Tissue and Circulating Proprotein convertase subtilisin/kexin type 9 (PCSK9) as Promising Prognostic Biomarkers for Curative-Intent Colorectal Liver Metastases Resection: A Retrospective Cohort Study
Description
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of cholesterol metabolism homeostasis, yet its significance in colorectal cancer liver metastasis (CRLM) remains undetermined. Herein, we evaluated tissue and circulating PCSK9 as biomarkers for outcomes following curative-intent CRLM resection. Methods: We retrospectively assessed the data of 148 patients with CRLM who underwent curative-intent liver resection at the Sun Yat-sen University Cancer Center between March 2009 and December 2016. We measured PCSK9 expressions in paraffin-embedded sections of CRLM specimens via immunohistochemistry (IHC) and in plasma via enzyme-linked immunosorbent assay (ELISA). Additionally, we examined their immune profiles and correlated them with PCSK9 expression. Further, a modified version of the established Clinical Risk Score (CRS) that included PCSK9 was developed. Results: PCSK9 immunoreactivity was observed in 68.9% (102/148) of CRLM specimens. Elevated PCSK9 expression (IHC score > 4) predicted worse median OS (Not reached vs. 46.2 months; hazard ratio [HR] 1.79; P = 0.016) and RFS (31.0 months vs. 12.0 months; HR 1.85; P = 0.006) compared to low-expression group. Moreover, patients with plasma PCSK9 concentration above 75.4 ng/ml also had worse OS (47.8 months vs. 141.9 months, P = 0.016) and RFS (17.0 months vs. 47.0 months, P = 0.047). High PCSK9 expression was associated with an increased immune proportion score (IPS) of programmed cell death-ligand 1 (PD-L1) within the metastatic site (P = 0.043). The Lipid Metabolism-based Risk (LMR) score incorporated five independent predictors of poor OS: primary lymph node positivity, number of CRLM > 1, a maximum CRLM diameter > 5 cm, preoperative serum low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio > 2.9, and CRLM PCSK9 IHC score > 4. The LMR score showed a superior discriminatory capacity for OS compared to the CRS score, with a Harrell's C-index of 0.79 versus 0.72 (P = 0.001). Conclusions: The results of our study suggest that both tissue and plasma PCSK9 expressions hold promise as prognostic biomarkers for curative-intent resection of CRLM.