High Dual Expression of the Biomarkers CD44v6/α2β1 and CD44v6/PD-L1 Indicate Early Recurrence after Colorectal Hepatic Metastasectomy

SIMPLE SUMMARY: Distant metastasis in colorectal cancer still correlates with poor prognosis, emphasizing the high need for new diagnostic and therapeutic strategies. In the present study, liver and lung metastases revealed profound differences in the expression pattern of metastasis-driving protein biomarkers. This suggests the adaption of the therapy to the biology of the metastatic organ site. High expression of the cell adhesion molecule CD44v6 and high dual expression of CD44v6, combined with the cell adhesion molecules integrin α2β1, as well as the checkpoint inhibitor molecule PD-L1, correlated significantly with early recurrence after hepatectomy, in a substantial number of liver metastatic patients. These findings suggest the need for the implementation of biological risk factors into clinical risk scores, aiming to make the prognosis of the individual patient more precise. Further, dual expression of protein biomarkers that are druggable, such as CD44v6/α2β1 and CD44v6/PD-L1, can identify high-risk patients for targeted therapy that might provide a survival benefit. ABSTRACT: Considering the biology of CRC, distant metastases might support the identification of high-risk patients for early recurrence and targeted therapy. Expression of a panel of druggable, metastasis-related biomarkers was immunohistochemically analyzed in 53 liver (LM) and 15 lung metastases (LuM) and correlated with survival. Differential expression between LM and LuM was observed for the growth factor receptors IGF1R (LuM 92.3% vs. LM 75.8%, p = 0.013), EGFR (LuM 68% vs. LM 41.5%, p = 0.004), the cell adhesion molecules CD44v6 (LuM 55.7% vs. LM 34.9%, p = 0.019) and α2β1 (LuM 88.3% vs. LM 58.5%, p = 0.001) and the check point molecule PD-L1 (LuM 6.1% vs. LM 3.3%, p = 0.005). Contrary, expression of HGFR, Hsp90, Muc1, Her2/neu, ERα and PR was comparable in LuM and LM. In the LM cohort (n = 52), a high CD44v6 expression was identified as an independent factor of poor prognosis (PFS: HR 2.37, 95% CI 1.18–4.78, p = 0.016). High co-expression of CD44v6/α2β1 (HR 4.14, 95% CI 1.65–10.38, p = 0.002) and CD44v6/PD-L1 (HR 2.88, 95% CI 1.21–6.85, p = 0.017) indicated early recurrence after hepatectomy, in a substantial number of patients (CD44v6/α2β1: 11 (21.15%) patients; CD44v6/PD-L1: 12 (23.1%) patients). Dual expression of druggable protein biomarkers may refine prognostic prediction and stratify high-risk patients for new therapeutic concepts, depending on the metastatic location.