Long‑term complete response in a patient with postoperative recurrent ALK‑rearranged lung adenocarcinoma treated with crizotinib: A case report

  • Authors:
    • Takayuki Kosaka
    • Toshiki Yajima
    • Ei Yamaki
    • Seshiru Nakazawa
    • Kenji Tomizawa
    • Ryoichi Onozato
    • Ayako Yamazaki
    • Junko Hirato
    • Yasushi Yatabe
    • Kimihiro Shimizu
    • Akira Mogi
    • Ken Shirabe
  • View Affiliations

  • Published online on: July 3, 2019     https://doi.org/10.3892/mco.2019.1892
  • Pages: 309-312
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Abstract

Anaplastic lymphoma kinase (ALK) gene rearrangements are identified in approximately 5% of patients with non‑small cell lung cancer (NSCLC). Despite initial dramatic responses to ALK inhibitors, the majority of patients relapse within 1 year, owing to the development of resistance. Herein we present a case of variant type 2 ALK‑rearranged lung adenocarcinoma recurrence with multiple lung metastasis that maintained complete response over 5 years with crizotinib, which is the first approved ALK inhibitor. The efficacy of crizotinib may vary among ALK fusion variants and thus, variant type may represent an important factor in guiding the treatment strategy for ALK‑rearranged lung adenocarcinoma.

Introduction

Anaplastic lymphoma kinase (ALK) gene rearrangements are found in approximately 5% of non-small cell lung cancer (NSCLC) patients, and are enriched in patients with adenocarcinoma histology, patients with tumors of young onset, and never or light-smokers (1,2). Several ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib have been developed for ALK-positive NSCLC (37), and crizotinib was the first multi-targeted ALK-TKI to be approved. Despite initial dramatic responses to crizotinib, the majority of patients show relapse within 12 months because of the development of resistance (3). Only a few cases have shown long-lasting response to crizotinib, especially over 5 years. Here we experienced a very rare case of ALK-positive lung adenocarcinoma with postoperative recurrence that maintained complete response with crizotinib for over 5 years.

Case report

A 60-year-old male smoker with a right upper lobe lung tumor was referred to our hospital for operation (Fig. 1A). The patient had a medical history of controlled hypertension and hyperlipidemia. Transbronchial biopsy showed histology of adenocarcinoma. Radical right upper lobectomy with mediastinal lymph node dissection was performed. Pathological examination revealed moderately differentiated adenocarcinoma with acinar and solid component with cribriform pattern (Fig. 1B-D). Micropapillary component was identified within the acinar component and signet-ring cells were present in the solid component. The tumor was 7-cm in diameter and pleural invasion to superficial pleural connective tissue, vessel invasion, and lymphatic invasion were detected. Metastasis to hilar node was present, and the final pathological stage was IIB according to the 7th edition of tumor, node, and metastasis (TNM) classification. As postoperative adjuvant therapy, the patient was administered three cycles of carboplatin and S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan) followed by one year of tegafur-uracil (UFT; Taiho Pharmaceutical). One year after the operation, multiple small nodules were detected by computed tomography (CT) and follow-up CT scan showed that nodules continued to grow (Fig. 2A). At one year and 8 months after the operation, thoracoscopic resection of a nodule in the right lower lobe was performed for pathological diagnosis. Pathological examination of the lung nodule revealed identical histology as the initial surgical specimen (i.e., adenocarcinoma with solid tumor with acinar and micropapillary components). Lung cancer recurrence was diagnosed, and all other nodules detected by CT were also considered to be recurrent lesions. Magnetic resonance imaging of brain and 18F-fluorodeoxyglucose positron emission tomography revealed there was no other metastasis than multiple lung metastases. Immunohistochemical analysis of the initial surgical specimen using a commercial assay showed that tumor cells were positive for ALK and fluorescence in situ hybridization confirmed the presence of ALK gene rearrangement with a positive cell rate of 62%. Analysis of the initial surgical specimen by next-generation sequencing assay using FusionPlex (Archer, Boulder, CO, US) revealed a variant type 2 of echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement [exon 20 of EML4 fused to exon 20 of ALK (E20;A20)].

As the first-line treatment, crizotinib was administered twice daily (250 mg) and the size of multiple nodules remarkably decreased on follow-up CT after a month. Complete response was confirmed after 4 months (Fig. 2B) and was maintained over 5 years after the first administration of crizotinib. Grade 1 photopsia and diarrhea were the only adverse events observed.

