Original StudyEBUS-TBNA as a Promising Method for the Evaluation of Tumor PD-L1 Expression in Lung Cancer
Introduction
In recent years, progress has been made in the development of molecular targeted drugs in lung cancer.1, 2, 3, 4, 5, 6, 7, 8, 9 Therefore, identification of the tumor molecular characteristics is important for the management of the disease. Because most lung cancers are diagnosed at an advanced stage, we are frequently required to conduct molecular testing using a small amount of tumor tissue. To collect small amounts of tissue, transbronchial biopsy (TBB) has been conventionally performed.10, 11 Recently, endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is emerging as a novel minimally invasive method for collecting greater amounts of tissue than TBB from mediastinal and hilar lymph nodes.12, 13, 14, 15, 16
A growing body of evidence suggests that immune checkpoint inhibitors, such as anti-programmed death-ligand 1 (PD-L1) antibodies, have been effective in several malignancies including lung cancer.17, 18, 19, 20, 21, 22 PD-L1 is an immune modulator that promotes immunosuppression by binding to programmed cell death-1 (PD-1) of T cells. PD-L1 expression on tumor cells has been suggested as a predictive marker of clinical response to anti-PD-L1 antibodies.19, 23, 24 Because PD-L1 expression needs to be evaluated only by immunohistochemistry (IHC), an adequate amount of tumor tissue is a prerequisite for the precise molecular characterization. Molecular characterization using small amounts of biopsy materials has been considered to be difficult owing to the limited number of tumor cells. To evaluate tumor PD-L1 expression by IHC, collecting enough tumor cells has been recommended.19
To the best of our knowledge, the number and morphologic intactness of tumor cells collected by small tissue sampling has never been investigated. As a primary analysis, we examined the number and crush rate of tumor cells in EBUS-TBNA samples and compared them with those of TBB to evaluate the potential usefulness of EBUS-TBNA as a method for the evaluation of PD-L1 expression.
Considering the intratumoral heterogeneity in lung cancer and the practical usefulness of EBUS-TBNA, we need to examine the PD-L1 positivity on tumor cells in EBUS-TBNA samples compared with that in the corresponding primary tumor.17, 18, 25 Although several studies have examined the concordance in PD-L1 positivity between biopsy and surgical samples, their results still remain inconclusive.25 Therefore, as a secondary analysis, we investigated the correlation of PD-L1 positivity between the biopsy samples and the corresponding surgical samples, to confirm the concordance between EBUS-TBNA materials and the primary tumor tissues.
Section snippets
Ascertainment of Cases
Our primary analysis was to evaluate the adequacy of EBUS-TBNA as an evaluation method of PD-L1 expression immunohistochemically, compared with TBB samples. Figure 1 shows the flow chart of case selection for this primary analysis. We performed EBUS-TBNA for 213 cases at The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, between January 1, 2013 and December 31, 2014. EBUS-TBNA was conducted for the purpose of initial diagnosis or screening for hilar and/or
Clinicopathologic Characteristics
As a primary analysis, we assessed the adequacy of 97 EBUS-TBNA samples to evaluate PD-L1 immunohistochemical expression and compared the results with 20 cases with TBB samples. Clinicopathologic characteristics of the 97 EBUS-TBNA cases and the 20 TBB cases are shown in Table 1, indicating that the features of the TBB subset were similar to the whole series.
The clinicopathologic characteristics of samples used for our secondary analyses are shown in Supplemental Table 1 (in the online
Discussion
We conducted this study to examine the feasibility of using EBUS-TBNA samples for the evaluation of tumor PD-L1 expression in lung cancer. We have shown that EBUS-TBNA is a more robust method than TBB in terms of the number and the morphologic intactness of collected tumor cells.
Preliminary trials have demonstrated that PD-L1 expression might be heterogeneous, thus indicating that small biopsies might not be suitable for the assessment of PD-L1 expression. Our study showed that EBUS-TBNA, TBB,
Disclosure
Y. Ishikawa received research grants from Daiichi Sankyo Co, Ltd and is a consultant for Fujirebio Inc. M. Nishio received research grants from Novartis Pharma Co, Ltd, Ono Pharma Co, Ltd, Chugai Pharma Co, Ltd, Pfizer Co, Ltd, Bristol-Myers Squibb Co, Ltd, Eli Lilly Co, Ltd, Taiho Pharma Co, Ltd, Astellas Pharma Co, Ltd, and AstraZeneca Co, Ltd, and is a consultant for Novartis Pharma Co, Ltd, Ono Pharma Co, Ltd, Chugai Pharma Co, Ltd, Eli Lilly Co, Ltd, Taiho Pharma Co, Ltd, Pfizer Co, Ltd,
Acknowledgments
The authors thank Mr Motoyoshi Iwakoshi, Ms Miyuki Kogure, Ms Tomoyo Kakita, Ms Kimie Nomura, and Ms Hiroko Nagano for their technical assistance and Ms Yuki Takano, Ms Chikako Yoshida, and Ms Yuka Toyama for their secretarial expertise. Parts of this study were supported financially by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, including Grant Numbers 16K08679 (KI), 26430149 (HN), 15K08373 (NM), and 15H04714 (YI);
References (42)
- et al.
Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis
Lancet Oncol
(2011) - et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
Lancet Oncol
(2011) - et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Lancet Oncol
(2012) - et al.
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials
Lancet Oncol
(2015) - et al.
Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial
Lancet Oncol
(2016) - et al.
Transbronchial lung biopsy through the fibre optic bronchoscope. Results and complications in 452 examinations
Respir Med
(1994) - et al.
Diagnostic value of transbronchial lung biopsy under fluoroscopic guidance in solitary pulmonary nodule in an endemic area of tuberculosis
Respir Med
(1996) - et al.
Endobronchial ultrasonography for mediastinal and hilar lymph node metastases of lung cancer
Chest
(2002) - et al.
Real-time endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes
Chest
(2004) - et al.
Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis
Eur J Cancer
(2009)
Clinical and pathologic features of lung cancer expressing programmed cell death ligand 1 (PD-L1)
Lung Cancer
Reliability of small biopsy samples compared with resected specimens for the determination of programmed death-ligand 1 expression in non–small-cell lung cancer
Clin Lung Cancer
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration
Chest
Subtyping of non-small cell lung carcinoma: a comparison of small biopsy and cytology specimens
J Thorac Oncol
The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group
Lung Cancer
Adequacy of endobronchial ultrasound transbronchial needle aspiration samples in the subtyping of non-small cell lung cancer
Lung Cancer
The efficacy of EBUS-guided transbronchial needle aspiration for molecular testing in lung adenocarcinoma
Ann Thorac Surg
EGFR mutational genotyping of liquid based cytology samples obtained via fine needle aspiration (FNA) at endobronchial ultrasound of non-small cell lung cancer (NSCLC)
Lung Cancer
Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology
J Thorac Oncol
Patients with advanced non-small cell lung cancer: are research biopsies a barrier to participation in clinical trials?
J Thorac Oncol
Cited by (110)
Efficacy of Robotic Bronchoscopy for Molecular Marker Analysis in Primary Lung Cancer
2024, Clinical Lung CancerPD-L1 assessment in lung cancer biopsies—pitfalls and limitations
2024, International Journal of Biological MarkersA Case of ROS1 Fusion Gene-positive Lung Adenocarcinoma Diagnosed After Pulmonary Thromboembolism
2024, Japanese Journal of Lung Cancer