Cancer-related fatigue is one of the most common and persistent consequences of breast cancer treatment. A major 2026 study published in JAMA Network Open provides an important new perspective: long-term fatigue after breast cancer chemotherapy may be driven less by measurable cardiovascular dysfunction than by the interconnected effects of depression, psychological stress, and physical function.
For Exercise Oncology programs, this finding reinforces an increasingly important principle: exercise should be delivered as part of comprehensive survivorship care rather than simply as a fitness intervention.
Fatigue Can Persist Years After Treatment
The investigators studied 381 women including 236 with stage I to III breast cancer and 145 women without cancer. The study followed them for 24 months. Women with breast cancer received chemotherapy, aromatase inhibitor therapy, or both. Fatigue was measured using the validated Functional Assessment of Chronic Illness Therapy–Fatigue scale.
The results demonstrate how significant the problem can be. Among women receiving potentially cardiotoxic chemotherapy, 18.2% had clinically relevant fatigue two years after treatment, while 34.6% experienced a clinically significant increase in fatigue compared with their pretreatment level.
Importantly, fatigue was already present in some patients before treatment. Worse pretreatment fatigue predicted worse fatigue two years later, suggesting that fatigue assessment should begin at diagnosis, not months or years into survivorship.
The Heart Was Not the Primary Explanation
Because some breast cancer treatments can affect cardiovascular function, the investigators examined whether changes in cardiac function explained persistent fatigue.
Surprisingly, they did not.
Changes in left ventricular ejection fraction, cardiac strain, hematocrit, and 6-minute walk distance were not independently associated with the level of fatigue at 24 months. Instead, depressive symptoms and perceived stress emerged as the major factors associated with long-term fatigue.
The authors concluded that depressive symptoms were the principal mediator of long-term fatigue, with perceived stress making a smaller but significant contribution.
This does not mean fatigue is “just psychological.” Cancer-related fatigue is complex and multidimensional. Rather, the study demonstrates that clinicians should not assume persistent fatigue necessarily reflects cardiac dysfunction or simply the lingering physical effects of chemotherapy.
Where Exercise Oncology Becomes Especially Important
One finding is particularly relevant to CancerFitness.org.
Although changes in 6-minute walk distance did not explain the overall 24-month fatigue level, every 10-meter improvement in walking distance between months 3 and 24 was associated with a greater reduction in fatigue over time. Improvements in depressive symptoms were also associated with less worsening of fatigue.
That combination of physical function, fatigue, mood, and stress is precisely where well-designed Exercise Oncology programs can play an important role.
The authors specifically note that physical activity and psychosocial interventions have been associated with improvements in depressive symptoms and perceived stress and support screening breast cancer survivors for both depression and stress.
The study itself was observational, however, and did not test an exercise intervention. We therefore should not interpret it as proof that exercise would eliminate the long-term fatigue observed in these women. Instead, it helps identify potentially modifiable factors that an integrated survivorship program should address.
What This Means for Organizing Exercise Oncology Programs
This publication has important implications for how Exercise Oncology services should be structured.
Exercise programs should not wait until treatment has ended or until severe deconditioning develops. Baseline assessment should begin near diagnosis, including fatigue, functional capacity, physical activity, and appropriate psychosocial screening.
Programs should then reassess patients during treatment and throughout survivorship. The study’s measurements at pretreatment, three months, and 24 months demonstrate why longitudinal follow-up matters: fatigue can change substantially over time, and early fatigue predicts later problems.
Most importantly, Exercise Oncology should not operate in isolation. A mature program should create referral pathways connecting exercise professionals with oncology, rehabilitation, cardio-oncology, behavioral health, nutrition, and other supportive-care services. When persistent fatigue is accompanied by depression or substantial psychological stress, simply increasing an exercise prescription may not be enough.
The goal should be integrated symptom management combined with progressive restoration of physical capacity.
From “Exercise More” to Comprehensive Exercise Oncology
The central message of this study extends beyond breast cancer fatigue.
Two years after beginning treatment, 34% of women receiving adjuvant or neoadjuvant chemotherapy experienced a clinically significant increase in fatigue, and that fatigue was partially mediated by depressive symptoms and stress rather than changes in cardiovascular function.
For CancerFitness.org, this reinforces an essential distinction between simply recommending physical activity and establishing a true Exercise Oncology program.
Exercise Oncology should be assessed, individualized, progressive, longitudinal, and integrated into multidisciplinary cancer care. Its purpose is not merely to improve fitness. It is to help patients preserve and recover physical function while addressing the interconnected challenges that influence quality of life throughout treatment and survivorship.
Call to Action
Cancer-related fatigue should not be accepted as an unavoidable price of surviving cancer.
Cancer centers and oncology practices should incorporate systematic fatigue and functional assessment into care beginning at diagnosis and establish referral pathways to appropriately supervised Exercise Oncology and psychosocial services.
For patients and survivors: ask your oncology team about exercise before, during, and after treatment—not only after fatigue and physical decline have become established.
At CancerFitness.org, our goal is to help move Exercise Oncology from recommendation to implementation—making individualized exercise assessment, prescription, monitoring, and supportive care part of comprehensive cancer treatment and survivorship.
Reference: Long-Term Fatigue After Treatment for Breast Cancer. Nancy E. Avis, PhD; Nathaniel S. O’Connell, PhD; Shannon L. Mihalko, PhD; Jennifer H. Jordan, PhD; et al. JAMA Network Open. 2026;9(8):e2629862. doi:10.1001/jamanetworkopen.2026.29862.
