Key Points Why was this study done? This trial was done to determine if letrozole (also called Femara®) would reduce the risk of cancer recurrence among women who have completed 4.5 to six years of tamoxifen therapy. (Question 1) Who participated in the study? The study involved 5,187 women - 1,404 in Canada, 3,607 in the United States and 176 in Europe. All women were post-menopausal, had taken tamoxifen for 4.5 to six years after the diagnosis and treatment of their original cancer and had been off tamoxifen for less than three months before starting the study medication. (Question 2) What is letrozole? Letrozole is a type of drug called an aromatase inhibitor. Aromatase inhibitors work by limiting the ability of an enzyme called aromatase to create estrogen - a major growth factor in hormone-receptor positive breast cancers. (Question 3)

ABOUT THE STUDY

This trial was done to determine if letrozole (also called Femara®) would reduce the risk of cancer recurrence among women who have completed 4.5 to six years of tamoxifen therapy.

After diagnosis and initial treatment, breast cancer continues to recur for many years. Taking tamoxifen therapy for five years after a breast cancer diagnosis significantly reduces the risk of recurrence among post-menopausal women who had been treated for early-stage breast cancer and who had a hormone-receptor positive form of the disease (disease that responds to hormone therapy). However, clinical trials have shown that tamoxifen therapy stops being effective after five years. To date, no treatment has been available for women after this five-year period.

2. Who participated in the study?

The study involved 5,187 women - 1,404 in Canada, 3,607 in the United States and 176 in Europe. All women were post-menopausal, had taken tamoxifen for 4.5 to six years after the diagnosis and treatment of their original cancer and had been off tamoxifen for less than three months before starting the study medication.

Ninety-eight percent of the women in the trial had hormone-receptor positive breast cancer. The receptor status was unknown in only 2 percent.

3. What is letrozole?

Letrozole is a type of drug called an aromatase inhibitor. Aromatase inhibitors work by limiting the ability of an enzyme called aromatase to create estrogen - a major growth factor in hormone-receptor positive breast cancers. These drugs have been shown to almost completely suppress estrogen levels in post-menopausal women.

Letrozole comes in pill form and is taken once a day. It is manufactured under the brand name Femara® by Novartis.

4. Why was letrozole chosen for this study?

Letrozole was chosen because it was known to be a very powerful aromatase inhibitor and had been shown to be very effective in women with advanced breast cancer.

5. Were all women participating in the study given letrozole?

No. The study was a double-blinded placebo controlled trial. That means that half of the women (2,593 women) in the trial were given letrozole and the other half (2,594 women) were given a placebo - an inactive pill that looks like letrozole. Neither the women nor their doctors knew whether they were taking letrozole or the placebo. In this way, both the effectiveness and the side effects of letrozole compared to the placebo could be truly evaluated as accurately as possible.

6. How is letrozole different from tamoxifen?

Letrozole suppresses the production of estrogen. Tamoxifen has no effect on the production of estrogen. Rather, it prevents the binding of estrogens to the estrogen-receptors of the cancer cells and therefore blocks the stimulation of the tumour.

7. Were women who had received chemotherapy to treat their original cancer eligible for the study?

Yes. Women were eligible to participate in the trial whether or not they had received previous chemotherapy. Approximately half of the patients had previously received chemotherapy. They were equally assigned to the letrozole or placebo groups in the study.

8. What did patients participating in the study have to do?

All women took a daily pill that was either letrozole or the placebo. They were seen by their doctor every six months in the first year, and once a year after that. A history and physical examination were performed at each visit, as well as an annual mammogram. Any symptoms or physical findings indicating recurrent cancer were investigated. Side effects were noted at each visit.

9. Is it ethical to give women who have survived breast cancer a placebo when they could be offered a treatment?

When this trial began, there was no treatment for women completing five years of tamoxifen. Until now, there was no indication that the treatment used in the trial would be effective.

10. Who coordinated and funded the study?

The Canadian-led international study was conceived of and chaired by Paul Goss, M.D., at Princess Margaret Hospital in Toronto, Ontario, Canada, and coordinated with funding from the Canadian Cancer Society by the National Cancer Institute of Canada Clinical Trials Group at Queen's University in Kingston, Ontario, Canada. James Ingle, M.D., Mayo Clinic, led the trial in the United States for the American cooperative groups. The study received additional support from the U.S. National Cancer Institute and Novartis Pharmaceuticals, the manufacturer of letrozole. The study was monitored by an independent data safety monitoring committee.

ABOUT THE RESULTS

11. What were the results of the study?

The study found that cancer returned much less often in the women taking letrozole compared to those on placebo.

