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Open Access 01-12-2016 | Research

ALK-rearranged pulmonary adenocarcinoma in Thai Patients: From diagnosis to treatment efficacy

Authors: Pimpin Incharoen, Thanyanan Reungwetwattana, Sakditad Saowapa, Kaettipong Kamprerasart, Duangjai Pangpunyakulchai, Lalida Arsa, Artit Jinawath

Published in: World Journal of Surgical Oncology | Issue 1/2016

Abstract

Background

Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in 3 % to 13 % of non-small cell lung carcinoma patients, and these patients benefit from ALK inhibitors. The aim of this study was to determine the prevalence, the clinical and histological characteristics and the treatment outcomes of ALK-rearranged lung adenocarcinoma using immunohistochemistry (IHC) IHC, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methodologies.

Methods

A total of 268 pulmonary adenocarcinoma patients were screened for ALK expression by ALK IHC, which was confirmed by FISH and/or RT-PCR for ALK gene rearrangement. The treatment outcomes of ALK-rearranged patients were retrospectively reviewed.

Results

ALK gene rearrangement was identified in 26 cases (9.7 %) with no EGFR co-mutation, and it showed significant associations with younger age, female sex and non-smoker status (p < 0.05). A cribriform growth pattern was identified as the dominant histologic feature, and a solid signet ring cell component was focally present in a minority of the cases. Among 12 ALK-rearranged patients with conventional treatment, seven cases in the early stage of disease were cured and alive, and five patients in the late stage of the disease progressed and died, with a median overall survival (OS) at 14 months. Of the 14 patients receiving crizotinib, all of them had clinical benefit from crizotinib treatment, with one patient having a complete response (CR), 12 patients having a partial response (PR) and one patient having stable disease (SD). On the cutoff date, six of 14 patients were continuing crizotinib treatment with a median time of response of 7.5 (3–13) months, while eight patients had disease progression, and five of them died with a median OS at 8 months.

Conclusion

ALK gene rearrangement tended to occur in younger, non-smoking, female patients. ALK IHC is a reliable screening method to detect ALK gene rearrangement. Crizotinib therapy provided treatment benefit in ALK-rearranged adenocarcinoma patients especially in advanced stages of the disease.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.CrossRefPubMed

Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, et al. Annual Report to the Nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 2014;120(9):1290–314.CrossRefPubMedPubMedCentral

Cheng I, Le GM, Noone AM, Gali K, Patel M, Haile RW, et al. Lung Cancer Incidence Trends by Histology Type among Asian American, Native Hawaiian, and Pacific Islander Populations in the United States, 1990–2010. Cancer Epidemiol Biomarkers Prev. 2014;23(11):2250–65.CrossRefPubMed

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.CrossRefPubMed

Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154–62.CrossRefPubMedPubMedCentral

Zhang Y, Sun Y, Pan Y, Li C, Shen L, Li Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res. 2012;18(7):1947–53.CrossRefPubMedPubMedCentral

Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.CrossRefPubMed

Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 2008;68(13):4971–6.CrossRefPubMed

Takeuchi K, Choi YL, Togashi Y, Inamura K, Togashi Y, Hatano S, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15(9):3143–9.CrossRefPubMed

10.

Togashi Y, Soda M, Sakata S, Sugawara E, Hatano S, Asaka R, et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One. 2012;7(2):e31323.CrossRefPubMedPubMedCentral

11.

Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247–53.CrossRefPubMedPubMedCentral

12.

Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115(8):1723–33.CrossRefPubMed

13.

Takahashi T, Sonobe M, Kobayashi M, Yoshizawa A, Menju T, Nakayama E, et al. Clinicopathologic features of nonsmall-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol. 2010;17(3):889–97.CrossRefPubMed

14.

Zhang X, Zhang S, Yang X, Yang J, Zhou Q, Yin L, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer. 2010;9:188.CrossRefPubMedPubMedCentral

15.

Wang Z, Zhang X, Bai H, Zhao J, Zhuo M, An T, et al. EML4-ALK rearrangement and its clinical significance in Chinese patients with advanced non-small cell lung cancer. Oncology. 2012;83(5):248–56.CrossRefPubMed

16.

Li Y, Li Y, Yang T, Wei S, Wang J, Wang M, et al. Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PLoS One. 2013;8(1):e52093.CrossRefPubMedPubMedCentral

17.

Mino-Kenudson M, Chirieac LR, Law K, Hornick JL, Lindeman N, Mark EJ, et al. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res. 2010;16(5):1561–71.CrossRefPubMedPubMedCentral

18.

Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008;3(1):13–7.CrossRefPubMed

19.

Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15(16):5216–23.CrossRefPubMedPubMedCentral

20.

Jokoji R, Yamasaki T, Minami S, Komuta K, Sakamaki Y, Takeuchi K, et al. Combination of morphological feature analysis and immunohistochemistry is useful for screening of EML4-ALK positive lung adenocarcinoma. J Clin Pathol. 2010;63:1066–70.CrossRefPubMed

21.

Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H, et al. Comprehensive histologic analysis of ALKrearranged lung carcinomas. Am J Surg Pathol. 2011;35:1226–34.CrossRefPubMed

22.

Nishino M, Klepeis VE, Yeap BY, Bergethon K, Morales-Oyarvide V, Dias-Santagata D, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol. 2012;25(11):1462–72.CrossRefPubMed

23.

Lantuejoul S, Rouquette I, Blons H, Le Stang N, Ilie M, Begueret H, et al. French multicentric validation of ALK rearrangement diagnostic in 547 lung adenocarcinomas. Eur Respir J. 2015;46(1):207–18.CrossRefPubMed

24.

Sholl LM, Weremowicz S, Gray SW, Wong KK, Chirieac LR, Lindeman NI, et al. Combined use of ALK immunohistochemistry and FISH for optimal detection of ALK-rearranged lung adenocarcinomas. J Thorac Oncol. 2013;8(3):322–8.CrossRefPubMedPubMedCentral

25.

Wallander ML, Geiersbach KB, Tripp SR, Layfield LJ. Comparison of reverse transcription-polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization methodologies for detection of echinoderm microtubuleassociated proteinlike 4-anaplastic lymphoma kinase fusion-positive non-small cell lung carcinoma: implications for optimal clinical testing. Arch Pathol Lab Med. 2012;136(7):796–803.CrossRefPubMed

26.

Camidge DR, Kono SA, Flacco A, Tan AC, Doebele RC, Zhou Q, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res. 2010;16(22):5581–90.CrossRefPubMedPubMedCentral

27.

Paik JH, Choe G, Kim H, Choe JY, Lee HJ, Lee CT, et al. Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol. 2011;6(3):466–72.CrossRefPubMed

28.

Yoshida A, Tsuta K, Nitta H, Hatanaka Y, Asamura H, Sekine I, et al. Bright-field dual-color chromogenic in situ hybridization for diagnosing echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-positive lung adenocarcinomas. J Thorac Oncol. 2011;6(10):1677–86.CrossRefPubMed

29.

Kim H, Yoo SB, Choe JY, Paik JH, Xu X, Nitta H, et al. Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol. 2011;6(8):1359–66.CrossRefPubMed

30.

Sanders HR, Li HR, Bruey JM, Scheerle JA, Scheerle JA, Meloni-Ehrig AM, et al. Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer Genet. 2011;204(1):45–52.CrossRefPubMed

31.

McLeer-Florin A, Moro-Sibilot D, Melis A, Salameire D, Lefebvre C, Ceccaldi F, et al. Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: a French study. J Thorac Oncol. 2012;7(2):348–54.CrossRefPubMed

32.

Murakami Y, Mitsudomi T, Yatabe Y. A Screening Method for the ALK Fusion Gene in NSCLC. Front Oncol. 2012;2:24.CrossRefPubMedPubMedCentral

33.

Park HS, Lee JK, Kim DW, Kulig K, Kim TM, Lee SH, et al. Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients. Lung Cancer. 2012;77(2):288–92.CrossRefPubMed

34.

Conklin CM, Craddock KJ, Have C, Laskin J, Couture C, Ionescu DN. Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-small-cell lung carcinoma and is antibody dependent. J Thorac Oncol. 2013;8(1):45–51.CrossRefPubMed

35.

Minca EC, Portier BP, Wang Z, Lanigan C, Farver CF, Feng Y, et al. ALK status testing in non-small cell lung carcinoma: correlation between ultrasensitive IHC and FISH. J Mol Diagn. 2013;15(3):341–6.CrossRefPubMed

36.

Martinez P, Hernández-Losa J, Montero MÁ, Cedrés S, Castellví J, Martinez-Marti A, et al. Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients. PLoS One. 2013;8(1):e52261.CrossRefPubMedPubMedCentral

37.

Zhang YG, Jin ML, Li L, Zhao HY, Zeng X, Jiang L, et al. Evaluation of ALK Rearrangement in Chinese Non-Small Cell Lung Cancer Using FISH, Immunohistochemistry, and Real-Time Quantitative RT- PCR on Paraffin-Embedded Tissues. PLoS One. 2013;8(5):e64821.CrossRefPubMedPubMedCentral

38.