Discussion

We present here a case of ALK-rearranged lung adenocarcinoma with postoperative multiple pulmonary metastases that showed complete response to crizotinib over a period of 5 years. The majority of patients treated with crizotinib have a relapse within 1 year (3). Clinical trials of crizotinib revealed that progression-free survival (PFS) was 10.9 months after first line treatment (3) and 7.7 months in patients who had received one prior platinum-based regimen (8). Rangachari et al (9), reported two cases of advanced lung adenocarcinoma with a PFS exceeding 5 years with crizotinib as first-line treatment. To the best of our knowledge, the current case is the third reported case of long-lasting PFS by crizotinib treatment exceeding 5 years. In addition, the current case is the first case depicting long-term complete response to crizotinib after postoperative recurrence. The previous report by Rangachari et al (9), does not include clinical and pathological details of the two cases with long-lasting PFS, and thus it is difficult to discuss the clinicopathological tendencies of these cases.

Several variants of the EML4-ALK fusion have been previously reported (1012). The most frequent variants are variant 1 (33%), in which exon 13 of EML4 is fused to exon 20 of ALK (E13;A20); variant 3a/b (29%), in which exon 6a or 6b of EML4 is fused to exon 20 of ALK (E6a/b;A20); and variant 2 (9%), in which exon 20 of EML4 is fused to exon 20 of ALK (E20;A20) (11). Other minor variants have also been reported. Recent studies have suggested that the response to crizotinib differs according to the ALK rearrangement variant (1318) (Table I). Li et al (13), reported that patients with variant 2 had a longer PFS compared with patients with other variants. These clinical results are supported by in vitro studies in which Ba/F3 cells expressing variant 2 had higher sensitivity to crizotinib compared with cells expressing other variants (15,19). The results of these studies are consistent with our case, since our patient also had variant 2 fusion and achieved long PFS with crizotinib. However, such clinical differences in response or PFS vary amongst reports (1318). Because the previous clinical studies were performed in small cohorts (Table I), a definitive conclusion has not yet been established.

Table I.

Different of efficacy of crizotinib among ALK fusion variants.

Table I.

Different of efficacy of crizotinib among ALK fusion variants.

Variant 1Variant 2Variant 3a/b



First author (Ref. no.)Total caseCaseORRPFSCaseORRPFSCaseORRPFS
Lei et al (18)612273%11.0 manon-v1/3a/b; n=21 ORR 81%, PFS 7.4 m1856%10.9 m
Cha et al (17)321030%x2100%x850%x
Yoshida et al (16)351974%11.0 manon-v1; n=16 ORR 63%, PFS 4.2 m
Woo et al (15)51anon-v3a/b; n=24, ORR 83%, 2-year PFSR: 76%2075%2-year
PFSR 26.4%
McLeer-Florin et al (14)18v1/2; n=6, ORR 60%, PFS 314 d863%192 d
Li et al (13)601446%10.7 m967%18.5 m2065%7.9 m

a including several types of variant. ORR, overall response rate; PFS, progression free survival; PFSR, progression free survival rate; m, months; d, days; n, number; x, data not shown.

In the treatment of EGFR mutated lung cancer, EGFR-TKIs sometimes maintain a good response for a long time. Lin et al analyzed patients with EGFR mutation treated with EGFR-TKIs and found that 14.6% of patients were 5-year survivors (20). The absence of extrathoracic metastasis was a significant factor associated with prolonged overall survival (20). In our case, the patient had multiple metastatic nodules, but these were limited to pulmonary metastases. Thus, similar to EGFR mutated lung cancer, absence of extrathoracic metastasis may also be a factor related to long-lasting CR for patients with ALK rearrangement.

In conclusion, here we presented a very rare case of variant type 2 ALK-rearranged lung adenocarcinoma that maintained complete response with crizotinib over 5 years. The efficacy of crizotinib may vary among ALK fusion variants, indicating that ALK variant type may represent an important factor in guiding the treatment strategy for ALK-rearranged lung adenocarcinoma. A large cohort analysis is required for further study.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

All data generated or analyzed during the present study are included in this published article.

Authors' contribution

TK designed the study. TK, TY, EY, SN, KiS, KT, RO, AM, KeS wrote the manuscript. KT, TY, EY, SN, KT, RO, KiS, AM, and KeS have contributed to the clinical management of the patient. AY and JH analyzed pathological findings. YY performed the next-generation sequencing assay. All authors critically reviewed the manuscript and approved the final manuscript.

