Ten years of tamoxifen reduces breast cancer recurrences, improves survival

The findings from the ATLAS trial -- presented at the San Antonio Breast Cancer Symposium (SABCS) and published in The Lancet on December 5 -- are likely to change clinical practice, several researchers said.

Nearly 7,000 women with early-stage, estrogen receptor-positive breast cancer were enrolled in the trial between 1996 and 2005. After taking tamoxifen for 5 years, participants were randomly assigned to continue taking tamoxifen for another 5 years or to stop taking it.

From 5 to 9 years after the women began tamoxifen therapy, there was little difference in outcomes between the two treatment groups. This finding is consistent with those from other trials of adjuvant tamoxifen therapy, which showed that 5 years of tamoxifen can substantially reduce the risk of the cancer returning and of cancer death in the next few years, what one of the trial investigators, Dr. Richard Gray of Oxford University, UK, called a "carryover effect."

The improved outcomes with longer tamoxifen use emerged only after the 10-year mark, Dr. Gray explained during an SABCS press briefing. Among the women who took tamoxifen for 10 years, the risk of breast cancer returning between 10 and 14 years after starting tamoxifen was 25 percent lower than it was among women who took it for 5 years, and the risk of dying from breast cancer was nearly 30 percent lower.

Overall, from 5 to 14 years after participants began tamoxifen treatment, the risk of the cancer returning and the risk of dying from breast cancer was lower in women who took tamoxifen for 10 years, compared with those who took it for 5 years.

Tamoxifen can have side effects, including hot flashes, fatigue, and an increased risk of blood clots and endometrial cancer. But there was no substantial increase in serious side effects, including endometrial cancer incidence or death, in women who took tamoxifen for the longer period, Dr. Gray reported. The absolute increased risk of death from endometrial cancer in women who took tamoxifen for 10 years versus 5 years was 0.2 percent.

The risk-benefit ratio of any treatment must always be seriously considered, he stressed. But, in the case of extended tamoxifen treatment, he argued, the "risks are far smaller than the benefits."

At least one other trial of extended tamoxifen therapy reached the opposite conclusion to the ATLAS trial. This much smaller trial (about 1,200 patients) conducted in the United States by the National Surgical Adjuvant Breast and Bowel Project (NSABP), ran from the early 1980s to the mid-1990s. It found that continuing adjuvant treatment with tamoxifen beyond 5 years did not decrease breast cancer recurrences or deaths.

Why the trials had different findings is unclear. However, with its larger size and longer follow-up, the ATLAS results are more definitive, noted several researchers.

The ATLAS results will have "a major, immediate impact on premenopausal women" with early-stage, estrogen receptor-positive breast cancer, said Dr. Peter Ravdin of the University of Texas Health Sciences Center at San Antonio.

That patient population represents a substantial number of women diagnosed with breast cancer in the United States each year, approximately 30,000 to 35,000 women. Postmenopausal women with early-stage, estrogen receptor-positive breast cancer are often treated with aromatase inhibitors after tamoxifen. However, aromatase inhibitors are not effective in premenopausal women, Dr. Ravdin explained, so tamoxifen is the standard of care in these patients.

"We can now tell [premenopausal patients] that clinical evidence shows that 10 years [of tamoxifen] is superior to 5 years," Dr. Ravdin said. "And I'm going to be comfortable doing that."

But the decision to use tamoxifen for the extended period is by no means clear cut, he stressed.

Women with a higher risk of their cancer returning long after adjuvant therapy ends, such as those whose cancers had infiltrated their lymph nodes or who had larger tumors, "will definitely be strong candidates for continuation of [tamoxifen] therapy," he said. But a woman at low risk of recurrence at any point "may very well rationally decide she doesn't want to take tamoxifen beyond 5 years," he added.

The findings may have implications for postmenopausal women as well, said Dr. Claudine Isaacs, co-director of the breast cancer program at Georgetown Lombardi Comprehensive Cancer Center.

Postmenopausal women are often prescribed 5 years of adjuvant therapy with an aromatase inhibitor. (Some women, however, receive tamoxifen followed by an aromatase inhibitor over a 5-year period.) But, Dr. Isaacs noted, a fair number of women can't tolerate aromatase inhibitors because of their side effects, so the ATLAS results may lead some clinicians and their postmenopausal patients to consider whether an extended duration of adjuvant tamoxifen may be appropriate.

Even for postmenopausal women who can tolerate aromatase inhibitors, the ATLAS findings raise other questions, observed Dr. Trevor Powles of the Cancer Center London in an accompanying editorial in The Lancet.

"No data are available to suggest that [the aromatase inhibitor] letrozole for 5 years is better for long-term benefit than 10 years of tamoxifen, which has a proven effect in terms of long-term risk reduction of relapse and mortality," Dr. Powles wrote.

In a post on her "Chemobrain" blog, breast cancer survivor and cancer advocate AnneMarie Ciccarella urged women who are candidates for adjuvant tamoxifen, regardless of their menopausal status, to carefully consider their options. "Sit down with your doctor. Ask questions. Understand how this study impacts your own set of circumstances," she wrote. "Remember, there is no cookie cutter answer."