The participants in the study - post-menopausal women who had been treated for early-stage breast cancer and who were give letrozole or a placebo after completing five years of taxomifen therapy - were followed for an average of 2.4 years and for as long as five years. 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 an average of four years, 13 percent of the women on the placebo, but only 7 percent those on letrozole had recurred. These reductions included fewer recurrences in the breast where the original cancer occurred, in the opposite breast and in internal organs.

The results of this study appeared in the advance on-line edition of the New England Journal of Medicine on Oct. 9, 2003.

This study was the first to use an aromatase inhibitor during years five through 10 after a breast cancer diagnosis in patients who had completed five years of treatment with tamoxifen.

12. Why was the study stopped early?

It was stopped early because there was a significant decrease in recurrence among the group taking letrozole compared to the group taking a placebo.

The study was monitored by an expert, independent data safety monitoring committee. This committee reviewed the side effect data every six months and in late August 2003, saw the first data analyzed about patient outcome. The committee concluded that the results indicated taking letrozole was so beneficial that women should have the opportunity to take the drug. They recommended that the trial be stopped and that the women participating in the trial be informed if they had been receiving letrozole or the placebo. Women who have been receiving the placebo are now being given the option of taking letrozole.

13. What were the side effects of letrozole?

The most common side effects were hot flashes, sweating, edema, sore muscles and fatigue. Of these, hot flashes and sore muscles were more common in those receiving letrozole than the placebo, but vaginal bleeding was more common in those taking the placebo.

Letrozole is already available to treat certain forms of breast cancer and has generally well-tolerated side effects. The side effects seen in this study were consistent with those previously seen. Only 4.5 percent of women taking letrozole stopped the medication due to side effects, whereas 3.6 percent taking the placebo did so.

One concern about lowering estrogen levels over the long term is that it could cause thinning of the bones (osteoporosis) and raise cholesterol levels, leading to more heart attacks. The researchers noted that osteoporosis was diagnosed slightly more frequently among women taking letrozole - 5.7 percent vs. 4.5 percent on placebo. A separate sub-study in a few hundred women is looking at this question in more detail. The researchers will follow the women on letrozle for a longer period of time to ascertain the long-term effects on their bones.

There was no increase in cholesterol or significant difference in heart events in women receiving letrozole, although the follow-up has so far been short.

14. Would taking osteoporosis medication help to prevent any effects of letrozole on the bones?

The researchers are not sure, but there are studies underway to evaluate the effect of bisphosphonates on bones in women receiving letrozole. Results of these studies will help to answer this question. At present, the researchers do recommend that women taking letrozole consider calcium supplements and vitamin D. In addition, women taking this drug should have the status of their bone density determined and followed to check for osteoporosis, which would indicate the need for additional treatment such as bisphosphonates.

15. Did the study look at differences in the effectiveness of the drug among women of varying ethnic groups?

Women of a variety of ethnicities were enrolled in the study. It is believed that the therapy should be as effective in women of varying ethnic groups, but the study results are not able to answer this question definitively.

16. How many women are potentially affected by these results?

Approximately 3/4 of breast cancer patients are post-menopausal and more than 2/3 of these women have hormone-receptor positive tumours. As a result, more than 50 percent of breast cancer survivors are post-menopausal women who take tamoxifen for a planned course of five years to reduce recurrence.

17. Have the women who participated in the study been informed of the results of the study?

All doctors who enrolled patients in this clinical trial have been informed of the results of the study and are in the process of informing their patients. Women who have been taking the placebo are being given the option of starting to take letrozole. Women who have been taking letrozole will be offered the option of continuing to take the drug for up to five years.

APPLYING THE RESULTS

18. Based on the results of the study, who should consider taking letrozole?

Women completing about five years of tamoxifen and having stopped tamoxifen less than three months previously should consider taking letrozole.

19. How long should these women take letrozole?

For women in the study, the plan was to give letrozole for five years. Because the study was halted early, there are very few women who have completed five years of letrozole. However, there are a large number of women who have safely completed three years. Therefore, the researchers feel able to recommend at least three years at this time. The researchers will continue to follow the women in the study and report on their tolerance of the drug as they complete the full five years of treatment.

20. Is letrozole the only option for women after tamoxifen?

Based on the results of this study, letrozole is the first therapy that has been shown to be effective for this group of women.

21. Who else should consider taking letrozole?

Although researchers limited participation in the study to women who had completed 4.5 to six years of tamoxifen and who had been off the drug for less than three months, there may be other women with breast cancer who should consider letrozole. For example, women who have been off tamoxifen for more than three months may wish to consider letrozole.

As with all cancer therapy decisions, all women should discuss with their doctor their individual risk of cancer returning and then weigh the good and bad effects of letrozole in their individual cases.

