ALK and PD-L1 Expression in Non-Small Cell Lung Cancer through Immunohistochemical Assays in Indonesia
DOI:
https://doi.org/10.36497/jri.v45i3.794Keywords:
NSCLC, biomolecular diagnosis, immunohistochemistry, ALK, PD-L1Abstract
Advanced therapies for non-small cell lung carcinoma (NSCLC), such as targeted therapy and immunotherapy, are available; however, their administration is contingent upon the availability of biomolecular tests. In the Indonesian context, EGFR testing is covered by the national health insurance (JKN). As recommended on the Indonesian Clinical Guideline for Lung Cancer, if EGFR test is negative, further testing including ALK and PD-L1 immunohistochemistry, is required. Nevertheless, the JKN does not currently cover ALK and PD-L1 IHC tests, which restricts access to the precise therapies. This study aims to determine the positivity rates of ALK and PD-L1 IHC tests. This study employs a cross-sectional approach to analyze 2,553 ALK and PD-L1 IHC tests conducted from 2019 to 2023, sourced from four major provinces in Indonesia. The positivity of ALK IHC tests is 8% with a median age of 52 years. The positivity rate for PD-L1 IHC in all patients is 49%, while based on the tumour proportion score (TPS), TPS ≥50% is 17% and TPS 1-49% is 32%. ALK positivity correlates with age and female gender (p < 0.001 and p = 0.006). Conversely, PD-L1 positivity statistically correlates with cancer type and PD-L1 (p = 0.008). ALK positivity in NSCLC in Indonesia is relatively high (8%) with a relatively young median age of 52 years and is predominantly found in females. PD-L1 positivity does not significantly differ by gender and age but positively correlates with adenocarcinoma cancer type.
NSCLC, biomolecular diagnosis, immunohistochemistry, ALK; PD-L1Downloads
References
GLOBOCAN 2022. The Global Cancer Observatory. 2022 [online]. https://gco.iarc.fr/
Risnawati, Zuraidah E, Susanto YDB. Deteksi Anaplastic Lymphoma Kinase Gene Rearrangement (ALK Gene Rearrangement) pada Adenokarsinoma Paru Sebagai Molekul Target Pengobatan pada Kanker Paru Jenis Karsinoma Bukan Sel Kecil. Majalah Pratista Patologi. 2019; 6:41-54
Andarini S, Syahruddin E, Aditya N, Zaini J, Kurniawan F D, Ermayanti S, et al. Indonesian society of respirology (isr) consensus statement on lung cancer screening and early detection in Indonesia. J Respirol Indones. 2023; 43 (20): 144–50.
Prof. DR. Dr. IB Ngurah Rai, SpP(K); Manajemen Kelainan Respirasi dengan Fokus Unit Layanan Primer; PT Percetakan Bali; Denpasar
Shimizu T, Yokoi T, Tamaki T, Kayoko K, Inagaki N, Nomura S. Comparative analysis of carboplatin and paclitaxel combination chemotherapy schedules in previously untreated patients with advanced non-small cell lung cancer. Oncol Lett 5. 2013;761-7.
Syahruddin E, Wulandari L, Sri Muktiati N, Rima A, Soeroso N, Ermayanti S, et al. Uncommon EGFR mutations in cytological specimens of 1,874 newly diagnosed Indonesian lung cancer patients. Lung Cancer (Auckl). 2018 Mar 23;9:25-34
Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. The Lancet Oncol. 2013;14:777-86
Kementerian Kesehatan Republik Indonesia. Standar Tarif Pelayanan Kesehatan dalam Penyelenggaraan Program Jaminan Kesehatan. 2023. diakses melalui jdih.kemkes.go.id
Kementerian Kesehatan Republik Indonesia. Pedoman Nasional Pelayanan Kedokteran Tata Laksana Kanker Paru. 2023. Diakses melalui jdih.kemkes.go.id
Inamura K. Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification. Front Oncol. 2017 Aug 28;7:193
ALK Mutation (Gene Rearrangement) [internet]. 2021 [diakses pada 27 Feb 2024] Tersedia di: https://www.testing.com/tests/alk-mutation-gene-rearrangement/
Poh ME, How SH, Ho GF, Pang YK, Hasbullah HH, Tho LM, et al. Real-World Treatment and Outcomes of ALK-Positive Metastatic Non–Small Cell Lung Cancer in a Southeast Asian Country. Cancer Management and Research, 2023:15, 31–41
Liang H, Song X, Zhang Y, Zhang S, Li F, Fang J, et al. Real-world data on EGFR/ALK gene status and first-line targeted therapy rate in newly diagnosed advanced non-small cell lung cancer patients in Northern China: A prospective observational study. Thorac Cancer 2019, 10: 1521-32
Jazieh AR, Gaafar R, Errihani H, Jaafar H, Al Dayel F, Bahnassy AA, et al. Real-World Data on the Prevalence of Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer in the Middle East and North Africa. JCO Glob Oncol. 2021 Sep;7:1556-63
Illei PB, Wong W, Wu N, Chu L, Gupta R, Schulze K, et al. ALK testing trends and patterns among community practices in the United States. JCO Precision Oncology 2018; 2:1-1.
