Dynamic monitoring of PD‐L1 and Ki67 in circulating tumor cells of metastatic non‐small cell lung cancer patients treated with pembrolizumab

Abstract

Programmed cell death protein ligand‐1 ( PD‐L1 ) expression in non‐small cell lung cancer (NSCLC) tumors guides treatment selection. PD‐L1 expression in circulating tumor cells (CTCs) may provide further information. We have explored PD‐L1 and marker of proliferation Ki‐67 ( Ki67 ; also known as MKI67 ) in CTCs in longitudinal samples of 47 advanced NSCLC patients receiving pembrolizumab. A triple immunofluorescence, against cytokeratin, PD‐L1, and Ki67, was performed on peripheral blood mononuclear cells, at baseline, post‐first cycle, post‐third, and primary resistance (PMR). Patients displaying PMR (progression at first evaluation) were classified as progressive disease (PD) and those with clinical benefit as disease control (DC). CTCs were categorized as PD‐L1high/low/medium/negative and Ki67 + or Ki67 − . CTC evaluation revealed a significant increase in the PD‐L1low CTC rate at PMR compared to baseline (2.5% at baseline vs. 36.5% at PMR), whereas a reduction in the PD‐L1high CTC rate was observed (31.5% vs. 0%, respectively). Investigation of CTC status between PD and DC patients showed that PD patients more frequently increased total and PD‐L1low CTCs after first cycle compared to DC (83% of PD vs. 37% of DC and 67% of PD vs. 8% of DC, respectively). Progression‐free survival (PFS) was longer in patients with decreased total and PD‐L1low CTCs after first cycle compared to those with increased CTCs (median PFS: not reached vs. 2 months). PD‐L1 + patients presenting a high Ki67 index (% Ki67 + CTCs > 30%) before treatment had a shorter PFS compared to those with a low Ki67 (≤ 30%), and overall survival (OS) was shorter in PD‐L1 + patients harboring Ki67 + CTCs compared to those not presenting (median OS: 11.8 months vs. 33.1 months, respectively). In sequential samples of patients with a durable benefit, a low Ki67 index was observed. Our results suggest that monitoring PD‐L1 and Ki67 expression in CTCs of NSCLC patients treated with pembrolizumab may be predictive for pembrolizumab efficacy.

Circulating Tumour Cells: Detection and Application in Advanced Non-Small Cell Lung Cancer

“…Moreover, patients with a reduction of total and PD-L1-low CTCs after the first cycle of pembrolizumab presented a longer PFS. To the contrary, PD-L1-positive patients with a Ki67 index > 30% on baseline presented shorter PFS and OS compared to those harbouring Ki67 ≤ 30% [116].…”

“…To the contrary, Kulasinghe et al reported no association between PFS and presence of PD-L1-positive CTCs in advanced NSCLC patients [91]. Spiliotaki et al explored PD-L1 and Ki-67 in CTCs of 47 advanced NSCLC patients receiving pembrolizumab [116]. Blood samples were analysed at baseline, post-first cycle, post-third, and primary resistance (PMR).…”

Vanadium Carbide MXenzyme Harnessing Photothermal Effects for Targeted Lung Tumor Suppression and Inflammation Eradication

“…It is mainly located in the cell nucleus and is expressed at high levels during the S phase and M phase. [ 31 ] Ki67 expression is used to evaluate the proliferation activity and division status of tumor cells, which is valuable for assessing tumor malignancy and prognosis. [ 32 ] Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) is used to detect apoptosis in cells; this method involves the detection of repairable structure ends of DNA fragmentation during apoptosis.…”

Combining PD-1 or PD-L1 inhibitors with chemotherapy is a good strategy for the treatment of extensive small cell lung cancer: A retrospective analysis of clinical studies

“…Circulating tumour cells (CTCs) are a “liquid biopsy specimen” that can replace the primary tumour ( 41 ). The expression of PD-L1 in CTCs can be used to evaluate the efficacy of PD-1/PD-L1 mAbs in non-small cell lung cancer patients ( 42 , 43 ). The use of CTCs to evaluate the expression of PD-L1 in SCLC may overcome the heterogeneity of PD-L1 expression.…”