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Long-term adjuvant endocrine therapy reduces contralateral breast cancer risk in community setting

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October 6, 2016

Adjuvant endocrine therapy with tamoxifen or aromatase inhibitors reduced the risk for contralateral breast cancer in women with invasive breast cancer treated in the community setting, according to retrospective study results.

The risk for contralateral breast cancer markedly decreased as the duration of tamoxifen therapy increased, results showed.

Gretchen L. Gierach

Approximately 5% of women diagnosed with breast cancer will develop contralateral breast cancer within 10 years. Randomized studies have indicated that endocrine therapy including tamoxifen or aromatase inhibitors reduce the risk for cancer in the opposite breast.

Gretchen L. Gierach, PhD, MPH, investigator in the metabolic epidemiology branch of the NCI, and colleagues sought to determine whether the protective influences of endocrine therapy extended to women treated in the community medical setting, where gaps in treatment and variations in therapy duration are more likely to occur.

The study included data from 7,541 women (median age at diagnosis, 60.6 years; range, 24.9-84.9; 92.9% non-Hispanic white) diagnosed with primary unilateral invasive breast cancer between January 1990 and December 2008.

The researchers analyzed data from study participants from 1 year after diagnosis until the development of contralateral breast cancer or another second cancer, death, last tumor-registry follow-up or end of follow-up. Investigators measured receipt and duration of tamoxifen or other aromatase inhibitors using electronic prescription records.

Median follow-up was 6.3 years (range,1-20.9).

Fifty-two percent (n = 3,900) of the study population used tamoxifen for a median duration of 3.3 years (range, 0.3-16.2). Factors associated with tamoxifen use included non-Hispanic white race, age younger than 50 years at diagnosis, stage II disease at diagnosis, ER–positive disease and moderately differentiated grade.

Further, 1,929 women (25.6%) received aromatase inhibitors, with (n = 963) or without (n = 966) tamoxifen.

A total of 248 women developed contralateral breast cancer during follow-up (invasive, n = 203; in situ, n = 45).

Use of endocrine therapy occurred less frequently among women who developed contralateral disease than among those who did not (51.2% vs. 65.3%).

The researchers observed an inverse association between decreased contralateral breast cancer risk and increased duration of endocrine therapy. Current tamoxifen users had a RR for contralateral disease of 0.76 (95% CI, 0.64-0.89) per year of use, with an approximately 66% risk reduction for 4 years of therapy compared with nonusers.

Although women who ceased tamoxifen had a smaller risk reduction than current users, they still carried a significant risk reduction for at least 5 years after therapy cessation (RR = 0.48 per year of use; 95% CI, 0.71-0.99).

Women who received aromatase inhibitors without tamoxifen had a reduced risk for contralateral breast cancer compared with nonusers (RR = 0.48; 95% CI, 0.22-0.97).

Women with ER–positive primary breast cancers who received tamoxifen had a significantly reduced risk for ER–positive contralateral breast cancers, whether they were current users (RR = 0.68 per year; 95% CI, 0.54-0.84) or former users with fewer than 3 years since last use (HR = 0.79; 95% CI, 0.67-0.91) or 3 to fewer than 5 years since last use (HR = 0.83; 95% CI, 0.7-0.98).

However, researchers found little indication that tamoxifen therapy reduced ER–negative contralateral breast cancer risk.

Further, tamoxifen therapy did not reduce the risk for contralateral breast cancer among women whose primary cancer was ER negative; however, researchers noted there were few patients in these subgroups.

Due to the retrospective nature of the study, endocrine therapy durations were not standardized, which researchers noted may serve as a potential confounding factor. Further, the researchers did not have access to patients’ menopausal status, which may influence receipt of tamoxifen.

“The present is an opportune time for clinicians to engage in shared, informed decision-making with patients regarding the best treatment course for breast cancer,” Gierach and colleagues wrote. “If adjuvant endocrine therapy is indicated for breast cancer treatment, our findings in concert with trial data suggest that women should be encouraged to complete the full course.”

V. Craig Jordan

Women with breast cancer for whom tamoxifen is recommended must be encouraged to adhere to the full course of therapy, Balkees Abderrahman, MD, postdoctoral fellow, and V. Craig Jordan, OBE, PhD, DSc, FMedSci, professor of breast medical oncology and cellular oncology at The University of Texas MD Anderson Cancer Center, wrote in a related editorial.

“Simply stated: no medicine, no benefit,” Abderrahman and Jordan wrote. “Low adherence results in early recurrence, increased medical costs and a much worse quality of life. ... 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. This unanticipated mechanism can prevent contralateral breast cancer or save the lives of patients with breast cancer after adjuvant therapy.” – by Cameron Kelsall

Disclosure: The researchers report no relevant financial disclosures. Jordan reports scientific advisory board positions with Sermonix and Shenogen. Abderrahman reports no relevant financial disclosures.

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Debra Patt

Therapies like tamoxifen and aromatase inhibitors that provide reduction of estrogen exposure are some of our best tools to fight breast cancer. In addition to endocrine therapy’s use in the reduction of breast cancer recurrence for survivors of invasive breast cancer and chemoprevention of invasive breast cancer in women with ductal carcinoma in situ (DCIS) and other high-risk lesions, there is a reduction in risk for developing an invasive breast cancer in the contralateral breast among breast cancer survivors. 

The incidence of contralateral breast cancer and appreciation of the magnitude of risk reduction from endocrine treatment as chemoprevention was previously less well understood. The recent study by Gierach and colleagues in JAMA Oncology, which associated adjuvant endocrine therapy with a reduction in contralateral breast cancer risk, helps quantify the risk reduction. Five percent of women who survive breast cancer develop a contralateral breast cancer within 10 years. In this study, when endocrine therapy was taken for an average of 4 years, at 10 years there was a 3% risk reduction in the development of contralateral breast cancer.

This study is important because it recognizes the substantial benefits of chemoprevention. There have been increasing trends to undergo contralateral prophylactic mastectomy, and the decision for surgical management is largely due to the fear of developing contralateral breast cancer. It is useful to have this knowledge on the chemopreventive benefits of endocrine blockade, as it can be used to increase health literacy around the risk for contralateral breast cancer and empower informed decision-making between doctors and their patients. It seems likely that fewer women may elect to have aggressive surgery if they perceive their risk for developing a contralateral breast cancer can be reduced to an acceptable level with less aggressive treatment strategies.

It is important that breast cancer survivors with ER–positive cancers are encouraged to continue their adjuvant treatment as indicated. In recent years, the recommended length of endocrine blockade therapy for women with ER–positive invasive breast cancers that continue to have risk for recurrence has been extended from 5 years to 10 years. Although this is a standard recommendation, many women discontinue treatment prematurely due to adverse events. The new information that compliance not only prevents recurrence of the primary breast cancer, but may also prevent new tumors, should prompt discussions between doctors and patients, further enhancing patient health literacy about the additional benefits of these treatments.

Debra Patt, MD, MPH, MBA

Texas Oncology

Disclosure: Patt reports no relevant financial disclosures.