Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer

Abstract

Purpose: Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer.

Patients and methods: A discovery set (one trial, n = 824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non-small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set.

Results: Discovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points).

Conclusion: Intense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non-small-cell lung cancer.

Fig 1.

Histopathologic examples of lymphocytic infiltration. (A) Nonintense lymphocytic infiltration in an adenocarcinoma. (B) Nonintense lymphocytic infiltration in a squamous cell carcinoma. (C) Intense lymphocytic infiltration in an adenocarcinoma. (D) Intense lymphocytic infiltration in a squamous cell carcinoma.

Fig 2.

Survival curves for tumor lymphocytic infiltration (TLI; intense and nonintense) for overall survival (OS; A and B) and disease-free survival (DFS; C and D) in the discovery (A and C) and validation (B and D) sets. The P value of the log-rank test and the unadjusted hazard ratios (HRs) and 95% CIs are reported.

Fig A1.

Flowchart. Patients with missing slides correspond to patients whose blocks were not sent for histologic review. Patients with missing TLI correspond to patients with blocks of insufficient performance for quantitative histologic review and evaluation. ANITA, Adjuvant Navelbine International Trialist Association; CALGB, Cancer and Leukemia Group B; IALT, International Adjuvant Lung Cancer Trial; LACE-Bio, Lung Adjuvant Cisplatin Evaluation-Biomarker; SCLC, small-cell lung cancer; TLI, tumor lymphocytic infiltration.

Fig A2.

Survival curves for tumor lymphocytic infiltration (TLI; intense and nonintense) for specific disease-free survival (SDFS) on discovery (A) and validation (B) sets. The P value of the log-rank test and the unadjusted hazard ratios (HRs) and 95% CIs are reported.

Fig A3.

Survival curves for tumor lymphocytic infiltration (TLI; intense and nonintense) for overall survival (OS; A and B), disease-free survival (DFS; C and D,) and specific disease-free survival (SDFS; E and F) on the combined set (discovery + validation) by treatment arm. The P value of the log-rank test and the unadjusted hazard ratios (HRs) and 95% CIs are reported. CT, chemotherapy.