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Depression is a common acute and potentially long-term, debilitating behavioral toxicity of breast cancer and its treatment, occurring in up to 30% of women with breast cancer. Depression also has been associated with increased breast cancer mortality,[7, 8] and clinical trials of interventions that reduce depressive symptoms have reported increased survival in women with metastatic disease.[7, 9] Many factors may contribute to depression, including age at diagnosis, tumor stage, surgery, and chemotherapy.[1, 3, 5, 6] However, data are limited on depression in patients with breast cancer who are receiving radiation.
Recent data indicate that radiation provides a significant survival advantage for patients after breast-conserving surgery. However, predictors of depression during and after radiation remain largely unexplored, as studies are limited by small patient numbers, cross-sectional designs, and retrospective, secondary analyses.[2, 4, 6, 11] Furthermore, among the few longitudinal studies of depression during radiation, patients have been treated in a highly varied manner (lumpectomy vs mastectomy, with or without chemotherapy, and various radiation doses), and within this literature, there are several inconsistencies regarding symptom trajectory and severity as well as clinical and psychosocial predictors of depression. Clinical factors associated with increased depression during radiation include advanced cancer stage, mastectomy, prior chemotherapy, higher radiation duration/dose, younger age, and increased body mass index (BMI).[2, 12] However, data also suggest that depression is related to baseline psychosocial characteristics, including education level, relationship status, and anxiety and distress.[13, 14] Collectively, these reports suggest the need for prospective, longitudinal studies of patients uniformly treated with standardized surgery and radiation controlling for relevant clinical and psychosocial characteristics to clarify primary risk factors for depression, especially depression that persists after treatment.
One proposed mechanism linking depression to cancer treatments, including radiation, is inflammation. Increased inflammatory markers are identified in patients with depression, and the administration of inflammatory cytokines leads to depressive symptoms. Recent data also suggest that blockade of inflammatory cytokines reduces depressive symptoms, and specifically fatigue, in cancer patients.
Although radiation is known to cause tissue injury and induce a subsequent inflammatory response, only one study has evaluated the relationship between depression and inflammation in women undergoing breast radiation. In that study, soluble interleukin-6 receptor (sIL-6R) levels were significantly elevated in patients with high versus low depression. Many more studies have examined inflammatory mediators of fatigue, which is included in the diagnostic criteria for depression.[3, 11, 15, 17] Nevertheless, results from these studies have been inconsistent, possibly due to varying strategies for measuring cytokines and a lack of longitudinal data.[11, 18, 19] Fatigue during radiation has been associated with increased levels of IL-6, IL-1 receptor antagonist (IL-1ra), and C-reactive protein (CRP).[17, 18] However, other investigators have not reported this relationship after controlling for factors, including BMI.[3, 6, 19]
Although the data suggest a potential relationship among depression, inflammation, and radiation, the inflammatory signaling pathways have not been explored. One candidate pathway involves nuclear factor kappa B (NF-κB). NF-κB is a lynchpin signaling molecule in the inflammatory cascade and is implicated in cancer development and treatment resistance.[20, 21] Fatigued breast cancer survivors have increased activation of NF-κB–regulated genes. Because radiation increases NF-κB pathway activity in breast cancer cells, NF-κB activation may extend beyond the breast to peripheral tissues as a general response to tissue injury, and ultimately, may contribute to behavioral morbidities, including depression. Of note, chemotherapy has been associated with NF-κB activation both in breast cancer tissue and in peripheral blood.[16, 23]
To further explore clinical and inflammatory factors associated with depression in women receiving radiation, we conducted a longitudinal study before, during, and after a standardized course of radiation. The primary objective was to determine which factors were predictive of persistent depressive symptoms after radiation. In addition, we examined the relationship between the clinical factors predictive of depression and inflammation including circulating inflammatory biomarkers and inflammatory gene transcripts. Special emphasis was placed on the potential role of NF-κB and its downstream mediators, tumor necrosis factor (TNF), IL-1, and IL-6.
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Prior chemotherapy was associated with significantly higher depression scores before, during, and after breast cancer radiation independent of chemotherapy type or whether it was received as neoadjuvant or adjuvant treatment, underscoring a persisting effect of chemotherapy up to several months after the last cycle of treatment. Only the women who received chemotherapy had increased expression of NF-κB–regulated gene transcripts and increased plasma levels of the downstream inflammatory mediators IL-6 and sTNFR2. In addition, baseline NF-κB DNA binding independently predicted depression after radiation when the analysis was controlled for multiple clinical factors, including BMI, initial cancer stage, age, endocrine therapy, and antidepressant use. Thus, chemotherapy-induced inflammation may be an important mechanism by which patients with breast cancer develop depression, and those who previously received chemotherapy may be the most at risk for both increased inflammation and depression during and after radiation.
