Q: I’ll be completing five years of tamoxifen therapy for breast cancer in the next couple of months. Should I take letrozole next?
Answer from the expert staff of breast cancer research at the Robert W. Franz Cancer Research Center at Providence Portland Medical Center: Evidence published in the Oct. 9, 2003 Web version of the New England Journal of Medicine (NEJM) indicates that postmenopausal breast cancer patients should strongly consider letrozole (Femara) therapy following five years on tamoxifen (Nolvadex).
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| Estrogen stimulates breast cancer growth in estrogen receptor-postive (ER+) tumors. Graphic courtesy of Novartis Pharmaceuticals. |
Both letrozole and tamoxifen work by interfering with the ability of estrogen to stimulate breast cancer cells. Letrozole, one of three commercially available aromatase inhibitors, dramatically reduces the production of estrogen in postmenopausal women. This drug is only effective in postmenopausal women. Tamoxifen, a selective estrogen receptor modulator (SERM), blocks estrogen from binding to its receptors in breast cancer cells. Tamoxifen is effective in both premenopausal and postmenopausal women.
The study summarized in NEJM involved more than 5,000 postmenopausal, early-stage, estrogen receptor-positive breast cancer patients who had recently completed five years of tamoxifen therapy. Researchers assigned half of the study participants to letrozole and the other half to a placebo. The study was originally intended to last five years, but a review of the data at the study’s midpoint showed such overwhelming benefit from letrozole that the independent data-monitoring safety board halted the study, informed participants of the results so that patients on placebo could have the option of switching over to letrozole, and published their findings.
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| Letrozole reduces estrogen production in postmenopausal women and helps "starve" tumors. Graphic courtesy of Novartis Pharmaceuticals. |
After a median follow-up of two and a half years, evidence showed that letrozole reduced the risk of local or distant recurrence or new, opposite-side (contralateral) breast cancers by 43 percent, which was a highly significant difference. Before the study was stopped, 75 women in the letrozole group had experienced one of these events, compared with 132 in the placebo group. The estimated four-year, cancer-free survival rate was 93 percent in the letrozole group vs. 87 percent in the placebo group.
There were fewer deaths from any cause in the letrozole group (42 vs. 31) and deaths from breast cancer (17 vs. 9), but these were not statistically significant differences. Side effects were similar to those seen with anastrozole (Arimidex) in the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, including an increased risk of osteoporosis.
Tamoxifen has been studied for many years now, and a series of trials has established that five years of treatment is superior to one or two years, and 10 years of treatment is not better than five years. Similar studies testing the optimal duration of aromatase inhibitor treatment have not been performed, but researchers are currently recommending that women follow five years of tamoxifen therapy with five years of letrozole.
For women who have completed or will complete five years of adjuvant tamoxifen, the recommendation to consider letrozole treatment is straightforward. The question of what to recommend for women starting on adjuvant hormonal therapy now is more vexing.
The ATAC trial has demonstrated that anastrozole significantly reduces breast cancer recurrences and new contralateral breast cancers compared to tamoxifen when given to early-stage breast cancer patients as the initial adjuvant hormonal therapy. Should women take tamoxifen for the first five years (and risk a higher chance of recurrence compared to anastrozole) and then switch to letrozole? Or, should the patient take anastrozole first followed by tamoxifen? Or followed by letrozole? Or followed by more anastrozole?
Clinical trials that are currently underway will provide some but not all of the answers to these questions. We’ll have more information in the next few years about the ideal sequencing and duration of these adjuvant therapy drugs, so stay in communication with your oncologist in order to stay current with this changing aspect of breast cancer care.
What we’re certain of now is that letrozole benefits breast cancer patients who’ve taken tamoxifen for five years. If you fit this description, you should ask your doctor about letrozole. Most breast cancer recurrences occur more than five years after the initial diagnosis – so a therapy that significantly reduces risk in this time frame is extremely important.
If you completed five years of tamoxifen therapy some time ago, you may still benefit from letrozole therapy. The drug kills cancer that’s too small to be detected, so in theory it should provide benefit for a number of years after tamoxifen – though we don’t yet know if there’s a definite post-tamoxifen window in which letrozole is effective. Clearly researchers in this letrozole study thought the drug would benefit women who’d been off tamoxifen for some time: All the participants had stopped tamoxifen before the trial began, and after two and a half years the researchers recommended that those on the placebo consider taking letrozole.
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October 2003
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