Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors
Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression.
Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured.
Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: −0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: −0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover.
Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI.
KeywordsAromatase inhibitors Arthralgia Patient outcome assessment Crossover Quality of life
This study was supported in part by U01-GM61373 and 5T32-GM08425 (DAF), M01-RR00042 (UM), M01-RR00750 (IU), and M01-RR00052 (JHU). NJS was supported (in part) by Cancer Center Biostatistics Training Grant 5T32-CA083654 (to J. Taylor). NLH was a Damon Runyon-Lilly Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (Grant number CI-53-10) and by an American Cancer Society Research Scholar Grant. Additional support was provided by Fashion Footwear Association of New York/QVC Presents Shoes on Sale (DFH). In addition, the ELPh trial was supported by grants from Pfizer, Inc. and Novartis Pharma AG, who provided study medication.
Abbvie, Merck, Pfizer, MedImmune, Celgene, Puma Biotechnology, and Novartis (VS); Pfizer and Novartis (AMS); AstraZeneca, Janssen Research and Development, Puma Biotechnology, Pfizer, Eli Lilly Company (DFH); WellPoint and Genentech (CFS).
Compliance with ethical standards
Conflict of interest
Employment or Leadership Position: None, Consultant or Advisory Role: Walgreens and Pfizer (CFS); Pfizer (DFH), Stock Ownership: Immunomedics (CFS) Oncoimmune and InBiomotion (DFH), Honoraria: Pfizer (AMS); Lilly (DFH), All other authors had no conflicts of interest to disclose.
- 3.Burstein HJ, Lacchetti C, Anderson H et al (2016) Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol 34:1689–1701. doi: 10.1200/JCO.2015.65.9573 CrossRefPubMedGoogle Scholar
- 7.Yardley D, Green NB, Papish S, et al (2009) Rheumatologic Evaluation of Adjuvant Letrozole in Post-Menopausal Breast Cancer Patients Discontinuing Anastrozole Due to Grade 2-3 Arthralgia—Myalgia. In: San Antonio Breast Cancer Symp. p Cancer Res 2009;69(24 Suppl):Abstract nr 805Google Scholar
- 8.Renshaw L, McHugh R, Williams L (2007) Comparison of joint problems reported by patients in a randomized adjuvant trial of anastrozole and letrozole. In: Breast Can Res Treat. p 106(Suppl 1):S108–S109. Abstract 2072Google Scholar
- 16.Carpenter JS, Andrykowski MA, Wilson J, et al Psychometrics for two short forms of the center for epidemiologic studies-depression scale. Issues Ment Health Nurs 19:481–94Google Scholar
- 17.Stafford L, Judd F, Gibson P et al (2014) Comparison of the hospital anxiety and depression scale and the center for epidemiological studies depression scale for detecting depression in women with breast or gynecologic cancer. Gen Hosp Psychiatry 36:74–80. doi: 10.1016/j.genhosppsych.2013.08.010 CrossRefPubMedGoogle Scholar
- 19.Farrar JT, Pritchett YL, Robinson M et al (2010) The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: analyses of data from clinical trials of duloxetine in pain disorders. J Pain 11:109–118. doi: 10.1016/j.jpain.2009.06.007 CrossRefPubMedGoogle Scholar
- 23.Briot K, Tubiana-Hulin M, Bastit L et al (2010) Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: the ATOLL (articular tolerance of letrozole) study. Breast Cancer Res Treat 120:127–134. doi: 10.1007/s10549-009-0692-7 CrossRefPubMedGoogle Scholar