Clinical Pearls for Practice: Tamoxifen: Is 10 Years the New 5?

Guest post by Melanie Danilak, BSc. Pharm, ACP (Pharmacy Clinical Educator, Cross Cancer Institute, Alberta Health Services)

By now we have all been approached by our patients who are confused about what they have heard on the news or read in the local paper:  should I be taking tamoxifen for longer than 5 years?  Results of the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial1, presented at SABCS 2012 and published in Lancet in March, 2013 had many of us re-thinking our usual "stop after 5 years" advice regarding adjuvant tamoxifen duration.  The presentation of the aTTom (Adjuvant Tamoxifen – To Offer More?) trial2 at ASCO in June, 2013 has provided even more strength to the argument that a longer duration of tamoxifen may indeed be better.  The results of these trials are summarized below.

Summary of Recent Trials Comparing 10 Years versus 5 Years of Tamoxifen

Trial

Size

Breast Cancer Recurrence

Breast Cancer Mortality

Overall Survival

aTTom2

N = 6953

ER+=2755

580/3648 (10y) vs. 672/3485 (5y)

p = 0.003

392(10y) vs. 443(5y) deaths with recurrence

p = 0.05

849(10y) vs. 910(5y) deaths

p = 0.1

ATLAS1

N = 12 894

ER+=6846

617/3428 (10y) vs. 711/3418(5y)

RR 0.84, 95% CI 0.76-0.94

p = 0.002

ARR 3.7%

331(10y) vs. 397(5y) deaths with recurrence

p = 0.01

ARR 2.8%

639(10y) vs. 722(5y) deaths

p = 0.01

 

Previous trials investigating this question gave the impression that extending duration of tamoxifen past 5 years offered little benefit.  The NSABP B-14 trial3, looked at extending tamoxifen past 5 years as a secondary outcome.  This second part of the trial was stopped early, however, because at 7 years follow up, recurrence and mortality rates favored the placebo group.  What we have learned from recent findings, however, is that the beneficial effects of extending tamoxifen treatment past 5 years become most apparent during the second decade after diagnosis (i.e., after taking 10 years of tamoxifen).  Other trials, such as the Scottish Adjuvant Tamoxifen Trial and ECOG 4181/5181 had small numbers of ER positive patients and were underpowered to detect the differences in outcome we are now seeing in these recent studies4.

What about safety? 

Endometrial cancer,  one of the most serious risks with tamoxifen therapy, was addressed in both trials.   They both reported a doubling of the risk of endometrial cancer and  increases in endometrial cancer mortality rates.

Risk of Endometrial Cancer with 10 Years versus 5 Years of Tamoxifen

Trial

Endometrial Cancer

aTTom2

Incidence 2.9%(10y) vs. 1.3%(5y)

Mortality 1.1% vs. 0.6%

ATLAS1

Incidence 3.1%(10y) vs. 1.6%(5y)

Mortality 0.4% vs. 0.2%

Putting it all together, while this new evidence gives us more confidence that it is effective and relatively safe to keep women on tamoxifen past 5 years, many questions are still unanswered.  We do not know how 10 years of tamoxifen compares to any of the treatment strategies which include aromatase inhibitors and we do not know if it is safe and effective to take tamoxifen for more than 10 years.

For premenopausal women, who do not have the option of taking an aromatase inhibitor, these findings provide a means to improve recurrence and mortality rates where few other options are available.  Unfortunately, only about 10% of patients in the ATLAS trial were premenopausal1.  The endometrial cancer risk with tamoxifen, however, is thought to be much lower in premenopausal women5.

Finally, we can’t forget all of the research that has shown us that compliance with endocrine therapy tends to decrease with each additional year on treatment6.  If keeping women adherent for 5 years is already an issue, what will trying for 10 years be like?

At our centre, 10 years of tamoxifen has made its way into our list of options, and is especially considered for high risk patients who can not take an aromatase inhibitor.  Hopefully this post will spark some discussion about what other centers are doing!

From ASCO Post:

References

  1. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, 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(9869): 805-816.
  2. Gray R, Rea D, Handley K, Bowden SJ, Perry P, Earl HM, et al.  Attom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6953 women with early breast cancer.  J Clin Oncol 2013; 31: (Suppl; abstr 5)
  3. 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 randomised trial.  J Natl Cancer Inst 2001; 93: 684-90.
  4. Burdette-Radoux S, Muss HB.  A question of duration: do patients with early-stage breast cancer need more than five years of adjuvant endocrine therapy? Clinical Breast Cancer 2009; 9: S37-41.
  5. Bakkum-Gamez JN, Laughlin SK, Jensen JR, et al.  Challenges in the gynecologic care of premenopausal women with breast cancer.  Mayo Clin Proc. 2011; 86: 229-40.
  6. Partridge AH, Wang PS, Winer EP, et al. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 2003; 21(4): 602-606.