Women on Adjuvant Tamoxifen, AIs Urged to Stay the Course

Alexander M. Castellino, PhD

October 18, 2016

A 'real-world' study from the community setting has confirmed findings from clinical trials: It shows that women diagnosed with invasive breast cancer who took long-term tamoxifen or aromatase inhibitors (AIs) had lower risk for cancer in the opposite, or contralateral, breast.

The study of more than 7500 patients with breast cancer found that the longer the women stayed on therapy, the lower their risk for contralateral breast cancer. For example, in women who took tamoxifen for 4 years, the contralateral breast cancer risk was reduced by 66%.

The study was published online October 6 in JAMA Oncology.

Long-term therapy with antiestrogens — mainly tamoxifen or AIs — is standard for postmenopausal women after surgery for estrogen receptor (ER)–positive invasive breast cancer. These guidelines are based on clinical trial data.

"Now, these findings in the community setting along with data from clinical trials show that if adjuvant therapy is indicated, clinicians should urge patients to complete the full course of therapy," Gretchen L. Gierach, PhD, MPH, from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Bethesda, Maryland, and lead author of the study, told Medscape Medical News.

"The rules from animal studies are upheld in the real-world setting," V. Craig Jordan, OBE, PhD, DSc, professor of Breast Medical Oncology and chief, Section of Basic Science Research and Pharmacology, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News. Dr Jordan was a coauthor of an editorial that accompanied this study, along with colleague Balkees Abderrahman, MD.

"Our animal studies in the 1970s told us that longer therapy was going to be more protective," Dr Jordan said. He speculated that "we may have to give it for life." Indeed, some women in the study had been receiving tamoxifen for more than 16 years.

Study Details

Dr Gierach and her colleagues examined the records of two cohorts from the Kaiser Permanente Northwest Center for Health Research (Oregon) or the Kaiser Permanente Institute for Health Research (Colorado) who received an initial diagnosis of unilateral breast cancer between 1990 and 2008.

Data were analyzed for contralateral breast cancer diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the healthcare plan, or end of study follow-up.

Treatment with tamoxifen, AIs, other hormonal or chemotherapeutic agents, and radiotherapy were extracted from prescription and medical records.

Results

In the eligible cohort of 7541 women, initial median age at diagnosis was 60.6 years (range, 24.9 to 84.9 years) and women were predominantly postmenopausal and white.

During the median follow-up time of 6.3 years (range, 1.0 to 20.9 years), 248 women developed contralateral breast cancer, with stage, grade, histologic findings, and ER status of the initial diagnosis being similar among those who did and those who did not develop contralateral breast cancer.

Fifty-two percent (3900 of 7541) of women used tamoxifen, and median duration of use was 3.3 years (range, 0.3 to 16.2 years).

Dr Gierach and colleagues showed that contralateral breast cancer decreased with increasing tamoxifen use. Among current users, the relative risk (RR) was 0.71 for less than 1 year of use (not significant) and 0.26 for at least 4 years of use.

In current users, the RR was 0.76 per year of tamoxifen use (significant), and the investigators estimated a significant 66% RR reduction for 4 years of use compared with nonusers.

For former users, the RR per year of tamoxifen use was smaller, but significant, even after stopping of tamoxifen for 5 years.

Compared with tamoxifen, use of AIs is more recent in clinical practice and in their cohort of women. Dr Gierach and colleagues reported that 25.6% (1929 of 7541) received AIs (anastrozole more often and letrozole less frequently). Median duration of AI therapy taken with (n = 963) and without (n = 966) tamoxifen was 2.2 years (range, 0.3 to 10.2) and 2.9 years (range, 0.3 to 9.5), respectively.

Compared with nonusers, RR for AI use alone was 0.48, with a significant 52% risk reduction for contralateral breast cancer.

No association between tamoxifen use and reduced risk for contralateral breast cancer was noted for women whose initial breast cancer was ER negative, Dr Gierach indicated.

When looking at cumulative incidence of contralateral breast cancer, Dr Gierach and colleagues noted that ER-positive patients who did not use tamoxifen had a 10-year cumulative incidence of 4.9%. The incidence was lower among women who took tamoxifen for less than 4 years (3.3%) and lowest in women who took tamoxifen for at least 4 years (1.6%).

For women who lived for at least 5 years after the initial diagnosis, using tamoxifen for at least 4 years was estimated to prevent three contralateral breast cancers per 100 women by 10 years after the first diagnosis of ER-positive breast cancer. At 15 years, it was estimated that tamoxifen use was likely to prevent four contralateral breast cancers.

