European Journal of Cancer (2015) 51, 1853– 1855

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Letter to the Editor

PD-L1 expression in small cell lung cancer Takefumi Komiya ⇑, Rashna Madan Division of Hematology/Oncology, Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, United States Received 16 April 2015; accepted 15 June 2015 Available online 3 July 2015

To the editor: We read with great interest, the recently published article: ‘PD-L1 expression in small cell neuroendocrine carcinomas’ [1]. Schultheis et al. conducted a retrospective analysis of PD-L1 expression in 61 pulmonary and 33 extrapulmonary cases of small cell carcinomas. Tissue microarrays (TMAs) were generated after selecting cases of 43 primary and 49 distant metastases (51 resected specimens, 43 biopsies). Immunohistochemistry of PD-L1 was performed with two different antibodies which include 5H1, a non-commercial and widely used monoclonal antibody. Surprisingly, none of the tumours showed PD-L1 protein expression in the tumour cells. However, PD-L1 was detected in tumour-associated macrophages in a subset (18.5%) of cases. RNA-seq analysis for 43 available primary small cell lung cancer (SCLC) showed moderate expression in 37.2% of cases. This was consistent with lack of expression with IHC analysis. Recently, cancer immunotherapy targeting co-inhibitory signals has developed with great success. Inhibitors of immune check points such as CTL4 and PD-1 yielded clinical benefits in multiple types of malignancy [2]. Single-agent anti-PD-1 inhibitor therapy DOI of original article: 10.1016/j.ejca.2014.12.006.

⇑ Corresponding author: Tel.: +1 913 588 4709.

E-mail address: [email protected] (T. Komiya). http://dx.doi.org/10.1016/j.ejca.2015.06.003 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.

improved patient survival in metastatic melanoma and squamous non-small cell lung cancer (NSCLC) over chemotherapy [3,4]. Tumour response was reported in several other cancers as well [5]. The broad activity spectrum of anti- PD-1/PD-L1 inhibitors attracted us to conduct an IHC study in both SCLC and NSCLC. Commercially available TMAs (US Biolab, Gaithersburg, MD) containing 100 cases of SCLC, each represented by 1 mm cores in triplicate, were stained with a commercially available rabbit monoclonal anti PDL1 antibody , EPR1161(2) (Abcam Cambridge, MA). Contradictory to Schulthesis et al., a total of 82 out of 99 cases (82.8%) of SCLC showed positive cell surface/membranous staining in over 5% of tumour cells (Fig. 1). Staining of TMAs containing NSCLC specimens (75 cases, each represented by a single 1.5 mm core) showed PD-L1 expression in 45.2%, which is similar to other studies [6,7]. Our study with frequent expression of PD-L1 in SCLC was supported by a study in Japan. In the Japanese study, Ishii et al. reported results of PD-L1 immunostaining in SCLC utilising a rabbit monoclonal antibody (Abcam, Cambridge, United Kingdom (UK)) [8]. Expression of PD-L1 in tumour cells as defined by >5% of positive cells was observed in 71.6% (73 of 102) SCLC cases. PD-L1 staining was significantly associated with limited stage, and was independently predictive of longer overall survival. The definitive reason for the discrepancy among studies is unclear. We observed differences in clinical

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T. Komiya, R. Madan / European Journal of Cancer 51 (2015) 1853–1855

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% All

(n=73)

Squamous (n=30)

Others (n=43)

NSCLC

(n=99) SCLC

Fig. 1. Frequency of PD-L1 expression in lung cancer. Percentages of tumours with positive staining are shown.

characteristics between studies. The study by Ishii et al. was limited to SCLC patients whose tissue material derived predominantly (81.4%) from primary lung lesions. Given the very limited role of surgery in SCLC, most materials were presumably collected via biopsies. In contrast, Schultheis et al. reported that although 65% of cases were pulmonary small cell carcinoma, 54% of specimens were obtained via resection. Frequent resection in this study suggests they included many stage I SCLCs which we see rarely [9]. Nevertheless, the large difference in PD-L1 expression rate among the studies does not seem to be easily explained by patient selection. The choice of antibody and other methodological differences likely plays a role. Both Ishii et al. and our study used a commercially available anti-PD-L1 antibody that demonstrated extensive staining of SCLC, whereas Schultheis et al. compared two different antibodies, both of which showed similar lack of staining in their cohort of SCLC. Several other factors are known to alter immunoreactivity in formalin fixed paraffin embedded (FFPE) tissues. These included delay to fixation, prolonged or inadequate fixation and inadequate types of fixative [10]. Unfortunately, information regarding these factors is not generally reported. Interpretive and analytic factors may play another role. Our study and that of Ishii et al. used the same cut-off value of 5% while that of Schultheis et al. utilised the Allred system. However, the different scoring methods would again not explain the discrepant results between the studies. Despite no positive staining in tumour cells, Schultheis et al. found that 18.5% of cases showed PD-L1 expression in tumour-infiltrating macrophages. Recent studies demonstrated that clinical tumour response to anti-PD-1 therapy was best associated with PD-L1 expression in tumour-infiltrative immune cells [11,12]. Taken together, frequent PD-L1 expression in either tumour or immune cells in SCLC indicates that targeting PD-1 axis holds a promise for clinical

development in SCLC. Further development of reliable and consistent biomarker assays to predict clinical benefit in human SCLC trials is required. Conflict of interest statement None declared. Acknowledgements The authors would like to thank Ms. Marilyn Nielsen, Ms. Colleen Reilly and Ms. Carolyn Foster for administrative, technical and writing assistance. References [1] Schultheis AM, Scheel AH, Ozretic´ L, George J, Thomas RK, Hagemann T, et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer 2015;51(3):421–6. [2] Zamarin D, Postow MA. Immune checkpoint modulation: Rational design of combination strategies. Pharmacol Ther 2015 [Epub ahead of print]. [3] Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372(4):320–30. [4] CheckMate-017, A phase 3 study of opdivo (nivolumab) compared to docetaxel in patients with second-line squamous cell nonsmall cell lung cancer. http://news.bms.com/press-release/checkmate-017-phase-3-study-opdivo-nivolumab-compared-docetaxelpatients-second-line-s. [5] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443–54. [6] Yang CY, Lin MW, Chang YL, Wu CT, Yang PC. Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer 2014;50(7):1361–9. [7] Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015 [Epub ahead of print]. [8] Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol 2015;10(3):426–30.

T. Komiya, R. Madan / European Journal of Cancer 51 (2015) 1853–1855 [9] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Small cell lung cancer, Version 1.2015. . [10] Apple S, Pucci R, Lowe AC, Shintaku I, Shapourifar-Tehrani S, Moatamed N. The effect of delay in fixation, different fixatives, and duration of fixation in estrogen and progesterone receptor results in breast carcinoma. Am J Clin Pathol 2011;135(4):592–8.

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[11] Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563–7. [12] Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515(7528):558–62.

PD-L1 expression in small cell lung cancer.

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