ABSTRACT
Introduction: Expression of programmed death-ligand 1 (PD-L1) is the only routinely used tissue biomarker for predicting response to programmed cell death protein 1/PD-L1 inhibitors. It is to date unclear whether PD-L1 expression is preserved in brain metastases (BMs). Methods: In this single-center, retrospective study, we evaluated PD-L1 expression using the SP263 assay in consecutively resected BMs of lung carcinomas and paired primary tumors, diagnosed from 2000 to 2015, with correlation to clinicopathological and molecular tumor and patient characteristics. Results: PD-L1 tumor proportional score (TPS) could be evaluated on whole tissue slides in 191 BMs and 84 paired primary lung carcinomas. PD-L1 TPS was less than 1% in 113 of 191 (59.2%), 1% to 49% in 34 of 191 (17.8%), and greater than or equal to 50% in 44 of 191 (23.0%) BMs. TPS was concordant between BMs and paired primary lung carcinomas in most cases, with discordance regarding the clinically relevant cutoffs at 1% and 50% in 18 of 84 patients (21.4%). Four of 18 discordant cases had no shared mutations between the primary lung carcinoma and BM. Intratumoral heterogeneity, as assessed using tissue microarray cores, was only significant at the primary site (p Wilcoxon signed rank = 0.002) with higher PD-L1 TPS at the infiltration front (mean = 40.4%, interquartile range: 0%-90%). Neither TPS greater than or equal to 1% nor TPS greater than or equal to 50% nor discordance between the primary lung carcinoma and BMs had prognostic significance regarding overall survival or BM-specific overall survival. Conclusions: PD-L1 expression was mostly concordant between primary lung carcinoma and its BM and between resections of BM and stereotactic biopsies, mirrored by tissue microarray cores. Differences in PD-L1 TPS existed primarily in cases with TPS greater than 10%, for which also human assessment tends to be most error prone.
ABSTRACT
BACKGROUND: Brain metastases present a significant complication in lung cancer with an unmet therapeutic need. METHODS: In this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3. RESULTS: Among 444 consecutive brain metastases, 210 (49%) originated from lung cancer. Analysis was successful in 111 samples, including 54 pairs of brain metastasis and primary tumour. Most driver alterations were preserved in brain metastases. Private alterations exclusive to primary tumours, brain metastases or both sites (intersecting cases) were present in 22%, 26% and 26% of cases, respectively. Seven percent had no shared mutations. KRAS mutations were more frequent in primary tumours metastasised to the brain (32/55, 58%) compared to TCGA (33%, p < 0.005) and own data from routine diagnostics, independent from clinical or pathological characteristics. Fourteen cases showed alterations in the EGFR signalling pathway including additional KRAS alterations that were private to brain metastases. KRAS G12C was detected most frequently (26% of patients) and KRAS G12C and G13C variants were significantly enriched in brain metastases. Synchronous and metachronous cases had a similar mutation profile. CONCLUSIONS: Our results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.
