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Original Investigation
June 17, 2021

Association of Modifiable Risk Factors With Early Discontinuation of Adjuvant Endocrine Therapy: A Post Hoc Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Biostatistics Center, Dana Farber Cancer Institute, Boston, Massachusetts
  • 3Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
  • 4Department of Radiology, University of Michigan Comprehensive Cancer Center, Ann Arbor
  • 5Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia
  • 6Center for Statistical Sciences, Brown University, Providence, Rhode Island
  • 7Canadian Cancer Trials Group, McMaster University, Hamilton, Ontario, Canada
  • 8Department of Medicine, Stanford Cancer Center Palo Alto, Stanford, California
  • 9Department of Social Sciences and Health Policy, Wake Forest University Health Sciences, Winston Salem, North Carolina
JAMA Oncol. Published online June 17, 2021. doi:10.1001/jamaoncol.2021.1693
Key Points

Question  What risk factors are associated with early discontinuation of endocrine therapies among women with breast cancer in the Trial Assigning Individualized Options for Treatment?

Findings  In this post hoc analysis of a randomized clinical trial, including 954 women with breast cancer, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies.

Meaning  Patient-reported outcomes can identify patients at increased risk for early discontinuation of endocrine therapies and select intervention targets.

Abstract

Importance  Early discontinuation of adjuvant endocrine therapy (ET) is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the recommended full 5 years of ET treatment.

Objective  To identify the association between early discontinuation of ET in the Trial Assigning Individualized Options for Treatment (TAILORx) and modifiable risk factors, polypharmacy, and types of additional medications such as antidepressants and opioids.

Design, Setting, and Participants  This post hoc analysis includes a subgroup of 954 patients with breast cancer in TAILORx, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer and started ET within a year of study entry. Analyses were conducted in the intent-to-treat population. Statistical analysis took place from January 15, 2020, to April 6, 2021.

Main Outcomes and Measures  Participants completed measures on cancer-related health-related quality of life including physical well-being and social well-being prior to initiating ET. Early discontinuation of ET was defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence. Kaplan-Meier estimates were used to calculate discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET with patient-level factors.

Results  A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. In a joint model, receipt of chemoendocrine therapy (vs receipt of ET only; hazard ratio [HR], 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005), worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002), and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were individually and significantly associated with a higher probability of early discontinuation of ET. Only antidepressant use at study baseline was associated with early discontinuation (HR, 1.87; 95% CI, 1.23-2.84; P = .003).

Conclusions and Relevance  In this post hoc analysis of a randomized clinical trial, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies. These results support systematic screening for patient-reported outcomes and depressive symptoms to identify women at risk for discontinuation of ET.

Trial Registration  ClinicalTrials.gov Identifier: NCT00310180

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    1 Comment for this article
    EXPAND ALL
    Endocrine therapy should be adjusted in evaluation of risk factors for early discontinuation
    Shen Tian | Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University
    Endocrine therapy should be adjusted in evaluation of risk factors for early discontinuation

    Shen Tian1*, Juan Wu1*, Ling-quan Kong1#
    * These authors have contributed equally to this work.

    Author Affiliations:
    1Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
    #Corresponding author:
    Dr. Ling-quan Kong, Department of Endocrine and Breast Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. E-mail: huihuikp@163.com Tel:+8613101380893;

    Yanez B, Gray RJ et al. reported in the post hoc analysis of TAILORx study that age older than 40 years were
    associated with a lower probability of early discontinuation of endocrine therapy (ET), and poor social well-being, poor physical well-being and comorbid depression, were significant risk factors for early discontinuation of ET.1 However there might be some limitations in the conclusion.
    According to the NCCN guidelines, premenopausal breast cancer patients with the diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative are recommended treatment of tamoxifen, ovarian suppression/ablation with tamoxifen or aromatase inhibitors (AIs), or tamoxifen followed by AIs. While postmenopausal breast cancer patients with same molecular subtype are recommended treatment of AIs or tamoxifen.2 Actually the prevalence of side effects of tamoxifen and AIs, such as vulvo-vaginal symptoms and musculoskeletal symptoms, are different3, which leads to different levels of poor physical well-being and depression. Furthermore, patients younger than 40 years, especially treated with ovarian suppression/ ablation, even suffer more severe estrogen deprivation than those only with tamoxifen and postmenopausal patients. Hence, the physical well-being or comorbid depression level attributable to ET may be varied with different ET options among patients younger than 40 years and postmenopausal patients, leading to different adherence rates.4 Therefore, in order to explore the risk factors of discontinuation of ET, the treatment protocols of ET should also be adjusted.
    CONFLICT OF INTEREST: None Reported
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