What are the benefits and adverse effects of tamoxifen adjuvant therapy for breast cancer?

Updated: May 21, 2019
  • Author: Erin V Newton, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
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The 2000 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis demonstrated that the risk reduction from adjuvant tamoxifen is similar in older and younger women (or even superior in older women). [41]

Relative risk of recurrence by patient age was as follows:

  • Older than 70 years - 0.49
  • 60-69 years - 0.55
  • 50-59 years - 0.66
  • 40-49 years - 0.71

Common adverse effects associated with tamoxifen included the following:

  • Hot flashes (up to 80%)
  • Vaginal bleeding (2-23%)
  • Vaginal discharge (13-55%)
  • Vaginal dryness (< 1%)
  • Dyspareunia (3-5%)
  • Urinary frequency or urgency (10%)
  • Mood changes (12-18%)
  • Depression (2-12%)

Although many patients attribute postdiagnosis weight gain to tamoxifen, the literature suggests only a 5% increase in weight is associated with tamoxifen use.

A study by Varga et al found that concomitant tamoxifen therapy demonstrated an independent role in the development of radiogenic lung fibrosis. [42]

A study by Tang et al compared the Oncotype DX Recurrence Score (RS) with the Adjuvant! scoring system in terms of genomic prediction of outcome and response to adjuvant chemotherapy in patients with ER-positive breast cancer. Both scoring systems provided strong independent prognostic information in tamoxifen-treated patients. [43] Combining RS and individual clinicopathologic characteristics was superior to prognostic discrimination using RS and the Adjuvant! system. The study’s authors suggest that RS should still be used for estimating relative chemotherapy benefit. [43]

Tamoxifen is a prodrug that is metabolized primarily by the cytochrome P450 (CYP2D6) system to its active metabolite, endoxifen. More than 80 different alleles of the CYP2D6 gene have been identified, with varying activity levels. Consequently, patients can be categorized by their level of CYP2D6 activity into high/extensive or low/poor metabolizers.  Some laboratories now offer CYP2D6 testing for patients treated with tamoxifen, but this testing is still controversial. For more information on tamoxifen metabolism, see Tamoxifen Metabolism and CYP2D6.

Up to 7% of the white and black populations are poor metabolizers of tamoxifen. Poor metabolizers have been shown in several retrospective studies to have lower disease-free survival and higher recurrence rates than extensive metabolizers. Poor metabolizers also seem to tolerate tamoxifen better, with less severe hot flashes and endocrine-related toxicities.

Considerable interest has arisen regarding tamoxifen and inhibitors of CYP2D6 activity. Many agents, of which the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac) and paroxetine (Paxil) are most prominent, are potent CYP2D6 inhibitors that can also decrease conversion of tamoxifen to endoxifen. [44]  

At the 2009 American Society of Clinical Oncology (ASCO) 45th annual meeting, experts presented contradictory results on the risk of breast cancer recurrence with the use of SSRIs in women taking tamoxifen to reduce their risk of recurrence. However, they concurred that until more data are available, these patients should avoid concomitant use of SSRIs. [44, 45, 46]

More recently, Donneyong et al found no increase in all-cause mortality in patients taking tamoxifen and potent CYP2D6-inhibiting SSRIs compared with patients taking tamoxifen and other SSRIs. [47]  These authors reviewed data from five US databases on 14,532 women who were prescribed an SSRI either before or during their tamoxifen treatment; of those, 5,799 were prescribed paroxetine or fluoxetine, while the remainder received the weak CYP2D6 inhibitors citalopram, escitalopram, fluvoxamine, or sertraline.

Although the study sample was large, the study period was only 2 years, which many experts feel is too short to permit definitive conclusions. Consequently, until longer-term followup data become available, the use of potent CYP2D6 inhibitors should be avoided if possible in patients on tamoxifen. Other strong inhibitors of CYP2D6 include quinidine, risperidone, and tenofovir.

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