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Long-Term Data from 20 Trials Confirm Tamoxifen’s Long-Lasting Benefit


In a pooled analysis of data from participants in 20 clinical trials, women with estrogen receptor-positive breast cancer who were assigned to receive about 5 years of adjuvant treatment with tamoxifen had a lower risk of recurrence in the 15 years after starting treatment than women who did not receive tamoxifen. Women who took tamoxifen also had a one-third reduction in the risk of dying from breast cancer throughout the 15-year follow-up period.


The Lancet, August 27, 2011 (see the journal abstract).


In many breast cancers, tumor cells have receptors for the hormone estrogen and may depend on estrogen for growth. For women with this type of breast cancer—called estrogen receptor-positive (ER-positive) breast cancer—hormone therapy (drugs that block the action of estrogen or prevent it from binding to the estrogen receptor) is a standard part of treatment.

The main drugs used in adjuvant hormone therapy for women with early-stage ER-positive breast cancer are tamoxifen and the aromatase inhibitors anastrozole, letrozole, and exemestane. Of these drugs, tamoxifen has been used the longest in breast cancer treatment. A number of trials testing adjuvant tamoxifen in early-stage breast cancer were initiated in the 1980s, enabling long-term follow-up studies.

In the study described below, researchers pooled data from 20 trials comparing about 5 years of adjuvant tamoxifen with no tamoxifen in women with early-stage breast cancer to determine whether its benefits extend up to 15 years after starting treatment.

The Study

Since 1985, an international team of researchers called the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has collected data from randomized clinical trials of treatments for early-stage breast cancer: surgery, radiation therapy, chemotherapy, and hormone therapy. Every 5 years, the EBCTCG performs a meta-analysis of the updated data from individual women enrolled in the trials they follow.

As of 2011, the EBCTCG had information on 21,457 women enrolled in 20 randomized trials of tamoxifen. In all of the trials, women with early-stage invasive breast cancer were randomly assigned to receive about 5 years of adjuvant tamoxifen or no hormone therapy. (Trials of tamoxifen for ductal carcinoma in situ were not included.)

The women had been followed for a median of 13 years. The researchers compared breast cancer recurrence, deaths from breast cancer, and all deaths among women who did and did not receive about 5 years of tamoxifen and who were followed for up to 15 years after the start of treatment.


About half of the participants (10,645) had ER-positive breast cancer. Among these women, adjuvant tamoxifen reduced the number of recurrences by half in the first five years after treatment began and by one-third in the next five years. No additional reduction in risk of recurrence was seen in the subsequent 5 years, but the risk remained lower in patients who took tamoxifen than in patients who had not taken it 15 years after treatment began—that is, reduction in risk seen in the first 10 years did not “wear off" over time. Even women whose tumors expressed only a small amount of ER had a substantially reduced risk of recurrence after taking tamoxifen.

Among women whose tumors did not express the estrogen receptor (ER-negative breast cancer), tamoxifen had no effect on recurrence. Expression of the progesterone receptor (PR), another hormone receptor, did not influence whether or not tamoxifen reduced the risk of recurrence. Therefore, the authors noted, PR measurements should not be used to determine which women should take tamoxifen.

Tamoxifen also reduced the risk of recurrence in those women with ER-positive breast cancer who received chemotherapy. This benefit was seen regardless of when tamoxifen was started, that is, at the same time as chemotherapy or after chemotherapy.

The decrease in recurrence risk for ER-positive breast cancer after tamoxifen treatment was accompanied by reductions in breast cancer deaths and in deaths overall. Throughout the 15 years since the beginning of treatment, the yearly rate of breast cancer deaths among patients with ER-positive breast cancer was about one-third lower among women who had received tamoxifen than among women who had not. Deaths from any cause were also substantially reduced in women who took tamoxifen.

The meta-analysis also confirmed that tamoxifen increases risks of uterine cancer and of blood clots in the lungs. With a mean follow-up of 10 years, among women with ER-positive breast cancer, nine women who received tamoxifen died of uterine cancer, compared with one woman who did not receive tamoxifen. There was little risk for uterine cancer, however, in women under the age of 54. In the first five years of the study, six women who received tamoxifen died of a blood clot in the lung (a pulmonary embolus), compared with none of the women who did not receive tamoxifen.


Recent large clinical trials have shown that aromatase inhibitors are actually better than tamoxifen at preventing recurrences in the first few years after treatment. However, Dr. Leslie Ford of NCI’s Division of Cancer Prevention said, “we don’t have the kind of long-term follow up as in this study" for the aromatase inhibitors because they are relatively new drugs. That makes long-term head-to-head comparisons impossible at this time. In addition, Dr. Ford added, tamoxifen is the only hormone therapy that can be given to premenopausal women. It is also an option for women who have too many side effects on an aromatase inhibitor, “so tamoxifen is still in our drug arsenal and shouldn’t be dismissed," she said.


“Longer follow-up of the trials of about 5 years of tamoxifen has greatly strengthened the evidence that substantially reduced mortality rates for breast cancer continue well beyond year 10, as a delayed effect of the greatly reduced recurrence rates during years 0-9. It has also produced strong evidence of a substantial effect even in disease that was only weakly ER positive…although not in disease that was wholly ER negative," the EBCTCG authors concluded.

The fact that, 15 years after the start of treatment, rates of relapse for women who took 5 years of tamoxifen remain lower than those for women who did not take the drug, “means that 5 years of tamoxifen can prevent a high proportion of recurrences and potentially cure many patients," wrote Dr. Stephen K. Chia from the British Columbia Cancer Agency and Dr. Antonio C. Wolff from The Johns Hopkins Kimmel Comprehensive Cancer Center in an accompanying editorial.

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