114P - The prognostic role of LAG-3 expression in metastatic colorectal cancer

Background

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that negatively regulates T cell activation and inhibits the immune microenvironment. We explored the prognostic effect of LAG-3-positive tumor-infiltrating lymphocytes (TILs) in metastasis colorectal cancer (mCRC) and its correlation with important genomic alterations of mCRC.

Methods

A total of 139 patients with mCRC were enrolled. Tissues from both the primary tumor and distant metastasis were evaluated for LAG-3 expression by immunohistochemical (IHC) staining. LAG-3 staining of TILs in either the tumor front or tumor center were considered positive. The level of LAG-3 expression was reported as the number of LAG-3-positive immune cells in one high-power field (HPF).

Results

LAG-3 expression was evaluated in 116 primary and 98 metastatic tumor samples. The level of LAG3 expression was higher in the primary tumors compared to the metastatic tumors (median 1.35 vs. 0.55/HPF, p = 0.033). We analyzed the clinicopathologic feature in populations with different levels of LAG3 expression (LAG-3+ TIL >0 vs. =0/HPF; ≥1 vs. <1; ≥3 vs. <3; ≥5 vs. <5; ≥10 vs. <10) in primary and metastatic tumor, respectively. In patients with primary tumors of LAG-3+ TIL >0, there was higher percentage of RAS mutation [54% vs. 20%, p= 0.007]. Patients with primary tumors of LAG-3+ TIL ≥5 more frequently exhibited high tumor mutation burden (TMB ≥10 mutations/mb) tumor than those of LAG-3+ TIL <5 [18% vs. 3%, p= 0.0036]. In subgroups of primary tumors with LAG-3 expression of 3, 5 and 10 or greater, overall survival (OS) were shorter than those with LAG-3 expression less than 3, 5 and 10, respectively [median: LAG-3+ TIL ≥3 vs. <3, 30.1 vs. 45.2 months, Hazard ratio (HR) 1.687, p = 0.035; ≥5 vs. <5, 28.3 vs. 44.6 months, HR 1.791, p = 0.025; ≥10 vs. <10, 28.0 vs. 45.2 months, HR 2.137, p = 0.0073]. This difference was not observed in metastatic tumors. Notably, in metastatic tumors, OS was longer in the LAG-3 >0 than LAG-3=0 group (51.9 vs. 32.5 months, HR 0.513, p = 0.0208).

Conclusions

LAG-3 expression level in primary CRC tumor was associated with negative survival outcome and can serve as a potential prognostic marker. Further studies are needed to explore the optimal cutoff level to identify the candidates that benefit most from LAG-3 blockade.

Clinical trial identification

B-ER-110-172; 23 June 2021.

Editorial acknowledgement

Legal entity responsible for the study

National Cheng Kung University Hospital.

Funding

National Cheng Kung University Hospital.

Disclosure

All authors have declared no conflicts of interest.