Lin HM, Wu Y, Yin Y, Niu H, Curran, EA, Lovly CM, et al.Real-world ALK Testing Trends in Patients With Advanced Non–Small-Cell Lung Cancer in the United States. Clinical Lung Cancer 2023;24,1: e39–e49
Adizie JB, Tweedie J, Khakwani A, Peach E, Hubbard R, Wood N, et al. Biomarker testing for people with advanced lung cancer in England. JTO Clinical and Research Reports 2021; 2(6):100176.
Eide IJZ, Nilssen Y, Stensland EM, Brustugun OT. Real-World Data on EGFR and ALK Testing and TKI Usage in Norway—A Nation-Wide Population Study. Cancers. 2023; 15(5):1505
Ryska A, Berzinec P, Brcic L, Cufer T, Dziadziuszko R, Gottfried M. et al. NSCLC molecular testing in Central and Eastern European countries. BMC Cancer. 2018:18, 269.
Uruga H, Mino-Kenudson M. ALK (D5F3) CDx: an immunohistochemistry assay to identify ALK-positive NSCLC patients. Pharmgenomics Pers Med. 2018 Sep 17;11:147-155
Shrinidhi N; Mansi S; Ullas B. Testing modalities for ALK-driven lung cancer: A narrative review. Cancer Research, Statistics, and Treatment 2023. 6(3):432-9.
Shen Q, Wang X, Yu B, Shi S, Liu B, Wang Y, Xia Q, Rao Q, Zhou X. Comparing four different ALK antibodies with manual immunohistochemistry (IHC) to screen for ALK-rearranged non-small cell lung cancer (NSCLC). Lung Cancer. 2015 Dec 1;90(3):492-8.
Liang H, Song X, Zhang Y, Zhang S, Li F, Fang J, et al. Real-world data on EGFR/ALK gene status and first-line targeted therapy rate in newly diagnosed advanced non-small cell lung cancer patients in Northern China: A prospective observational study. Thorac Cancer. 2019 Jul;10(7):1521-32
Chang GC, Yang TY, Chen KC, Hsu KH, Huang YH, Su KY, et al. ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Sci Rep. 2020; 10:21063.
Kim DW, Ahn MJ, Shi Y, De Pas TM, Yang PC, Riely GJ, Crinò L, Evans TL, Liu X, Han JY, Salgia R. Results of a global phase II study with crizotinib in advanced ALK-positive non-small-cell lung cancer (NSCLC). Annals of Oncology. 2012 Oct 1;23:xi32-3.
Liu Y, Ye X, Yu Y, Lu S. Prognostic significance of anaplastic lymphoma kinase rearrangement in patients with completely resected lung adenocarcinoma. Journal of Thoracic Disease. 2019 Oct;11(10):4258.
Zhou F and Zhou C. Lung cancer in never smokers—the East Asian experience. 2018. Transl Lung Cancer Res. 2018 Aug; 7(4): 450–463.
American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. [internet]. 2023. [diakses pada 1 Maret 2024]. Tersedia di: https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html
National Cancer Institute. Immune checkpoint inhibitors. NCI Dictionaries [internet]. 2019. [cited 28 February 2024] Available from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-checkpoint-inhibitor
Akhtar M, Rashid S, Al-Bozom IA. PD-L1 immunostaining: what pathologists need to know. Diagn Pathol. 2021 Oct 25;16(1):94
Wang S, Hao J, Wang H, Fang Y, Tan L. Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer. Oncoimmunology. 2018 Apr 24;7(8):e1457600
Yoneshima Y, Ijichi K, Anai S, Ota K, Otsubo K, Iwama E, et al. PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements. Lung Cancer 2018; 118:36-40.
Syahruddin E. Overview of advanced NSCLC focus on ALK rearrangement. Seminar Konferensi Nasional PDPI. Lampung. 2023
Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, et al. Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non-Small-Cell Lung Cancer. J Clin Oncol. 2017;35(34):3867-76
Kim H, Cung JH. PD-L1 Testing in Non-small Cell Lung Cancer: Past, Present, and Future. J Pathol Transl Med. 2019; 53(4): 199–206
Yu H, Boyle TA, Zhou C, Rimm DL, Hirsch FR. PD-L1 Expression in Lung Cancer. J Thorac Oncol. 2016 Jul;11(7):964-75.