22. Should women currently taking tamoxifen switch to letrozole?

No. This study does not suggest that replacing the initial five years of tamoxifen therapy with letrozole will be effective. It only shows that letrozole is of value in reducing breast cancer recurrence following 4.5 to six years of tamoxifen. Other studies are addressing whether letrozole is superior to tamoxifen as an initial therapy or whether stopping tamoxifen before five years and giving letrozole would be appropriate. Those results are not yet available.

23. Can pre-menopausal breast cancer survivors take this drug?

No. Letrozole is not effective for pre-menopausal women.

In pre-menopausal women, the predominant source of estrogen is the ovaries. Letrozole does not work to suppress the production of estrogen from the ovaries.

24. Should women taking another aromatase inhibitor (such as anastrozole [Arimidex®] or exemestane [Aromasin®]) switch to letrozole?

Researchers do not have data to determine if women taking another aromataase inhibitor should switch to letrozole. On October 5, 2005, the FDA approved exemestane tablets (Aromasin®, a product of Pfizer Inc.) for adjuvant treatment of postmenopausal women with estrogen receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy.

25. Should women with a family history of breast cancer consider taking this drug to help prevent breast cancer?

No. At this time, researchers do not have data to show that letrozole would prevent the development of breast cancer in high-risk women who have never had breast cancer. This trial was not designed to answer this question.

26. Should women currently undergoing chemotherapy or radiation take letrozole?

No. This study is not applicable to women with breast cancer currently undergoing chemotherapy or radiation. However, women who had chemotherapy or radiation before receiving five years of tamoxifen were included in the study, so women in this situation should consider taking letrozole.

27. Do the side effects of taking letrozole outweigh the benefits?

While each individual must evaluate the benefits and risks along with her physician, this study was stopped early because women taking letrozole were much less likely to have their cancer return than women taking a placebo, without a high rate of serious side effects.

OBTAINING THE TREATMENT

28. Is letrozole approved for use?

Yes. Letrozole has been approved for the treatment of advanced breast cancer and is available in Canada, the United States, and in many other countries around the world.

29. Does letrozole still need to be approved for this use before my doctor can prescribe it for me?

It is approved for treating post-menopausal women with advanced breast cancer. It has not yet been approved for treating women who have had their cancer removed and have not yet had recurrence. However, doctors are able to prescribe a drug for conditions that are not yet approved, provided there is firm evidence that it will be of value.

30. How do I get this drug?

This drug can only be obtained by prescription from a healthcare professional. Women should discuss the risks and benefits of this treatment option with their doctor.

31. Will this drug be covered by my health plan?

Public and/or private insurance plans may vary in whether they cover the cost of letrozole for this particular use. Women should check with their individual health care plans regarding coverage.

GETTING MORE INFORMATION

32. Where can I get a copy of the research paper?

The paper is entitled "A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer," NEJM, Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. http://content.nejm.org/cgi/content/full/349/19/1793

33. Through what hospitals and cancer care centers around the world were women enrolled in this study?

Women from nine countries participated in this study - Canada, United States, England, Belgium, Ireland, Italy, Poland, Portugal and Switzerland.

Visit www.cancer.ca or www.cancer.gov for a complete list of participating centers worldwide.

34. Where to do I find more information about breast cancer, this study and letrozole?

In Canada, call the Canadian Cancer Society at 1-888-939-3333, Monday to Friday, 9 a.m. to 6 p.m. or visit www.cancer.ca. Service is available in English and French.
In the United States, call the National Cancer Institute's Cancer Information Services 1-800-422-6237, Monday to Friday, 9 a.m. to 4:30 p.m. or visit cancer.gov. Service is available in English and Spanish.

Internationally, visit www.cancer.ca or cancer.gov.

SOME BREAST CANCER STATISTICS

35. What are my chances of being diagnosed with breast cancer?
In Canada:
In 2005, an estimated 21,600 women were diagnosed with breast cancer.
Breast cancer is the most frequently diagnosed cancer in Canadian women. Between 1992 and 2001, breast cancer incidence increased by 0.2 percent per year and mortality decreased by 2.8 per year.

In the United States:
In 2006, an estimated 214,640 women will be diagnosed with breast cancer.
Breast cancer is the most common cancer in women, excluding skin cancer. It accounts for nearly one in three cancers diagnosed in American women.
Between 1987and 2002, breast cancer incidence increased by 0.3 percent per year and mortality decreased by 2.3 percent between 1990-2002.

Note: This information package was developed by researchers involved in this clinical trial. It is not intended to replace the advice of a qualified healthcare provider.

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For a press release on this finding, go to http://cancer.gov/newscenter/pressreleases/letrozole

For more information on aromatase inhibitors, go to http://cancer.gov/clinicaltrials/developments/aromatase-inhibitors-digest

For more information about cancer, visit NCI's Web site at cancer.gov.

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