Topography-dependent Prognostic Value of CDK5 in Cetuximab-Treated, RAS/BRAF-wild-type Metastatic Colorectal Cancer: A Retrospective Tissue-Microarray Analysis

Introduction The prognostic value of cyclin-dependent kinase 5 (CDK5) was investigated in a cohort of patients with cetuximab-treated, chemotherapy-refractory, dual wild-type Rat Sarcoma and v-raf murine sarcoma viral oncogene homolog B1 (RAS/BRAF) metastatic colorectal adenocarcinoma. Methods Immunohistochemistry (IHC) was used to retrospectively analyze the expression of CDK5 in metastatic colorectal adenocarcinoma tissue samples of 129 patients. All statistical computations were performed in R 4.0.5. Dichotomous clinicopathological variables were then cross-tabulated across CDK5 strata and compared with Pearson’s χ 2 test. Cumulative survival probabilities were estimated via the Kaplan–Meier estimator and contrasted with the log-rank test. Independent prognostic determinants were ascertained through Cox proportional-hazards. Results 79 men and 50 women were enrolled in this study, with a median age 62.8 years. Among 129 specimens subjected to CDK5 IHC, 111 tumor cores yielded unequivocally evaluable results. 69 lesions were allocated to the low-to-intermediate expression tier (scores 0–2+), whereas 42 exhibited marked overexpression (score 3+). Elevated CDK5 immunoreactivity was shown to predict inferior progression-free survival (PFS) (7.0 versus 9.0 months; P =0.049) and a shortened cancer-specific survival (CSS) (27.8 vs 38.5 months; P =0.048). In addition, low-to-intermediate CDK5 expression remained independently associated with PFS (HR 0.544; 95 % CI 0.369–0.801; P =0.002) and CSS (HR 0.502; 95% CI: 0.329–0.766; P =0.001). CDK5 overexpression conferred a statistically significant detriment to PFS among patients harboring only extra-hepatic metastases ( P =0.012), while within the hepatic-metastatic subset, no survival discrepancy was discernible between the high and low-to-intermediate expression cohorts ( P =0.800). Conclusions Independent multivariable modelling identified elevated CDK5 as a robust predictor of both curtailed PFS and CSS. Intriguingly, this prognostic power appears to be contingent upon the site of disease: once the cancer metastasizes to the liver, the predictive signal of elevated CDK5 is abruptly extinguished.