Long-Term Fatigue After Treatment for Breast Cancer
Nancy E. AvisNathaniel S. O’ConnellShannon L. MihalkoJennifer H. JordanAmy C. LaddGlenn J. LesserKristine C. OlsonKathryn E. WeaverEmily V. DresslerPamela J. GrizzardBeverly LevineTonya MooreBonnie KyMary Helen HackneyPeter BrubakerKerryn W. RedingAlexander R. LucasMoriah P. BellissimoF. Gerard MoellerDalane W. KitzmanCraig A. HamiltonHeidi D. KlepinJoseph YeboahWilliam NtimVlad G. ZahaRalph D’AgostinoW. Gregory Hundley
Key result
Breast cancer therapy linked to fatigue in ~34% of patients, driven by depressive symptoms over LVEF.
- Estimate -0.77
- 95% CI -0.83 to -0.71
- P<.001
- n=381
Figures
Why the study?
Patients with breast cancer may experience long-term fatigue after treatment that reduces quality of life, but the associated cardiac, psychological, and treatment factors are not fully identified.
Does breast cancer treatment with chemotherapy or aromatase inhibitors increase long-term fatigue in patients with stage I to III breast cancer compared to noncancer comparators, and is this mediated by changes in left ventricular function?
Key Points
- To determine cardiac, psychological, and cancer treatment factors associated with fatigue before and 24 months after treatment for breast cancer.
- Conducted across multiple community hospital-based cancer centers among 381 participants, including 236 with stage I to III breast cancer and 145 noncancer comparators (mean age, 54 years; NCT02791581).
- Evaluated participants receiving potentially cardiotoxic chemotherapy or aromatase inhibitors alongside controls over 24 months of follow-up.
- Assessed fatigue using the Functional Assessment of Chronic Illness Therapy Fatigue scale alongside measures of left ventricular ejection fraction, circumferential strain, 6-minute walk distance, depressive symptoms, and perceived stress.
- At 2 years, 33 patients (18.2%) receiving chemotherapy experienced clinically relevant fatigue and 62 (34.6%) experienced a significant increase in fatigue from baseline (both χ2 test P < .001 vs aromatase inhibitors and controls).
- Only depressive symptoms (estimate, −0.77; 95% CI, −0.83 to −0.71; P < .001) and perceived stress (−0.32; 95% CI, −0.41 to −0.24; P < .001) mediated 24-month posttreatment fatigue.
- Baseline-adjusted changes in left ventricular ejection fraction, left ventricular strain, hematocrit, and 6-minute walk distance were not associated with 24-month posttreatment fatigue.
Study Design
Type
Cohort (n=381)
Multicenter
Yes
Structured PICO
Does breast cancer treatment with chemotherapy or aromatase inhibitors increase long-term fatigue in patients with stage I to III breast cancer compared to noncancer comparators, and is this mediated by changes in left ventricular function?
P
Population
381 women, including 236 with stage I to III breast cancer receiving chemotherapy or aromatase inhibitors and 145 noncancer comparators, were followed for 24 months to assess factors mediating long-term fatigue.
E
Exposure
Breast cancer treatment including potentially cardiotoxic chemotherapy (inclusive of doxorubicin or without doxorubicin) or aromatase inhibitors (anastrozole, letrozole, or exemestane) only.
C
Comparator
Noncancer comparators (convenience sample of female family and friends without a history of cancer, breast surgery, or chemotherapy).
O
Outcome
Fatigue assessed by the Functional Assessment of Chronic Illness Therapy Fatigue scale at 24 months post-treatment.patient reported
Main Result
Effect estimate: Estimate -0.77 (95% CI -0.83 to -0.71)
p-value: p=<.001
Long-term fatigue following breast cancer treatment is primarily mediated by depressive symptoms and perceived stress, rather than chemotherapy-induced changes in left ventricular function.
Limitations
- Conducted during the COVID-19 pandemic, leading to some missed or delayed scheduled visits.
