Updated Guidelines Advise 10 Years of Tamoxifen in HR-Positive Breast Cancer

Harold J. Burstein, MD, PhD

The ASCO clinical practice guideline now recommends treatment with adjuvant tamoxifen for 10 years in women with stage I-III hormone receptor (HR)-positive breast cancer, based on data from the collection of 5 clinical trials.

Included the studies supporting the new guideline were the large aTTom and ATLAS phase III trials. In the aTTom study, women continuing tamoxifen for 10 years had a 25% lower recurrence rate and a 23% lower breast cancer mortality rate compared to those who stopped at 5 years. In the large ATLAS trial, there was a 2.8% reduction in mortality risk for continuing treatment with tamoxifen and the rate of recurrence for those receiving tamoxifen for 10 years was 25% less compared to those receiving just 5 years of treatment.

"Tamoxifen taken for five years has been the standard adjuvant endocrine treatment for decades, but we now have evidence to recommend up to 10 years of tamoxifen for women with hormone receptor-positive breast cancer," Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute and co-chair of ASCO's Expert Panel that wrote the guideline update, said in a press release. "Postmenopausal women also have the option of taking an aromatase inhibitor as an alternative to tamoxifen or in sequence after tamoxifen. Aromatase inhibitors are not recommended for premenopausal women."

According to the updated guideline, adjuvant endocrine therapy with tamoxifen for 5 years should be offered to pre-/peri-menopausal women. After this, if the patient remains premenopausal, they should be offered continued tamoxifen for an additional 5 years. If postmenopausal, patients should be treated with continued tamoxifen or an aromatase inhibitor (AI) for an additional 5 years -- totaling 10 years of adjuvant endocrine therapy.

The guideline suggests that postmenopausal women should be treated with either tamoxifen for 10 years, an AI for 5 years, tamoxifen for 5 years followed by an AI for up to 5 years, or tamoxifen for 2-3 years followed by an AI for up to 5 years. Ten consecutive years of treatment with an AI was not recommended.

Intolerance can be utilized to help guide the treatment decision, the guideline suggests. For instance, if a patient cannot receive tamoxifen, an AI should be administered. Additionally, the guideline noted that if an AI was administered but discontinued at less than 5 years that tamoxifen should be administered for a total of 5 years. Moreover, if a patient had previously received tamoxifen for 2-3 years, they should be offered an AI for up to 5 years, for a total duration of treatment of 7-8 years

In the supporting phase III ATLAS trial that was published in Lancet, 10 years of tamoxifen reduced the risk of dying by 29% during the second decade after diagnosis compared with 5 years of treatment.

ATLAS enrolled 6846 women with ER-positive breast cancer who had been taking tamoxifen for 5 years. Women were randomized to 5 more years of tamoxifen or no more tamoxifen. At nearly an 8-year follow-up, 1328 recurrences and 728 deaths as a result of recurrence were reported.

In the second decade after diagnosis, women who continued on tamoxifen had a 25% lower recurrence rate and 29% lower breast cancer mortality rate compared with women who stopped after 5 years of tamoxifen. The risk of dying due to breast cancer 5-14 years after diagnosis was 12.2% for continuing tamoxifen versus 15% for those who only had 5 years of treatment, representing an absolute gain of 2.8% favoring continuing treatment with tamoxifen for 10 years.

A significant benefit for 10 years versus 5 years of tamoxifen was observed for recurrence (rate ratio[RR] = 0.75 for 10 years vs RR = 0.90 for 5 years; P = .002) and breast cancer mortality (RR = 0.71 in 10 years vs RR = 0.97, P = .01).

In the aTTom study that was presented at the 2013 ASCO Annual Meeting, 10 years of adjuvant tamoxifen substantially reduced late breast cancer recurrence and mortality among women with ER-positive breast cancer. This study randomized 6953 women with breast cancer who had been taking tamoxifen for 5 years to continue receiving tamoxifen for another 5 years or stop taking the drug.

With follow-up of more than 10 years, there were 580 recurrences among women who had taken tamoxifen for 10 years, compared with 672 recurrences in the shorter-term treatment arm (P = .003). There were 392 breast cancer deaths after recurrence among participants who had taken the drug for a decade, compared with 443 deaths among those in the 5-year arm (P = .05).

When the results of the aTTom study and the ATLAS trial were combined, the statistical significance of the benefits of longer tamoxifen administration was enhanced, with improvement in recurrence rates (P < .0001), breast cancer mortality (P = .002), and overall survival (P = .005).

"It is important for clinicians and patients to discuss the trade-offs between potential risks of side effects and potential benefits of taking adjuvant endocrine therapy for up to 10 years," Jennifer Griggs, MD, MPH, co-chair of the ASCO Expert Panel that helped create the guideline, said in a press release. "Many women taking adjuvant tamoxifen experience side effects, and these appear to persist with longer duration. However, the trials did not find any new or unexpected side effects."

The disadvantages of taking tamoxifen for 10 years may include continuing menopausal symptoms, such as night sweats and hot flashes. Longer duration of treatment increases the risk of endometrial cancer: In the aTTom trial, there were 102 cases and 37 (1.1%) deaths attributed to endometrial cancer in the 10-year tamoxifen arm, compared with 45 cases and 20 (0.6%) deaths in the 5-year group.

However, it was concluded that the benefits demonstrated by a longer duration of treatment with tamoxifen outweighed the possible risks, which warranted the new guideline.