Breast Cancer Research and Treatment

, Volume 164, Issue 2, pp 411–419

Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors

  • Kunal C. Kadakia
  • Kelley M. Kidwell
  • Nicholas J. Seewald
  • Claire F. Snyder
  • Anna Maria Storniolo
  • Julie L. Otte
  • David A. Flockhart
  • Daniel F. Hayes
  • Vered Stearns
  • N. Lynn Henry
Clinical trial

DOI: 10.1007/s10549-017-4260-2

Cite this article as:
Kadakia, K.C., Kidwell, K.M., Seewald, N.J. et al. Breast Cancer Res Treat (2017) 164: 411. doi:10.1007/s10549-017-4260-2



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.


Aromatase inhibitors Arthralgia Patient outcome assessment Crossover Quality of life 

Supplementary material

10549_2017_4260_MOESM1_ESM.docx (73 kb)
Supplementary material 1 (DOCX 73 kb) Online Supplement 1—Diagram of the primary patient reported outcome analysis. PRO patient reported outcomes, AI aromatase inhibitor; Δ change

Funding information

Funder NameGrant NumberFunding Note
American Cancer Society
  • Research Scholar Grant
National Institutes of Health
  • U01-GM61373, 5T32-GM08425, M01-RR00042, M01-RR00750, M01-RR00052
  • 5T32-CA083654
  • 5T32-GM08425
Damon Runyon Cancer Research Foundation
  • CI-53-10
Fashion Footwear Association of New York/QVC Presents Shoes on Sale
      Novartis Pharma

        Copyright information

        © Springer Science+Business Media New York 2017

        Authors and Affiliations

        • Kunal C. Kadakia
          • 1
        • Kelley M. Kidwell
          • 2
        • Nicholas J. Seewald
          • 3
        • Claire F. Snyder
          • 4
        • Anna Maria Storniolo
          • 5
        • Julie L. Otte
          • 6
        • David A. Flockhart
          • 7
        • Daniel F. Hayes
          • 8
        • Vered Stearns
          • 9
        • N. Lynn Henry
          • 10
        1. 1.University of Michigan Comprehensive Cancer CenterAnn ArborUSA
        2. 2.Department of BiostatisticsUniversity of Michigan School of Public HealthAnn ArborUSA
        3. 3.Department of BiostatisticsUniversity of MichiganAnn ArborUSA
        4. 4.Division of General Internal MedicineJohns Hopkins School of MedicineBaltimoreUSA
        5. 5.Melvin and Bren Simon Cancer CenterIndiana University School of MedicineIndianapolisUSA
        6. 6.School of NursingIndiana UniversityIndianapolisUSA
        7. 7.Division of Clinical Pharmacology, Department of MedicineIndiana University School of MedicineIndianapolisUSA
        8. 8.Breast Oncology ProgramUniversity of Michigan Comprehensive Cancer CenterAnn ArborUSA
        9. 9.Breast Cancer Program, Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimoreUSA
        10. 10.Division of OncologyHuntsman Cancer Institute, University of UtahSalt Lake CityUSA

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