Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial

Abstract

Background: On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important.

Patients and methods: Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy.

Results: Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk.

Conclusion: A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.

Figures

Figure 1.

Patients from the BIG 1-98 trial included and excluded in this study according to treatment group and availability of tumor material. Tam, tamoxifen; Let, letrozole; ER, estrogen receptor.

Figure 2.

Kaplan–Meier estimates of DFS according to treatment group and (A, B) ER status, (C, D) PgR status, (E, F) Ki-67 LI status, and (G, H) HER2 status. DFS, disease-free survival; ER, estrogen receptor; PgR, progesterone receptor; LI, labeling index.

Figure 3.

STEPP analysis of 5-year DFS according to level of centrally assessed (A) ER expression (%), (B) PgR expression (%), (C) Ki-67 LI (%), and (D) HER2 status. Rug plots along the x-axis display the distribution of individual values. STEPP, subpopulation treatment effect patternplot; DFS, disease-free survival; ER, estrogen receptor; PgR, progesterone receptor; LI, labeling index.

Figure 4.

STEPP analysis of 5-year DFS according to level of composite measure of prognostic risk (A) among all patients and (B) according to treatment assignment. Rug plots along the x-axis display the distribution of individual values. STEPP, subpopulation treatment effect pattern plot; DFS, disease-free survival.