The prognostic impact of tumor mutations and tumor-infiltrating lymphocytes in patients with localized pMMR colorectal cancer – A systematic review and meta-analysis

Background
Tumor mutations and the composition of the tumor microenvironment have prognostic and therapeutic significance in colorectal cancer (CRC). However, immunotherapy remains a challenge for patients with proficient mismatch repair (pMMR) CRC. In this paper, the association between tumor-infiltrating lymphocytes (TILs) and tumor mutations on survival outcomes in patients with localized pMMR CRC was examined.
Methods
A systematic review of the literature and a meta-analysis were conducted in accordance with the PRISMA guidelines. The literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The outcomes of interest were overall survival, disease-free survival, and cancer-specific survival. The risk of bias was assessed through the Newcastle-Ottawa Scale and the quality of the cumulative evidence was evaluated through the modified GRADE approach.
Findings
In total, 8498 articles were screened for eligibility and 44 articles were included in the meta-analysis with 33,704 patients in total. Patients with high infiltration of any TILs showed significantly improved overall survival (HR = 0.57, 95 % CI: 0.49–0.67, I2: 0 %), especially for the subgroup of CD3 + (HR = 0.52, 95 % CI: 0.38–0.71, I2: 0 %) and CD8 + (HR = 0.60, 95 % CI: 0.37–0.99, I2: 10 %) TILs. Patients with BRAF mutation (HR = 2.68, 95 % CI: 1.47–4.89, I2: 83 %) and KRAS mutation (HR = 1.25, 95 % CI: 1.18–1.33, I2: 0 %) showed decreased overall survival.
Interpretation
High infiltration of TILs, especially CD3 + and CD8 + , was associated with significantly improved survival, while BRAF and KRAS mutations were correlated with worse survival outcomes for patients with non-metastatic pMMR CRC.