A new multicenter study shows women who receive treatment for breast cancer can face long-term, intractable fatigue years after improvement or resolution of chemotherapy-related cardiac dysfunction or anemia.

Depression, and to a lesser extent, stress, emerged as independent factors linked to fatigue and mediating it at 2 years post-treatment.

By the end of the study, a third of women with breast cancer were “much more fatigued relative to where they were before cancer treatment,” senior study author W. Gregory Hundley, MD, told Medscape Medical News.

When someone is stressed or depressed, the ability of the prefrontal cortex to regulate the amygdala weakens, and the amygdala becomes more active or reactive than usual. An overactive amygdala can put the sympathetic nervous system into a “fight-or-flight” mode. In this mode, the body ends up in a heightened state of alertness, which over time can cause exhaustion. In addition, when the sympathetic nervous system stays switched on for too long, the body’s stress hormone system releases hormones such as cortisol. This in turn puts a body in a constant, low-grade stress response, and that persistent biological stress is thought to contribute to chronic fatigue in breast cancer survivors.

“[These changes] promote systemic sterile inflammation and heighten fatigue. Secondly, depression and stress diminish sleep and sleep quality, both of which also promote fatigue,” explained Hundley, who is a cardiologist, professor of internal medicine, and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

The new research was published online on August 18, 2026, in JAMA Network Open.

Study Methodology and Findings

Hundley and colleagues followed 236 women with stage I-III breast cancer before the individuals had received treatment and serially assessed them for at least 2 years. Of these women, 117 received chemotherapy including doxorubicin, 84 received chemotherapy without doxorubicin, and 35 received aromatase inhibitors without chemotherapy. The authors compared these women’s outcomes with those of another 145 women without cancer.

The researchers had initially hypothesized that left ventricular dysfunction or presence of anemia would explain the long-term fatigue following chemotherapy or aromatase inhibitors. However, neither factor was relevant.

Although investigators focused on 24-month outcomes, this longitudinal study included other assessment timepoints. Compared to the before cancer treatment, for example, there was “a lot more depression at 3 months,” Hundley said.

Anemia and decreased heart function are common at 3 months into treatment, but some of that is not necessarily related to what goes on 2 years later, he said.

At this timepoint, 18% of women receiving chemotherapy experienced clinically relevant fatigue (P < .001 relative to those receiving aromatase inhibitors or control individuals). In addition, almost 35% of the women on the same treatment experienced a significant increase in fatigue compared with before treatment (P < .001 relative to those receiving aromatase inhibitors or control individuals). Only depressive symptoms (P < .001) and perceived stress (P < .001) were associated with and mediated 24-month post-breast cancer treatment fatigue.

The researchers controlled for diabetes, hypertension, tobacco use, age, BMI, hematocrit, receipt of potentially cardioprotective medications, and chemotherapy regimens. They also performed a mediation analysis that revealed depression was driving 25% and stress another 5% of the fatigue.

Unique Study Features

Most previous studies of breast cancer and fatigue were done at academic medical centers, Hundley said. In contrast, the current research was performed in community-based healthcare systems, where 70%-80% of women receive their treatment for breast cancer.

The researchers noted that although the research included mostly White participants (75.9%), the percentage of Black women (17.3%) exceeded the proportion in many other studies.

Clinical Guidance

Once physiologic causes such as anemia and heart dysfunction are ruled out, the next step is not to discount the fatigue, Hundley said. Also, oncologists can inform women at the time of diagnosis that about 1 in 4 survivors could experience intractable fatigue 2 years after treatment.

The next steps for clinicians seeing breast cancer survivors with long-term fatigue are to screen these patients for depression and stress and come up with plans to treat those conditions when present, experts told Medscape Medical News.

The connection between depression and long-term fatigue seen in this study “highlights the importance of screening for posttreatment depression, normalizing it in conversation, and offering comprehensive resources to prevent and treat depression in cancer survivors,” said Jane Lowe Meisel, MD, medical oncologist at Winship Cancer Institute of Emory University in Atlanta and an American Society of Clinical Oncology expert in breast cancer.

How Does the Current Study Add to the Literature?

While another research team postulated that somatic symptoms such as fatigue can be misattributed to depression in people with cancer at 1 year, the current work found depression is an independent risk factor for fatigue at 2 years.

Other studies in the literature support a link between chemotherapy and fatigue primarily during and shortly after cancer treatment, whereas there is less consensus regarding a long-term, persistent effect. For example, in a 2021 imaging study, researchers found fatigue increased over time in a group that received chemotherapy vs in a group that did not. In addition, significantly higher fatigue in the chemotherapy group at 6 months post-treatment aligned with changes in brain network connectivity, suggesting a biological and not a psychological etiology.

The new study showed that “long-term fatigue in breast cancer survivors is primarily driven by worsening depression and perceived stress rather than cancer-related changes in cardiac function,” Meisel said.

Relatedly, other research including long-term survivors of breast cancer found that psychological factors were associated with mental and general fatigue. One of these was a 2022 study that assessed fatigue at 5-16 years after breast, prostate, or colorectal cancer. It showed that having ever been diagnosed with depression, and having depressive symptoms and fear of progression were associated with all symptoms of fatigue and with sleep problems, with the highest odds noted for affective, physical, and total fatigue.

Asked if oncologists should prepare women at the time of diagnosis for the possibility of long-term fatigue, Hundley said, “Yes, and there’s a little bit more to the story. More research is going to show [the importance of] that.”

Hundley reported receiving grants from the National Institutes of Health, the National Cancer Institute Community Oncology Research Program, and the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network during the conduct of the study. Meisel is an advisor to AstraZeneca, Eli Lilly and Company, GSK plc, Novartis, Pfizer, Sanofi Genzyme, and Seagen and a consultant for Olema and Sermonix and received research grant support from AstraZeneca, Olema, Pfizer, and Sermonix.