Comparing the Study With Others

The study confirms data from the 2011 Early Breast Cancer Trials Collaborative Group (EBCTCG) pooled analysis, also known as the Oxford Overview since the Data Management and Analysis Center is in Oxford, United Kingdom. The EBCTCG reported an absolute reduction of 3.2% for contralateral breast cancer at 15 years with 5 years of tamoxifen use compared with 4.0% from this study for at least 4 years of tamoxifen use.

"The agreement of our study with the EBCTCG's report regarding the effectiveness of tamoxifen therapy strengthens the evidence for a long-lasting reduction in CBC [contralateral breast cancer] risk both within and outside the clinical trial setting," the study authors write in their discussion.

Dr Gierach explained that this study differed from other observational studies, which were designed as cross-sectional or nested case-control studies. Some of these studies showed the protective effects of tamoxifen, but duration of tamoxifen therapy was not directly examined, she explained. "This observational study was able to fill in those gaps," she noted.

"The cohort design allowed for absolute risk estimation, which is essential for clinical decision making," the study authors write.

Message: No Medicine, No Benefit

Both Dr Jordan and Dr Gierach explained that adherence to long-term antiestrogen therapy is essential to accrue maximum benefits.

"Women not adhering to therapy run the risk of recurrence," Dr Jordan said.

However, nonadherence to endocrine therapy has been a challenge in the clinical management of these women, he acknowledged.

In their editorial, Dr Abderrahman and Dr Jordan indicated that low adherence to therapy resulted in early recurrence, increased medical costs, and a much worse quality of life.

Side effects of therapy have often been cited for low adherence. For tamoxifen, those include hot flashes, fluid retention, nausea, weight loss, and skin changes. Hot flashes and joint and muscle pain are also side effects of AIs.

However, the benefits far outweigh the risks, Dr Jordan indicated.

Because of the side effects of each therapy, some women tend to cycle between the two, Dr Gierach explained. Some women may not respond to tamoxifen therapy, she noted. Tamoxifen is a prodrug and must be metabolized; it is thought that some women cannot effectively metabolize tamoxifen because of genetic variants of CYP3 and CYP2D6.

Dr Gierach explained that published work from her group and from others has shown a tamoxifen-associated reduction in breast density, which can be determined from a mammogram. These declines in breast density are associated with reduced risk for breast cancer development and progression, she said.

"Breast density reduction may be a marker for the effectiveness of tamoxifen," she explained. "Measuring metabolites of tamoxifen in circulation might also enable us to identify women who respond best."

"If adjuvant endocrine therapy is indicated for breast cancer treatment, our findings suggest that women should be encouraged to complete the full course," she said.

Tamoxifen — From the Lab to the Clinic

Dr Jordan has earned the sobriquet "Father of Tamoxifen." When the compound, then known only by its code name ICI 46,474, failed as the morning-after pill in the early 1970s, Dr Jordan developed the clinical strategies of chemoprevention and long-term adjuvant therapy in animal models.

He explained that tamoxifen is a competitive inhibitor of estrogen for the estrogen receptor. Long-term tamoxifen blocks micrometastases, he pointed out. "By locking into the estrogen receptor, it prevents estrogen from exerting its proliferative signals," he said.

However, there was the worrisome notion that long-term use of tamoxifen would lead to resistance. Indeed, Dr Jordan's laboratory showed that in a tamoxifen-resistant mouse model, long-term use in animals transplanted with these tumors kept the animals alive. However, the more striking observation was that in animals with transplanted tamoxifen-resistant tumors, a small dose of estrogen caused tumor shrinkage. Instead of promoting tumor growth, estrogen killed tumors cells.

"In women whose bodies have been starved of estrogen, the hormone comes back as a jet fuel to kill the tumor," Dr Jordan told Medscape Medical News. But this happens only after 5 years of adjuvant therapy with an AI or tamoxifen, he pointed out.

"Tamoxifen must create selection pressure, lasting 5 years or more, to produce vulnerable breast cancer cells so that a woman's own estrogen becomes a paradoxical cytotoxic therapy once tamoxifen treatment is stopped," Dr Abderrahman and Dr Jordan write in their editorial.

The study authors have disclosed no relevant financial relationships. Dr Jordan reported being on the scientific advisory boards of Sermonix (Columbus, Ohio) and Shenogen (Beijing, China).

JAMA Oncol. Published online October 6, 2016. Abstract, Editorial

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