Extended Tamoxifen Use in Breast Cancer: Is Ten the Magic Number?

August 7, 2014
Eleonora Teplinsky, MD
Eleonora Teplinsky, MD

The majority of breast cancers are hormone-receptor (HR) positive. Sixty to 75% of women have estrogen receptor (ER)-positive breast cancer, and 65% of these cancers are also progesterone receptor (PR)-positive. It has been well established that for patients with HR-positive disease, adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor (AI) is a highly effective therapy.1

Initially, we knew that 1 to 2 years of tamoxifen was effective, but subsequent data showed that 5 years of adjuvant tamoxifen substantially reduced both recurrence rates throughout the first 10 years after diagnosis, and breast cancer mortality throughout the first 15 years. For decades, 5 years of tamoxifen therapy was the standard of care and later, postmenopausal patients were offered the option of taking an AI as an alternative to tamoxifen or in sequence after tamoxifen.1-4 However, the breast cancer community then raised the question: "Would 10 years be better than five?" Two large phase III randomized trials emerged to answer this question: the worldwide ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) Trial and the aTTom (adjuvant Tamoxifen – To offer more?) trial.4, 5

ATLAS randomized 12,894 women (between 1996 and 2005) with early breast cancer to continue tamoxifen for 10 years versus stopping at 5 years. The main analyses of breast cancer outcomes focused on the 6,846 women with ER-positive disease (6,048 women were excluded from analyses of main effects as ER status was negative or unknown). In regards to recurrence, 1,328 were recorded (899 during years 5 to 9, 379 during years 10 to 14, and 50 after reaching year 15). Among women with ER-positive disease, continuing tamoxifen for 10 years versus stopping at 5 years reduced the risk of recurrence (RR) (18% vs 20.8%; P= .002), breast cancer mortality (9.7% vs 11.6% in controls; P= .01) and overall mortality (18.6% vs 21.1%;  P= .01). RR during years 5 to 14 was 21.4% for women allocated to continue versus 25.1% for controls with an absolute risk reduction of 3.7%. There was no evidence of a rebound increase in the recurrence rate when tamoxifen treatment ended. Breast cancer mortality during years 5 to 14 was 12.2% for women allocated to continue versus 15.0% for controls with an absolute mortality reduction of 2.8%. ATLAS showed that the main effects of 10 years of tamoxifen on RR and particularly, on breast cancer mortality, became apparent only during the second decade after diagnosis.4

Similarly, aTTom randomized 6,953 women in the United Kingdom (during 1991 and 2005) with ER-positive (n=2,755) or ER untested (n=4,198) invasive breast cancer to stop tamoxifen at 5 years or to continue to 10 years. Continuing tamoxifen for 10 years versus stopping at 5 years reduced breast cancer recurrence (16.7% vs 19.3%; P= .003) and breast cancer mortality (11.3% vs 12.7%; P= .05). There was little effect on non-breast cancer mortality.  The reductions were time-dependent, meaning that the treatment allocation had little effect on recurrence rates or mortality during the period of 5 to 9 years after diagnosis. However, during the second decade after diagnosis, women who had been allocated to continue tamoxifen treatment had a 25% lower recurrence rate and a 23% lower breast cancer mortality rate compared to the women who had been allocated to stop after only 5 years.5

The results of these trials were practice changing. ASCO recently issued a Clinical Practice Guideline Focused Update on adjuvant endocrine therapy for women with HR-positive breast cancer. In addition to reviewing ATLAS and aTTom, the update also reviewed three additional trials: NSABP B-14, the Scottish Tamoxifen Trial, and the ECOG 4181/5181 Trials (not discussed here).6-9 In the update, ASCO’s “bottom line” was this:1

  • Pre- or peri-menopausal women who are diagnosed with HR-positive breast cancer should be offered adjuvant endocrine therapy with tamoxifen for an initial duration of 5 years followed by an additional 5 years of endocrine therapy (AI or tamoxifen), depending on their menopausal status. If they remain pre- or peri-menopausal or if menopausal status is unknown and cannot be determined, they should be offered to continue on tamoxifen for a total duration of 10 years. If women have become definitively postmenopausal, they should be offered continuous tamoxifen for a total duration of 10 years or they can switch to receive up to 5 years of an AI for a total duration of up to 10 years of adjuvant endocrine therapy.1
  • Women who are diagnosed with HR-positive breast cancer who are postmenopausal should be offered adjuvant endocrine therapy with either 10 years of tamoxifen, 5 years of an AI (the data is currently insufficient to recommend an AI for a duration of greater than 5 years), 5 years of tamoxifen initially followed by an AI for up to 5 years (total duration of up to 10 years), tamoxifen for a duration of 2 to 3 years followed by an AI for up to 5 years for a (total duration of up to 7 to 8 years of adjuvant therapy).1
  • Women who are postmenopausal and are intolerant to either tamoxifen or an AI should be offered an alternative type of adjuvant endocrine therapy.1

The published updated guidelines by ASCO (Burstein et al.) in the Journal of Clinical Oncology contain the complete recommendations and the strength of evidence supporting these recommendations.1

As with any change in practice, we must weigh the risks and benefits. What about the risk of endometrial cancer and venous thromboembolism that may be seen with an additional 5 years of tamoxifen therapy? Endometrial cancer was slightly more common with patients receiving extended therapy with tamoxifen versus 5 years: a cumulative risk of 3.1% vs 1.6% in ATLAS and an incidence of 2.9% vs 1.3% in aTTom.1 In ATLAS, the incidence of pulmonary embolism was higher in the continued tamoxifen group (0.63% vs 0.32%; P= .01) and not described in aTTom.1, 4, 5 However, despite the increased risks of continued therapy with tamoxifen, there's a clear benefit of extended endocrine therapy on decreased recurrence and mortality.

As such, we can now safely say that when it comes to tamoxifen: "Yes, 10 is the magic number."

 

References:

  • Burstein HJ, et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 2014; 32:2255-69.
  • Early Breast Cancer Trialists' Collaborative Group, Davies C, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011; 378:771-84.
  • Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 365:1687-717.
  • Davies C, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013; 381:805-16.
  • Gray RG, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breaast cancer. J Clin Oncol 31, 2013.
  • Fisher B, Dignam J, Bryant J, et al: Five Versus More Than Five Years of Tamoxifen for Lymph Node-Negative Breast Cancer: Updated Findings From the National Surgical Adjuvant Breast and Bowel Project B-14 Randomized Trial. J Natl Cancer Inst. 2001; 93:684-90.
  • Stewart HJ, et al. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br J Cancer. 1996; 74:297-9.
  • Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst. 2001; 93:456-62.
  • Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst. 1996; 88:1828-33.