Extended adjuvant tamoxifen for early breast cancer: a meta-analysis

Abstract

Background: Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear.

Methods: We conducted a systematic review and meta-analysis to quantify the benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (5 years of therapy). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for disease recurrence, death and adverse events. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried.

Results: Five trials comprising 21,554 patients were included. Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76-1.05, p = 0.17). There was no association between extended adjuvant tamoxifen and all-cause death (OR:0.99, 95% CI 0.84-1.16, p = 0.88). There was an apparent reduction in risk of recurrence occurring after completion of extended adjuvant tamoxifen with little evidence of effect during therapy, however, this difference was not significant (p for difference 0.10). Subgroup analysis suggested that a greater effect size among lymph node positive patients compared with those who are lymph node negative (NNT: 25 vs. 49). There was no apparent difference in the effect between pre- and post-menopausal patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65-2.58, p<0.001, number needed to harm:89).

Conclusion: In unselected patients, extended adjuvant tamoxifen is not associated with a significant reduction in recurrence, or a reduction in all-cause death. Patients with lymph node positive breast cancer may derive some benefit. Reduction in the risk of recurrence appears to occur only after completion of extended adjuvant therapy.

Figure 1. Flow diagram of literature search.

*Includes one commentary providing updated efficacy (but no toxicity) results of one of the included randomized trial.

Figure 2. Forest plots of odds ratios for breast cancer recurrence for patients treated with extended adjuvant tamoxifen (>5 years) versus adjuvant tamoxifen (5 years) based on primary analysis of individual trials.

Odds ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval. The diamonds represent the estimated pooled effect (labeled total).

Figure 3. Forest plots of odds ratios for breast cancer recurrence between years 5–9 and in years 10 and beyond for patients treated with extended adjuvant tamoxifen (>5 years) versus adjuvant tamoxifen (5 years) based on primary analysis of individual trials.

Odds ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval. The diamonds represent the estimated pooled effect based for each cohort individually (labeled subtotal) and for all cohorts together (labeled total).

Figure 4. Forest plots of odds ratios for breast cancer recurrence in node negative and in node positive patients with extended adjuvant tamoxifen (>5 years) versus adjuvant tamoxifen (5 years) based on primary analysis of individual trials.

Odds ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval. The diamonds represent the estimated pooled effect based for each cohort individually (labeled subtotal) and for all cohorts together (labeled total).

Figure 5. Forest plots of odds ratios for (A) all-cause death and (B) death without recurrence for patients treated with extended adjuvant tamoxifen (>5 years) versus adjuvant tamoxifen (5 years) based on primary analysis of individual trials.

Odds ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval. The diamonds represent the estimated pooled effect based for each cohort individually (labeled subtotal) and for all cohorts together (labeled total).