Significant increases in the expression of NF-κB–regulated gene transcripts were observed in the women who received chemotherapy, and NF-κB DNA binding was associated with depressive symptoms in the chemotherapy group but not in the no chemotherapy group throughout the study. Chemotherapy may activate NF-κB through the destruction of rapidly proliferating malignant and nonmalignant cells, leading to an inflammatory response. Moreover, chemotherapy can directly activate NF-κB signaling pathways in multiple cell types. Relevant to depression, NF-κB activation induces inflammatory cytokines, which can access the brain in humans and activates a central inflammatory response associated with altered metabolism of serotonin involved in depression. Stress-induced NF-κB activation leads to depressive-like behavior in rodents and inhibits neurogenesis in brain regions involved in depression.[15, 36] Neurogenesis is an important component of antidepressant action and may explain why some patients exhibited significant depressive symptoms after radiation despite antidepressant treatment. In terms of potential mechanisms that may explain the lingering effects of chemotherapy, NF-κB can undergo epigenetic modification leading to persistent activation and may explain the increased NF-κB gene transcripts reported in fatigued versus nonfatigued breast cancer survivors several years after completing treatment.
Previous research has suggested that specific downstream inflammatory mediators of NF-κB are associated with distinct behavioral morbidities of cancer treatment in long-term breast cancer survivors. For example, fatigue, but not depression, has been associated with elevated levels of sTNFR2, and it has been demonstrated that TNF inhibitors reduce fatigue in patients with advanced cancer.[16, 39] Increases in CRP and IL-1ra also have been correlated with fatigue after controlling for sleep and depression, and fatigue has been associated with sIL-6R independent of depression. In the current study, fatigue and depression were correlated significantly with each other at all time points. Baseline NF-κB DNA binding activity and IL-6 were correlated significantly with depression and fatigue after radiation. Nevertheless, consistent with previous studies, sTNFR2 and CRP were correlated with fatigue, but not with depression after radiation, supporting the notion that activation of fundamental inflammatory signaling pathways like NF-κB may be common to symptoms of both depression and fatigue, whereas more nuanced correlations between specific cytokines and specific symptoms may exist, especially after treatment.
Findings from the current study indicate that radiation did not contribute to depressive symptoms at the time points measured and did not appear to exacerbate preexisting depression. Regarding the trajectory of depressive symptoms and inflammation, no significant increases in depression or inflammatory markers were observed during or after radiation. In other studies of patients who did not receive chemotherapy, greater increases in depressive symptoms have been observed, although, compared with our study, there was more variability in radiation dose and areas treated.[3, 17] The results of the current study were unexpected but are important, because previous research has not adequately addressed the effect of multimodality therapy. On the basis of our data, the contribution of chemotherapy to persistent depression after radiation far outweighs any contribution from radiation alone.
Regarding clinical relevance, almost 30% of breast cancer patients who received chemotherapy plus radiation (compared with 5% of patients who received radiation alone) exhibited depressive symptoms (IDSSR scores ≥33), the severity of which would qualify them for a clinical trial of antidepressant medication. Given the impact of depression on quality of life as well as mortality, these results highlight the importance of psychiatric screening of breast cancer patients who have completed radiation and have previously received chemotherapy.
Several limitations and strengths of the study warrant consideration. Regarding limitations, the relatively small number of participants limits generalizability, although 42% of patients were African American, indicating that our findings may be largely independent of race. In addition, because participants were not assessed before chemotherapy, the chemotherapy effect on depression and the trajectory of this symptom during chemotherapy and surgery cannot be determined. It is also possible that the chosen time points missed acute inflammatory or behavioral changes because of radiation treatment. Moreover, factors like advanced cancer stage that contribute to the decision to treat with chemotherapy may be the same factors that are associated with depression, albeit initial cancer stage was not an independent predictor of depressive symptoms and, when it was included in multivariate analyses, did not affect the results. Furthermore, there may be an interaction between chemotherapy and radiation leading to persistent behavioral changes that are not observed in patients who forego radiation. A comprehensive, prospective, longitudinal study tracking patients from diagnosis through treatment with chemotherapy and surgery with or without radiation is needed to fully address this question. Regarding strengths, all patients underwent lumpectomy and received standard radiation treatment. Moreover, use of the IDS-SR, a validated index with established and defined cutoff scores for pathology, allowed us to determine the prevalence of moderate-to-severe cases of depression warranting treatment.
In summary, the activation of inflammatory signaling pathways, including NF-κB, appears to be a potential mechanism by which chemotherapy is linked to depression, thereby identifying a subgroup of patients at high risk for depression and a potential biologic pathway for intervention. Future longitudinal studies assessing breast cancer patients from diagnosis through each component of multimodal treatment are needed to clarify the time sequence linking chemotherapy, inflammation, and the development of depression.