Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer

Abstract

Background: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone.

Methods: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women.

Results: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with letrozole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (hazard ratio for letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected on the basis of previous reports of letrozole and tamoxifen therapy.

Conclusions: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with letrozole and tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.)

Figure 1. Design of the Trial

The numbers shown are for the intention-to-treat population, which excludes 18 enrolled women who did not receive a study treatment and who withdrew consent for use of their data (47 other women who refused study treatment did not withdraw consent for the use of their data and are included). The sequential-therapy analyses include 6182 women randomly assigned to one of four treatment groups (four-group randomization option only). The updated monotherapy analyses include 4922 women randomly assigned to letrozole monotherapy or tamoxifen monotherapy as part of either the two-group or the four-group randomization option.

Figure 2. Results of Cox Proportional-Hazards Analyses of Disease-free Survival, Overall Survival, and Time to Distant Recurrence, with Tamoxifen Followed by Letrozole as Compared with Letrozole Monotherapy and with Letrozole Followed by Tamoxifen as Compared with Letrozole Monotherapy

The events related to the end points are as follows: for disease-free survival, recurrence of the disease at a local, regional, or distant site; a new invasive cancer in the contralateral breast; any second (nonbreast) cancer; or death without a previous cancer event; for overall survival, death; and for time to distant recurrence, recurrence of cancer at a distant site. The models were stratified according to chemotstherapy use. The size of the boxes is inversely proportional to the standard error of the hazard ratio. As specified in the protocol, 99% confidence intervals are shown to account for multiple comparisons. Estimates of the percentage of patients without an event at 5 years are Kaplan–Meier estimates. Results of tests for interactions between treatment and nodal status were not significant. Nx denotes 0 positive axillary lymph nodes with 1 to 7 nodes examined.

Figure 3. Cumulative Incidence of the Recurrence of Breast Cancer

Results are shown for letrozole monotherapy as compared with tamoxifen followed by letrozole (Panels A and C) and for letrozole monotherapy as compared with letrozole followed by tamoxifen (Panels B and D). Both overall results (Panels A and B) and results according to nodal status (Panels C and D) are shown. The results are from a competing-risk analysis in which second, nonbreast cancers and deaths without a previous cancer event were considered as competing risks. The numbers of women with a first recurrence of breast cancer were as follows for the group assigned to letrozole monotherapy, the group assigned to tamoxifen followed by letrozole, and the group as signed to letrozole followed by tamoxifen, respectively: local recurrence, 12, 14, and 17 women; cancer in the contralateral breast, 18, 19, and 16; regional recurrence, 7, 3, and 6; distant recurrence, 112, 130, and 105; and recurrence at an unknown site, 0, 3, and 0. Second, nonbreast cancers (64, 65, and 59 in the three groups, respectively) and deaths without a previous cancer event (35, 25, and 33, respectively) were also recorded as first primary-end-point events.

Figure 4. Results of Cox Proportional-Hazards Analyses of Disease-free Survival, Overall Survival, and Time to Distant Recurrence, with Letrozole Monotherapy as Compared with Tamoxifen Monotherapy among Women Assigned to the Single-Agent Treatment Groups

Results are shown for the total cohort and according to nodal status. Results of the intention-to-treat and censored analyses are presented. The events related to the end points are as follows: for disease-free survival, recurrence of the disease at a local, regional, or distant site; a new invasive cancer in the contralateral breast; any second (nonbreast) cancer; or death without a previous cancer event; for overall survival, death; and for time to distant recurrence, recurrence of cancer at a distant site. The models were stratified according to study cohort (two-group or four-group randomization option) and chemotherapy use. The size of the boxes is inversely proportional to the standard error of the hazard ratio. Estimates of the percentage of patients without an event at 5 years are Kaplan–Meier estimates. The results of tests for interactions between treatment and nodal status were not significant. The intention-to-treat analysis included all women and all follow-up time and events according to treatment assignment. The exploratory censored analysis was identical except that it excluded (i.e., censored) events and follow-up beyond the time of selective crossover among women randomly assigned to tamoxifen. Both analyses were subject to potential biases that may have influenced the estimated magnitude of the benefit with letrozole as compared with tamoxifen.