- 61 of 381 participants dropped out before the 24-month follow-up.
- The study cohort consisted mostly of White participants.
- Observational cohort design means mediation estimates are interpretable as causal only under assumptions of no unmeasured confounding and correct temporal ordering.
- The noncancer comparator group was a convenience sample and does not represent a random sample.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“As a cardiologist, my instinct is always to look first at the heart. What this study tells us is that, in this case, the answer could lie elsewhere.”
“Chemotherapy wreaks havoc on the heart, but that didn't explain why women become more fatigued during and after treatment. This is fatigue two years after treatment began. It is persistent, and it has a big impact on quality of life, function and well-being. Treating the whole person is really important and could lead to improvements in fatigue down the road.”
“This research is important because it highlights the role of factors other than cardiovascular function in contributing to fatigue in breast cancer patients receiving chemotherapy and suggests avenues for reducing fatigue.”
Implication
Fatigue 2 years after breast cancer therapy may reflect psychological factors; leaves open whether interventions targeting depression or stress improve outcomes.
Abstract
Importance Patients with breast cancer (BC) may have long-term fatigue after treatment, which is associated with reduced quality of life. Objective To identify cardiac, psychological, and cancer treatment factors associated with fatigue before and 24 months after BC treatment. Design, Setting, and Participants This cohort study was conducted across multiple community hospital-based cancer centers among participants with stage I to III BC receiving potentially cardiotoxic chemotherapy or aromatase inhibitors and noncancer comparators. Participants were enrolled from May 2017 to July 2021 and followed up for 24 months. Data were analyzed between July 2023 and July 2026. Exposures Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy Fatigue scale. Main Outcomes and Measures It was hypothesized that chemotherapy-associated changes in left ventricular function were associated with and mediated 2-year post-BC treatment fatigue. Outcome measures included fatigue, sociodemographic variables, hematocrit, left ventricular ejection fraction and circumferential strain, cardiovascular comorbidities, 6-minute walk distance, perceived stress, and depressive symptoms. Results From a total of 381 patients, patients with BC (236) and noncancer comparators (145) had a mean (SD) age of 54 (12) years. Two years after BC treatment, 33 (18.2%) receiving potentially cardiotoxic chemotherapy experienced clinically relevant fatigue (χ 2 test P < .001 relative to aromatase inhibitors or controls), and 62 (34.6%) experienced a significant increase in fatigue relative to their precancer treatment fatigue level (χ 2 test P < .001, relative to aromatase inhibitors and controls). Independent of pretreatment and posttreatment left ventricular ejection fraction, diabetes status, hypertension, tobacco use, age, body mass index, hematocrit, receipt of potentially cardioprotective medications, and chemotherapy regimens, only depressive symptoms (estimate, −0.77; 95% CI, −0.83 to −0.71; P < .001) and perceived stress (−0.32; 95% CI, −0.41 to −0.24; P < .001) were associated with and mediated 24-month post-BC treatment fatigue measures. Baseline adjusted changes in 6-minute walk distance, left ventricular ejection fraction, and left ventricular strain were not associated with 24-month post-BC treatment fatigue levels. Conclusions and Relevance In this cohort study of patients with BC, clinically relevant fatigue increased in 34% of patients 2 years after initiating cancer treatment mediated partly by depressive symptoms and perceived stress regardless of cardiovascular risk factors, age, or change in left ventricular ejection fraction and/or strain. Trial Registration ClinicalTrials.gov Identifier: NCT02791581
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Cite This Study
Avis et al. (2026) conducted a cohort in Breast Cancer (n=381). Breast cancer treatment (chemotherapy or aromatase inhibitors) vs. Noncancer comparators was evaluated on Association of depressive symptoms with 24-month post-treatment fatigue (Estimate -0.77, 95% CI -0.83 to -0.71, p=<.001). Clinically relevant fatigue increased in 34% of patients 2 years after initiating breast cancer treatment, mediated partly by depressive symptoms and perceived stress rather than changes in left ventricular function.