Exponential Slope from Absolute Lymphocyte Counts during Radio-Chemotherapy Can Predict an Aggressive Course of Cervical Cancer

SIMPLE SUMMARY: Lymphopenia associated with clinical outcomes has three potential implications for cancer progression, treatment effects, and constitutional immune capacity. Neutrophil-to-lymphocyte ratio (NLR) and lymphopenia before and after treatment are biomarkers of immune suppression due to cancer progression and treatment effects. A decrease and an increase in the exponential slope (α) estimated from total absolute lymphocyte counts during concurrent radio–chemotherapy for cervical cancer are associated with aggressive and non-aggressive disease courses and are completely independent of stage and NLR. The association between survival and α-related mRNAs from plasma exosomes may imply an insufficient restoration of unstimulated lymphocytes in the context of immune response. The proposed α may be a practical and simple biomarker of constitutional immune capacity. ABSTRACT: This study aimed to investigate whether the exponential slope α from absolute lymphocyte counts during concurrent radio–chemotherapy (CRT) is associated with aggressive and non-aggressive courses of cervical cancer. We analyzed 362 patients with stage IB–IVB cervical cancer treated with CRT in two groups: 323 patients without mRNA data (cohort 1) and 39 with mRNA data (cohort 2) from plasma exosomes. We calculated the α of each patient; 69 patients who died of cancer in cohort 1 were divided into 44 who died within 30 months (aggressive group), and 25 who died after more than 30 months (non-aggressive group). The median follow-up periods of cohorts 1 and 2 were 63 and 28 months, respectively. The log2 fold change (log2FC) between read counts of mRNAs before treatment and after the second week of CRT was calculated. Multivariate analyses from cohort 1 showed that neutrophil-to-lymphocyte ratio (NLR) ≥ 2.43 and α < 0.08 were statistically significant predictors of disease-specific survival (DSS) in the aggressive group (DSS-A), whereas α ≥ 0.08 was the only significant predictor of DSS in the non-aggressive group (DSS-NA). The 2.5-year DSS-A and 8-year DSS-NA rates of patients with α ≥ 0.08 and α < 0.08 were 86.7% and 73%, and 78.5% and 94.8% in the high-NLR group, respectively. In cohort 2, patients with both NLR < 2.7 and α ≥ 0.07 had a higher 2.5-year DSS rate than did those with either NLR ≥ 2.72 or α < 0.07. E2F8 and STX6 significantly correlated with ɑ and survival. The 2.5-year DSS rates in patients with E2F8 + STX6 (log2FC) < 0.2429 and ≥0.2429 were 100% and 77.2%, respectively. The exponential slope α can potentially distinguish between aggressive and non-aggressive courses in cervical cancer patients.