PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability

Abstract

Immunotherapy with checkpoint inhibitors, allowing recovery of effector cells function, has demonstrated to be highly effective in many tumor types and represents a true revolution in oncology. Recently, the anti-PD1 agent pembrolizumab was granted FDA approval for the first line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors show PD-L1 expression in ≥ 50% of neoplastic cells and as a second line treatment for patients with NSCLC expressing PD-L1 in ≥1% of neoplastic cells, evaluated with a validated assay. For the large majority of patients such evaluation is made on small biopsies. However, small tissue samples such as core biopsies might not be representative of tumors and may show divergent results given the possible heterogeneous immunoexpression of the biomarker. We therefore sought to evaluate PD-L1 expression concordance in a cohort of 239 patients using tissue microarrays (TMA) as surrogates of biopsies stained with a validated PD-L1 immunohistochemical assay (SP263) and report the degree of discordance among tissue cores in order to understand how such heterogeneity could affect decisions regarding therapy.We observed a discordance rate of 20% and 7.9% and a Cohen's κ value of 0.53 (moderate) and 0,48 (moderate) for ≥ 1% and ≥ 50% cutoffs, respectively.Our results suggest that caution must be taken when evaluating single biopsies from patients with advanced NSCLC eligible for immunotherapy; moreover, at least 4 biopsies are necessary in order to minimize the risk of tumor misclassification.

Expression of programmed cell death ligand 1 in non–small cell lung cancer: Comparison between cytologic smears, core biopsies, and whole sections using the SP263 assay

“…Indeed, responses have also been observed in patients whose tumors were classified as PD‐L1–negative . This can be due to different reasons: newly discovered biological complexity underpinning the tumor–immunity interplay, PD‐L1 expression heterogeneity, different clones, and inter‐ and intraobserver variability . Notwithstanding these limitations, the determination of PD‐L1 expression in neoplastic cells is a necessary condition for the treatment of NSCLC with pembrolizumab: initially used in a second‐line setting for NSCLC expressing PD‐L1 in at least 1% of the sample, its indication has been subsequently extended to first‐line treatment as a monotherapy in NSCLC expressing PD‐L1 in at least 50% of neoplastic cells …”

“…In clinical practice, the determination of PD‐L1 on histological material is mostly performed on biopsy specimens rather than surgical resections. Given the heterogeneity of PD‐L1 expression within tumors, there is often a lack of concordance between the results obtained from biopsies and those obtained from surgical resection specimens . Therefore, we investigated whether a substantial difference between cytologic smears and core biopsies (as a surrogate of diagnostic biopsies) exists in terms of reliability for PD‐L1 determination, considering whole tumor sections as the reference.…”

MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC

“…In vitro and in vivo studies have confirmed the antitumor efficacy of PD-1 and PD-L1, which have emerged as important targets for immunotherapy. PD-1 is a type 1 transmembrane protein of the Ig superfamily [4, 7, 8], consisting of an extracellular N-terminal IgV-like domain, a transmembrane domain, and a cytoplasmic tail [4]. It engages in inhibitory signal transmission and is expressed on activated immune cell types.…”

“…Recently, programmed death 1/programmed cell death ligand-1 (PD-1/PD-L1) has become a popular target for immunotherapeutic blockade of co-inhibitory immune pathways [7]. PD-L1 is the major ligand of PD-1 and is expressed on a variety of cell types [8]. Importantly, PD-L1 is expressed on many tumors, including breast cancer, gastric cancer, NSCLC, pancreaticcancer, bladder cancer, cervical cancer, renal cell carcinoma,and melanoma.…”

Natural killer cells: From surface receptors to the cure of high‐risk leukemia (Ceppellini Lecture)

“…While the clinical usefulness of PD‐L1 expression as a suitable biomarker for response to treatment is clear, its predictive value is still unsatisfactory. Relevant limitations include intra‐ and inter‐tumor heterogeneity and technical issues related to the use of different mAbs and diagnostic material (cytology, diagnostic biopsies vs surgical specimens) . Thus, research in progress is focused on finding additional checkpoints to be exploited for targeting with therapeutic antibodies used alone or in combination.…”