Aromatase inhibitors are more effective than tamoxifen in preventing breast-cancer recurrence, but are associated with increased musculoskeletal side-effects, such as carpal tunnel syndrome. Researchers conducted a retrospective analysis of the Intergroup Exemestane Study to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with exemestane or with tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with early invasive breast cancer.

The primary endpoint for of the retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome.

The following findings were reported after a median follow-up of 91 months:

• Carpal tunnel syndrome had been reported for 66 (2.8%) of 2319 patients in the exemestane group vs. 13 (0.6%) of 2338 in the tamoxifen group (odds ratio [OR] 5.23, 99% CI 2.39 to 11.49; p<0.0001).

• More events occurred during treatment in the exemestane group than in the tamoxifen group (66 [2.8%] vs. 7 [0.3%], adjusted OR 9.90, 99% CI 3.52 to 27.82; p<0.0001).

• There was no significant difference between groups in events in the post-treatment period (10 with exemestane [0.4%] vs. 7 with tamoxifen [0.3%]; p=0.46).

• More patients in the exemestane group (1082 of 2319 patients, 46.7%) had musculoskeletal symptoms than in the tamoxifen group (901 of 2338, 38.5%; OR 1.48, 99% CI 1.32 to 1.67, p<0.0001).

• More events occurred during treatment in the exemestane group than in the tamoxifen group (984 [42.4%] vs. 776 [33.2%], adjusted OR 1.59, 99% CI 1.32 to 1.91; p<0.0001), with this difference persisting to some extent in the post-treatment period (449 [19.4%] vs. 390 [16.7%]; p=0.017).

• Of 73 on-treatment cases of carpal tunnel syndrome, 58 (79.5%) completed questionnaires were available: 27 patients (46.6%) had bilateral carpal tunnel syndrome and 31 (53.4%) had unilateral disease; 40 (69.0%) underwent surgical release. The disorder greatly affected daily-life activities in 21 (36.2%) cases.

• Occurrence of musculoskeletal symptoms, including carpal tunnel syndrome, was associated with improved disease-free survival in unadjusted analysis (p=0.023), but not with overall survival (p=0.36). However, after adjustment for possible confounding factors, musculoskeletal symptoms were not associated with disease-free survival (hazard ratio [HR] 0.96, 95% CI 0.82 to 1.14, p=0.67) or overall survival (HR 1.02, 95% CI 0.84 to 1.25, p=0.82).

The researchers conclude that “occurrence of carpal tunnel syndrome is higher in patients with breast cancer given exemestane than in those treated with tamoxifen, and surgical release might be necessary in most cases. Development of musculoskeletal symptoms in the first 6 months of treatment is not an independent biomarker of improved disease outcome. Further investigation is warranted into the relation between treatment-emergent musculoskeletal symptoms and clinical outcome in patients with breast cancer receiving hormonal therapy.”

An accompanying Comment article notes that the link between emergent musculoskeletal symptoms and breast-cancer outcomes has not been consistent, but if clinical research confirms such a link then further pharmacogenomic and pharmacogenetic studies could help to elucidate the mechanisms. The author stresses that “although confirmation of the link between emergent symptoms with aromatase inhibitors and risk of breast-cancer recurrence would help to guide clinical advice, based on current evidence clinicians should not use the onset of musculoskeletal symptoms to infer which patient will, or will not, benefit from adjuvant treatment with aromatase inhibitors.”