Wang L, Liu S, Discordant genomic correlates of PD-L1 expression in lung adenocarcinoma among multiple cohorts using dissimilar PD-L1 testing techniques. JCO 2020; 40:16
Marchetti A, Barberis M, Franco R, De Luca G, Pace MV, Staibano S, er al. Multicenter Comparison of 22C3 PharmDx (Agilent) and SP263 (Ventana) Assays to Test PD-L1 Expression for NSCLC Patients to Be Treated with Immune Checkpoint Inhibitors. J Thorac Oncol. 2017 Nov;12(11):1654-1663
Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol. 2017;12(2):208-22
Fu F, Deng C, Sun W, Zheng Q, Jin Y, Li Y, et al. Distribution and concordance of PD-L1 expression by routine 22C3 assays in East-Asian patients with non-small cell lung cancer. Respir Res (2022) 23(1):1–10.
Wu S, Shi X, Sun J, Liu Y, Luo Y, Liang Z, Wang J, Zeng X. The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma. Oncotarget. 2017; 8(10):16421-29
Rangachari D, VanderLaan PA, Shea M, Le X, Huberman MS, Kobayashi SS, et al. Correlation between Classic Driver Oncogene Mutations in EGFR, ALK, or ROS1 and 22C3-PD-L1 ≥50% Expression in Lung Adenocarcinoma. J Thorac Oncol. 2017;12(5):878-83
Rubio-Viqueira B, Tarruella MM, Lázaro M, Estévez SV, Córdoba-Ortega JF, Maiques IM, et al. PD-L1 testing and clinical management of newly diagnosed metastatic non-small cell lung cancer in Spain: MOREL study. Lung Cancer Manag. 2021 Nov 26;10(4):LMT53
Yang L, Xue R, Pan C. Prognostic and clinicopathological value of PD-L1 in colorectal cancer: a systematic review and meta-analysis. Onco Targets Ther. 2019;12:3671-82
Jain E, Sharma S, Aggarwal A, Bhardwaj N, Dewan A, Kumar A, et al. PD-L1 expression and its clinicopathologic and genomic correlation in the non-small cell lung carcinoma patients: An Indian perspective. Pathology - Research and Practice. 2021;Vol 228:153497
Kilaru S, Panda SS, Moharana L, Mohapatra D, Mohapatra SSG, Panda A, et al. PD-L1 expression and its significance in advanced NSCLC: real-world experience from a tertiary care center. J Egypt Natl Canc Inst. 2024;36:3
Lin G, Fan X, Zhu W, Huang C, Zhuang W, Xu H, et al. Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. Oncotarget (2017) 8(48):83986
Takada K, Okamoto T, Shoji F, Shimokawa M, Akamine T, Takamori S, et al. Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma. J Thorac Oncol. 2016 Nov;11(11):1879-1890
Gavralidis A, Gainor JF. Immunotherapy in EGFR-mutant and ALK-positive lung cancer: implications for oncogene-driven lung cancer. The Cancer Journal. 2020 Nov 1;26(6):517-24.
American Lung Association. PD-L1, PD1, TMB and Lung Cancer. [website] https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/pdl1-pd1-tmb
Zhang X, DeClue RW, Herms L, Yang M, Pawar V, Masters ET, et al. Real-World Treatment Patterns and Outcomes in PD-L1-Positive Non-Small Cell Lung Cancer. Immunotherapy, 2021;13(18): 1521–33
Putri, AW. Indonesia Siap Akses Imunoterapi, Harapan Baru Pasien Kanker-Dengan penanganan medis yang tepat, pasien kanker bisa tetap hidup produktif dan berkualitas [internet]. Kennedy, ES [editor]. 2019 [cited 2024 June 05]. Available from https://tirto.id/indonesia-siap-akses-imunoterapi-harapan-baru-pasien-kanker-eosz
Gosney JR, Paz-Ares L, Jänne P, Kerr KM, Leighl NB, Lozano MD, Malapelle U, Mok T, Sheffield BS, Tufman A, Wistuba II. Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation. ESMO open. 2023 Aug 1;8(4):101587.
Kerr KM, Bibeau F, Thunnissen E, Botling J, Ryška A, Wolf J, Öhrling K, Burdon P, Malapelle U, Büttner R. The evolving landscape of biomarker testing for non-small cell lung cancer in Europe. Lung Cancer. 2021 Apr 1;154:161-75.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, Huynh TG, Zhao L, Fulton L, Schultz KR, Howe E. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non–small cell lung cancer: a retrospective analysis. Clinical cancer research. 2016 Sep 15;22(18):4585-93
Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, Thai AA, Mascaux C, Couraud S, Veillon R, Van den Heuvel M. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Annals of Oncology. 2019 Aug 1;30(8):1321-8.
Oya Y, Kuroda H, Nakada T, et al. Efficacy of immune checkpoint inhibitor monotherapy for advanced non–small-cell lung cancer with ALK rear-arangement. Int J Mol Sci. 2020;21:2623
Arbour KC, Riely GJ. Systemic therapy for locally advanced and metastatic non–small cell lung cancer: a review. JAMA. 2019;322:764–774
Ota K, Azuma K, Kawahara A, et al. Induction of PD-L1 expression by the EML4–ALK oncoprotein and downstream signaling pathways in non– small cell lung cancer. Clin Cancer Res. 2015;21:4014–4021.
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