PD‐L1 expression in ROS1‐rearranged non‐small cell lung cancer: A study using simultaneous genotypic screening of EGFR, ALK, and ROS1

Abstract

BackgroundThe aim of the current study was to investigate the prevalence and clinicopathologic characteristics of ROS1‐rearranged non‐small cell lung cancer (NSCLC) in routine genotypic screening in conjunction with the study of PD‐L1 expression, a biomarker for first‐line treatment decisions.MethodsReflex simultaneous genotypic screening for EGFR by peptide nucleic acid clamping, and ALK and ROS1 by fluorescence in situ hybridization (FISH) was performed on consecutive NSCLC cases at the time of initial pathologic diagnosis. We evaluated genetic aberrations, clinicopathologic characteristics, and PD‐L1 tumor proportion score (TPS) using a PD‐L1 22C3 assay kit.ResultsIn 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) ROS1 and 19 (4.7%) ALK rearrangements, as well as 106 (26%) EGFR mutations. These mutations were mutually exclusive and were found in patients with similar clinical features, including younger age, a prevalence in women, adenocarcinoma, and advanced stage. The PD‐L1 assay was performed on 130 consecutive NSCLC samples. High PD‐L1 expression (TPS ≥ 50%) was observed in 29 (22.3%) tumors. PD‐L1 expression (TPS ≥ 1%) was significantly associated with wild type EGFR, while ROS1 rearrangement was associated with high PD‐L1 expression. Of the 14 cases with ROS1 rearrangement, 12 (85.7%) showed PD‐L1 expression and 5 (35.7%) showed high PD‐L1 expression.ConclusionIn the largest consecutive routine Asian NSCLC cohort analyzed to date, we found that high PD‐L1 expression frequently overlapped with ROS1 rearrangement, while it negatively correlated with EGFR mutations.

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer

“…13,14 It has been observed that up-regulated PD-L1 expression in NSCLC is correlated with oncogenic RAS signaling, while the tyrosine kinase ROS1 is involved in RAS signaling. 12,15 Most recently, high-level expression of PD-L1 has been associated with ROS1 rearrangement in NCSLC, 16,17 which is in line with other studies that PD-L1 expression in NSCLC is driven by aberrant activation of oncogenes (such as EGFR and ALK). [18][19][20][21] In this study, we found that PD-L1 expression was upregulated by ROS1 rearrangement through the MEK-ERK pathway signaling in NSCLC with Crizotinib resistance.…”

“…This finding is consistent with a recent report that high PD-L1 expression was significantly associated with ROS1 rearrangement in lung adenocarcinoma cohort. 16 Analyzing downstream signaling of ROS1 in response to Crizotinib (ROS1 inhibitor), we found depletion of PD-L1 expression was associated with the downregulation of MEK- ERK pathway signaling when HCC78 cells were treated with Crizotinib or ROS1 siRNAs. Our finding is in line with previous reported that PD-L1 expression is regulated through PI3K-AKT and RAS signaling in various solid tumors, as well as STAT3 or MEK-ERK pathway in some hematologic neoplasms.…”

“…26 Several oncogenic alterations, such as mutations in MET, KRAS and ALK, have been associated with upregulated expression of PD-L1 in NSCLC. 7,22,27 However, discordant correlation between these common oncogenic alterations and PD-L1 expression was also observed in a subset of NSCLC patients, 5,16 suggesting additional oncogenic alterations is needed to defined subpopulation of patients who might be beneficial from PD-1/PD-L1 inhibitors. Here, we reported that ROS1-fusion protein was correlated with up-regulated PD-L1 expression in primary NSCLC without EGFR and ALK alterations.…”

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

“…2). However, this "intrinsic" mechanism of PD-L1 upregulation is contrasted by several recent clinical studies concluding that PD-L1 is highly expressed in EGFR-wildtype NSCLC [135], and there is a negative correlation [43,[136][137][138][139] or no significant correlation [135] between EGFR mutations and PD-L1 expression. One meta-analysis [139] revealed lower PD-L1 expression rates in EGFR-mutant than in EGFRwildtype tumors (36.7% vs 44.1%, P < 0.05).…”

Lung cancer and molecular testing in small biopsies versus cytology: The Logics of Worlds

“…Patients presenting at advanced stages and with unresectable lung tumors, which represent more than 70% of cases, have particularly benefitted. 2,10,[18][19][20][21][22][23][24][25][26] This can be partially attributed to basing therapeutic decisions on tumor typing, which is increasingly possible with cytology. The technological reach of molecular diagnosis has also allowed increasing prominence for cytopathology.…”