Selinger CI, Rogers TM, Russell PA, O'Toole S, Yip P, Wright GM, et al. Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol. 2013;7:1–9.

39.

To KF, Tong JH, Yeung KS, Lung RW, Law PP, Chau SL, et al. Detection of ALK Rearrangement by Immunohistochemistry in Lung Adenocarcinoma and the Identification of a Novel EML4-ALK Variant. J Thorac Oncol. 2013;8(7):883–91.CrossRefPubMed

40.

Wu YC, Chang IC, Wang CL, Chen TD, Chen YT, Liu HP, et al. Comparison of IHC, FISH and RT-PCR methods for detection of ALK rearrangements in 312 non-small cell lung cancer patients in Taiwan. PLoS One. 2013;8(8):1–8.

41.

U.S. Food and Drug Administration. Approved Drugs. [Internet]. Silver Spring (MD): [update 2015 Oct 7; cited 2015 Oct 26] Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm395386.htm.

42.

The Orphan Druganaut Blog. FDA Breakthrough Therapy Designation: Roche Receives #24. [Internet]. c2012-2015. [2015 Oct 26] Available from: https://orphandruganaut.wordpress.com/2013/09/25/fda-breakthrough-therapy-designationroche-receives-24/.

43.

Soda M, Isobe K, Inoue A, Maemondo M, Oizumi S, Fujita Y, et al. A prospective PCR-based screening for the EML4-ALK oncogene in non-small cell lung cancer. Clin Cancer Res. 2012;18(20):5682–9.CrossRefPubMed

44.

U.S. Food and Drug Administration. Recently-approved Devices. [Internet]. Silver Spring (MD): [update 2014 Apr 23; cited 2015 Oct 26] Available from: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm454476.htm.

45.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed

46.

Wang J, Dong Y, Cai Y, Zhou L, Wu S, Liu G, et al. Clinicopathologic characteristics of ALK rearrangements in primary lung adenocarcinoma with identified EGFR and KRAS status. J Cancer Res Clin Oncol. 2014;140(3):453–60.CrossRefPubMed

47.

Sun JM, Lira M, Pandya K, Choi YL, Ahn JS, Mao M, et al. Clinical characteristics associated with ALK rearrangements in never-smokers with pulmonary adenocarcinoma. Lung Cancer. 2014;83(2):259–64.CrossRefPubMed

48.

Peled N, Palmer G, Hirsch FR, Wynes MW, Ilouze M, Varella-Garcia M, et al. Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer. J Thorac Oncol. 2012;7(9):e14–6.CrossRefPubMedPubMedCentral

49.

Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in nonsmall-cell lung cancer. N Engl J Med. 2010;363(18):1693–703.CrossRefPubMedPubMedCentral

50.

Bang YJ. Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med. 2012;136(10):1201–4.CrossRefPubMed

51.

Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4(12):1450–4.CrossRefPubMed

52.

Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.CrossRefPubMed

53.

Shaw AT, Yeap BY, Solomon BJ, 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;12(11):1004–12.CrossRefPubMedPubMedCentral

54.

Solomon BJ, Mok T, Kim DW, Riely GJ, Gainor J, Engelman JA, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.CrossRefPubMed

55.

Kijima T, Takeuchi K, Tetsumoto S, Shimada K, Takahashi R, Hirata H, et al. Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer. Cancer Sci. 2011;102(8):1602–4.CrossRefPubMed

56.

Akamatsu H, Ono A, Shukuya T, Tsuya A, Nakamura Y, Kenmotsu H, et al. Disease flare after gefitinib discontinuation. Respir Investig. 2015;53(2):68–72.CrossRefPubMed

57.

Hashisako M, Wakamatsu K, Ikegame S, Kumazoe H, Nagata N, Kajiki A. Flare phenomenon following gefitinib treatment of lung adenocarcinoma with bone metastasis. Tohoku J Exp Med. 2012;228(2):163–8.CrossRefPubMed

Title: ALK-rearranged pulmonary adenocarcinoma in Thai Patients: From diagnosis to treatment efficacy
Authors: Pimpin Incharoen
Thanyanan Reungwetwattana
Sakditad Saowapa
Kaettipong Kamprerasart
Duangjai Pangpunyakulchai
Lalida Arsa
Artit Jinawath
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2016
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/s12957-016-0893-6

At a glance: The STEP trials

Springer Medicine

ALK-rearranged pulmonary adenocarcinoma in Thai Patients: From diagnosis to treatment efficacy

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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