Inflammatory Cytokines and Comorbidity Development in Breast Cancer Survivors Versus Noncancer Controls: Evidence for Accelerated Aging?

Abstract

Purpose The sequelae of cancer treatment may increase systemic inflammation and create a phenotype at increased risk of functional decline and comorbidities, leading to premature mortality. Little is known about how this trajectory compares with natural aging among peers of the same age without cancer. This longitudinal study investigated proinflammatory cytokines and comorbidity development over time among breast cancer survivors and a noncancer control group. Methods Women (N = 315; 209 with breast cancer and 106 in the control group) were recruited at the time of their work-up for breast cancer; they completed the baseline questionnaire, interview, and blood draw (lipopolysaccharide-stimulated production of interleukin [IL] -6, tumor necrosis factor-α, and IL-1β). Measures were repeated 6 and 18 months after primary cancer treatment (cancer survivors) or within a comparable time frame (control group). Results There were no baseline differences in comorbidities or cytokines between survivors and the control group. Over time, breast cancer survivors had significantly higher tumor necrosis factor-α and IL-6 compared with the control group. Survivors treated with surgery, radiation, and chemotherapy accumulated a significantly greater burden of comorbid conditions and suffered greater pain associated with inflammation over time after cancer treatment than did the control group. Conclusion Survivors who had multimodal treatment had higher cytokines and comorbidities, suggestive of accelerated aging. Comorbidities were related to inflammation in this sample, which could increase the likelihood of premature mortality. Given that many comorbidities take years to develop, future research with extended follow-up beyond 18 months is necessary to examine the evidence of accelerated aging in cancer survivors and to determine the responsible mechanisms.

Fig 1.

CONSORT diagram of participant recruitment.

Fig 2.

Charlson comorbidity score and SF-36 pain score over time in cancer survivors versus control group. (A) Charlson comorbidity score over time. (B) SF-36 pain score over time. Note that higher scores indicate less pain. (C) Charlson comorbidity score over time by cancer treatment type. (D) SF-36 pain score over time by cancer treatment type. chemo, chemotherapy; SF-36, Rand 36-item Short Form Survey.

Fig 3.

Lipopolysaccharide-stimulated cytokines over time in cancer survivors versus control group. (A) Lipopolysaccharide-stimulated TNF-α over time. (B) Lipopolysaccharide-stimulated IL-6 over time. (C) Lipopolysaccharide-stimulated IL-1β over time. (D) Overall inflammation over time as measured by the cytokine z score. IL, interleukin; TNF, tumor necrosis factor.