Endocrine Therapy Adverse Events Predict Survival

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J. Clin. Oncol. 2013 Apr 22;[EPub Ahead of Print], DB Fontein, C Seynaeve, P Hadji, et al

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In an analysis of more than 9000 postmenopausal patients with hormone-sensitive early breast cancer treated with endocrine therapy, certain specific adverse events were associated with superior survival outcomes. The findings suggest that these AEs might be useful in predicting treatment response.

SUMMARY

PracticeUpdate Editorial Team

Adjuvant endocrine therapy improves outcomes in women with hormone-sensitive breast cancer, but agents that lower estrogen levels or block estrogen receptors (ERs) carry inconvenient side effects that may affect treatment compliance. Previous studies have linked the presence of some of these adverse effects with better outcomes.

Fontein et al investigated the relationship between three specific adverse events (AEs) of endocrine therapy—vasomotor symptoms (VMS), musculoskeletal and joint symptoms (MSAE), and vulvovaginal symptoms (VVS)—and treatment efficacy. They analyzed data from postmenopausal women with hormone receptor–positive early breast cancer who received endocrine therapy in the phase III Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.

In the TEAM study, 9766 patients were randomized to receive either the aromatase inhibitor exemestane for 5 years or the selective ER modulator tamoxifen for 2.5 to 3 years followed by exemestane to complete the 5-year regimen. The current analysis included 9325 patients after excluding patients who never started treatment or had an unknown start date, discontinued their allocated therapy within the first year, or had an event within the first year. Median follow-up was 5.13 years.

Within the first year of endocrine therapy, 32.2% of patients reported VMS, 28.3% had MSAE, and 12.3% had VVS. Multivariate analyses were adjusted for age at diagnosis, country, histologic grade, tumor size, nodal stage, most extensive surgery, radiotherapy, and chemotherapy.

In both univariate and multivariate analyses, patients who reported VMS or MSAE had a better disease-free survival (DFS) than patients who did not have these symptoms (multivariate hazard ratio [HR] for VMS, 0.731; for MSAE, 0.826). For those who reported VVS, DFS was significantly better after univariate analysis and borderline significant after multivariate analyses (HR, 0.769).

Patients who reported VMS or VVS had better OS than those who did not report these symptoms in both univariate and multivariate analyses (multivariate HR for VMS, 0.583; for VVS, 0.570). Improved OS for reporting of MSAE was borderline significant after multivariate analysis (HR, 0.811).

There were fewer instances of distant metastases (DM) among the patients with VMS and MSAE, compared with those without these symptoms (multivariate HR for VMS, 0.813; for MSAE, 0.749). The association of VVS with fewer cases of DM was significant after univariate but not multivariate analyses (HR, 0.687).

An important aspect of the current study was the inclusion of time on treatment. Early treatment discontinuation did not affect the risk of DM for VMS, MSAE, and VVS. For patients reporting VMS and MSAE, early discontinuation of treatment did not affect the improved DFS and OS seen in these patients. This was also true for patients reporting VVS for DFS but not OS. Thus, patients reporting specific AEs who did not complete the full 5 years of therapy still had better outcomes than patients with longer treatment duration who did not experience these symptoms.

Finally, outcomes for DFS, OS, and DM improved as the total number of specific AEs reported increased. In this analysis, as in the primary TEAM efficacy analysis, outcomes did not differ between the two treatment arms.

In conclusion, in a heterogeneous population of patients who received at least 1 year of adjuvant endocrine therapy, those who reported one or more specific AEs during the first year of treatment had better DFS and OS and fewer instances of DM than patients who did not report these symptoms. Of the three specific AEs analyzed, the strongest beneficial effect occurred with reports of VMS.

The authors speculated that the association between specific AEs of endocrine therapy and outcomes seen in their study has potential as a predictor and biomarker of treatment efficacy.

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