provided the drug for the trial.
Women participated in the study for an average of 2.4 years and for as long as five years. The study found that women taking letrozole had a reduction in the number of recurrences of cancer in their previously affected breast, a reduction in the number of new cancers in their opposite breast, and a reduction in the spread of the cancer outside their breast.
The side effects of letrozole, a pill which is taken once a day, are very similar to those experienced by women undergoing menopause. They were generally mild in study participants. Women in the study will continue to be followed to more thoroughly assess any effects of long-term use of letrozole on bone strength or other organs. Until these are known, patients should be monitored closely.
"The Canadian Cancer Society is pleased to have made a key contribution to this study," says Barbara Whylie, M.D., director of Cancer Control Policy for the Canadian Cancer Society. "We estimate that more than 20,000 Canadian women will be diagnosed with breast cancer this year and just over half of those are going to be eligible for this drug. That means these women will have a significantly improved hope for a future without cancer."
"This large trial only began in 1998 and we already have important results that will change clinical practice," says Jeffrey Abrams, M.D., coordinator of the U.S. National Cancer Institute's Cooperative Group breast cancer treatment trials. "This is a tribute to the patients and physicians who participated since their efforts will now have a positive impact on so many lives."
Participants in the clinical trial were enrolled through hospitals, cancer centers and institutes throughout Canada, the United States, England, Belgium, Ireland, Italy, Poland, Portugal and Switzerland. The European Organization for Research and Treatment of Cancer and the International Breast Cancer Study Group coordinated the European component of the trial.
The Canadian Cancer Society is the largest charitable funder of cancer research in Canada. It funds clinical trials research through its support of the National Cancer Institute of Canada Clinical Trials Group.
The National Cancer Institute is the primary U.S. agency for cancer research.