Possible Bioenergetic Biomarker for Chronic Cancer-Related Fatigue

Abstract

Background: Cancer-related fatigue (CRF) is a highly prevalent, debilitating, and persistent symptom experienced by patients receiving cancer treatments. Up to 71% of men with prostate cancer receiving radiation therapy experience acute and persistent CRF. There is neither an effective therapy nor a diagnostic biomarker for CRF. This pilot study aimed to discover potential biomarkers associated with chronic CRF in men with prostate cancer receiving radiation therapy.

Methods: We used a longitudinal repeated-measures research design. Twenty men with prostate cancer undergoing radiation therapy completed all study visits. CRF was evaluated by a well-established and validated questionnaire, the Patient-Reported Outcomes Measurement Information System for Fatigue (PROMIS-F) Short Form. In addition, peripheral blood mononuclear cells were harvested to quantify ribonucleic acid (RNA) gene expression of mitochondria-related genes. Data were collected before, during, on completion, and 24 months postradiation therapy and analyzed using paired t-tests and repeated-measures analysis of variance.

Results: The mean of the PROMIS-F T score was significantly increased over time in patients with prostate cancer, remaining elevated at 24 months postradiation therapy compared to baseline. A significant downregulated BC1 ubiquinol-cytochrome c reductase synthesis-like (BCS1L) was observed over time during radiation therapy and at 24 months postradiation therapy. An increased PROMIS-F score was trended with downregulated BCS1L in patients 24 months after completing radiation therapy.

Discussion: This is the first evidence to describe altered messenger RNA for BCS1L in chronic CRF using the PROMIS-F measure with men receiving radiation therapy for prostate cancer.

Conclusion: Our results suggest that peripheral blood mononuclear cell messenger RNA for BCS1L is a potential biomarker and therapeutic target for radiation therapy-induced chronic CRF in this clinical population.

Figure 1.. Changes in fatigue score over time in patients with prostate cancer undergoing radiation therapy (N=20)

The Patient-Reported Outcomes Measurement Information System measured fatigue for Fatigue (PROMIS-F) Short Form. X-axis indicates time points: Day 0 = prior to RT; Day 21 = Day 21 of RT, midpoint; Day 42 = completion of RT, 24 months = 24 months post-RT. Y-axis represents PROMIS-F T-score. Fatigue score has significantly increased at Day 42 of RT since baseline (Day 0), remaining significantly elevated 24 months post-RT in patients with RT (p < .01).

Figure 2.. Changes in messenger RNA expression levels of BCS1L over time in patients with prostate cancer undergoing radiation therapy (N=20)

BCS1L= BC1 (ubiquinol-cytochrome c reductase) synthesis-like. Left chart: Y-axis represents expression values assayed by monitoring in real-time polymerase chain reaction calculated as delta cycle threshold (Ct) value/number. The BCS1L Ct value was significantly increased at Day 21 and Day 42, remaining elevated 24 months post-RT, indicating a downregulated BCS1L over time in patients with RT compared to Day 0 (p = .02). Right chart: Y-axis represents expression values assayed by monitoring in real-time polymerase chain reaction calculated as fold change. The BCS1L fold change was significantly decreased over time (Day 21 and Day 42) and remained downregulated at 24 months post-RT (p = .03).

Figure 3.. Correlation between PROMIS-F score and BCS1L delta cycle value in patients with prostate cancer 24 months post-radiation therapy (N=20)

X-axis represents the delta cycle threshold (Ct) value/number for BCS1L (BC1 ubiquinol-cytochrome c reductase synthesis-like). Y-axis represents PROMIS-F T score. The increased fatigue score was trended with increased Ct value of BCS1L, downregulation of BCS1L in patients with prostate cancer at 24 months post-RT (r = 0.32, p = .09). T4 = 24 months post-RT.