Analysis Shows No Link Between Aromatase Inhibitor–Related Musculoskeletal/Vasomotor Symptoms and Relapse-Free Survival

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Vered Stearns, MD

Aromatase Inhibitors, Symptoms, and Survival

Our study, examining two [aromatase inhibitors], failed to show an association between new or worsening symptoms and outcome.

—Vered Stearns, MD, and colleagues

Retrospective analyses of the ATAC, TEAM, and BIG 1-98 adjuvant endocrine therapy trials in breast cancer have suggested that treatment-emergent endocrine symptoms may be associated with superior survival outcomes. In a study reported in the Journal of Clinical Oncology, Vered Stearns, MD, Professor of Oncology and Co-Director of the Breast Cancer Program at Johns Hopkins Medicine, Baltimore, and colleagues found no association of new or worsening vasomotor or musculoskeletal symptoms with relapse-free survival in patients receiving adjuvant aromatase inhibitor therapy with anastrozole or exemestane in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.27 trial.1

Study Details

In the MA.27 trial, 7,576 postmenopausal women with breast cancer were randomly assigned to 5 years of anastrozole or exemestane. There was no difference in efficacy or treatment adherence between treatment groups. Patient-reported symptoms were collected using Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month visits.

Landmark analyses excluding patients who had already experienced recurrence were used to assess the effects of new or worsening symptoms on subsequent relapse-free survival by evaluating the effect of having vs not having such symptoms at 3, 6, or 12 months after randomization. The effects of symptoms at 3 months were assessed using unplanned clinic visits due to severe toxicity within the first 3 months.

Frequency of Symptoms

A total of 7,344 patients were alive without relapse at 3 months; 96% were evaluable at both 6 and 12 months, and 34% of patients had vasomotor or joint symptoms at baseline in the evaluable populations at all three time points. Patients were categorized into three groups: those without either baseline vasomotor or grade 3 or 4 musculoskeletal symptoms at baseline (n = 5,645), those without any vasomotor or musculoskeletal symptoms at baseline (n = 4,877), and all patients.

The frequency of onset or worsening of symptoms was 19.2%, 25.4%, and 26.4% at 6 months and 38.0%, 52.9%, and 52.9% at 12 months in the three groups. The frequency of early severe toxicity clinical visits at 3 months was 3.9%, 5.2%, and 5.5% in the three groups.

There were numerous differences in baseline characteristics between patients with or without baseline symptoms who did or did not develop new or worsening symptoms at 3, 6, or 12 months; most notable was an effect of age, with development or worsening of symptoms being significantly more common in women aged ≤ 55 years. There were no significant differences between the anastrozole and exemestane treatment groups in time to discontinuation of therapy among patients with or without new or worsening vasomotor or musculoskeletal symptoms by 12 months.

No Effect on Relapse-Free Survival

New or worsening vasomotor or joint symptoms did not significantly affect relapse-free survival on univariate analysis at any time point for any of the three groups. Among patients without baseline vasomotor or grade 3 or 4 musculoskeletal symptoms, the relapse-free survival hazard ratios for those developing vasomotor symptoms or grade 3 or 4 musculoskeletal symptoms vs those not developing such symptoms were 0.62 (95% confidence interval [CI] = 0.33–1.18, P = .15) at 3 months, 0.80 (95% CI = 0.59–1.07, P = .13) at 6 months, and 0.81 (95% CI = 0.63–1.03, P = .09) at 12 months.

Among all patients, irrespective of baseline symptoms, the relapse-free survival hazard ratios for those developing new or worsened symptoms vs those not developing new or worsened symptoms were 0.88 (95% CI = 0.55–1.35, P = .5595) at 3 months, 0.84 (95% CI = 0.67–1.05, P = .1307) at 6 months, and 0.93 (95% CI = 0.76–1.14, P = .4803) at 12 months. In multivariate models including treatment and significant patient baseline characteristics and stratified by use of celecoxib, aspirin, and trastuzumab (Herceptin) and by lymph node status and prior chemotherapy, neither treatment nor new or worsening symptoms (P > .10) had a significant effect on relapse-free survival irrespective of the presence or absence of baseline symptoms.

The investigators noted that the high event-free survival rates (91% with exemestane and 91.2% with anastrozole at 4 years) in the MA.27 trial may have made it more difficult to demonstrate differences in relapse-free survival in landmark analyses in which events are excluded.

The investigators concluded:

[T]he majority of studies of patients who received tamoxifen or [aromatase inhibitor] reported a relationship between emergence of vasomotor and musculoskeletal symptoms and survival outcomes. Our study, examining two [aromatase inhibitors], failed to show an association between new or worsening symptoms and outcome. Predictive factors are required to determine treatment efficacy and treatment-emergent symptoms. Future prospective analyses of symptoms in [aromatase inhibitor] trials should ensure that symptoms are collected in a similar way to both the positive and negative trials to resolve the issue. Until then, treatment-emergent symptoms should be managed as effectively as possible to support treatment continuation, and it is premature to counsel patients on whether to continue or change their adjuvant [aromatase inhibitor] therapy based on ­symptoms.” ■

Disclosure: The study was supported by the Canadian Cancer Society Research Institute, U.S. National Cancer Institute, International Breast Cancer Study Group, Pfizer, Susan G. Komen for the Cure, and Avon Foundation New York. For full disclosures of the study authors, visit


1. Stearns V, Chapman JA, Ma CX, et al: Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol 33:265-271, 2015.

N. Lynn Henry, MD, PhD, of the University of Michigan Medical School, Ann Arbor, offers her perspective on the MA.27 trial discussed above.

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