Ethics approval and consent to participate

Ethical approval for this study was obtained from Gunma University Hospital Ethics Committee. The patient provided written informed consent.

Patient consent for publication

Written informed consent was obtained from the patient.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

ALK

anaplastic lymphoma kinase

NSCLC

non-small cell lung cancer

TKI

tyrosine kinase inhibitor

TNM

tumor, node, and metastasis

CT

computed tomography

EML4

echinoderm microtubule-associated protein-like 4

PFS

progression-free survival

References

1 

Soda M, Takada S, Takeuchi K, Choi YL, Enomoto M, Ueno T, Haruta H, Hamada T, Yamashita Y, Ishikawa Y, et al: A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA. 105:19893–19897. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Li T, Maus MK, Desai SJ, Beckett LA, Stephens C, Huang E, Hsiang J, Zeger G, Danenberg KD, Astrow SH and Gandara DR: Large-scale screening and molecular characterization of EML4-ALK fusion variants in archival non-small-cell lung cancer tumor specimens using quantitative reverse transcription polymerase chain reaction assays. J Thorac Oncol. 9:18–25. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 371:2167–2177. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, et al: Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 377:829–838. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, et al: First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet. 389:917–929. 2017. View Article : Google Scholar : PubMed/NCBI

6 

Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, Huber RM, West HL, Groen HJM, Hochmair MJ, et al: Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A randomized, multicenter phase II trial. J Clin Oncol. 35:2490–2498. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, Gainor JF, Johnson M, Dietrich J, James LP, et al: Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: An international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 18:1590–1599. 2017. View Article : Google Scholar : PubMed/NCBI

8 

Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 368:2385–2394. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Rangachari D, Le X, Shea M, Huberman MS, VanderLaan PA, Kobayashi SS and Costa DB: Cases of ALK-rearranged lung cancer with 5-year progression-free survival with crizotinib as initial precision therapy. J Thorac Oncol. 12:e175–e177. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Horn L and Pao W: EML4-ALK: Honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 27:4232–4235. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Sasaki T, Rodig SJ, Chirieac LR and Jänne PA: The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 46:1773–1780. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Lin JJ, Zhu VW, Yoda S, Yeap BY, Schrock AB, Dagogo-Jack I, Jessop NA, Jiang GY, Le LP, Gowen K, et al: Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J Clin Oncol. 36:1199–1206. 2018. View Article : Google Scholar : PubMed/NCBI

13 

Li Y, Zhang T, Zhang J, Li W, Yuan P, Xing P, Zhang Z, Chuai S, Li J and Ying J: Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants. Lung Cancer. 118:128–133. 2018. View Article : Google Scholar : PubMed/NCBI

14 

McLeer-Florin A, Duruisseaux M, Pinsolle J, Dubourd S, Mondet J, Phillips Houlbracq M, Magnat N, Fauré J, Chatagnon A, de Fraipont F, et al: ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer. Lung Cancer. 116:15–24. 2018. View Article : Google Scholar : PubMed/NCBI

15 

Woo CG, Seo S, Kim SW, Jang SJ, Park KS, Song JY, Lee B, Richards MW, Bayliss R, Lee DH and Choi J: Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Ann Oncol. 28:791–797. 2017.PubMed/NCBI

16 

Yoshida T, Oya Y, Tanaka K, Shimizu J, Horio Y, Kuroda H, Sakao Y, Hida T and Yatabe Y: Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol. 34:3383–3389. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Cha YJ, Kim HR and Shim HS: Clinical outcomes in ALK-rearranged lung adenocarcinomas according to ALK fusion variants. J Transl Med. 14:2962016. View Article : Google Scholar : PubMed/NCBI

18 

Lei YY, Yang JJ, Zhang XC, Zhong WZ, Zhou Q, Tu HY, Tian HX, Guo WB, Yang LL, Yan HH, et al: Anaplastic lymphoma kinase variants and the percentage of ALK-positive tumor cells and the efficacy of crizotinib in advanced NSCLC. Clin Lung Cancer. 17:223–231. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Heuckmann JM, Balke-Want H, Malchers F, Peifer M, Sos ML, Koker M, Meder L, Lovly CM, Heukamp LC, Pao W, et al: Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res. 18:4682–4690. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA and Johnson BE: Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol. 11:556–565. 2016. View Article : Google Scholar : PubMed/NCBI

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September 2019
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APA
Kosaka, T., Yajima, T., Yamaki, E., Nakazawa, S., Tomizawa, K., Onozato, R. ... Shirabe, K. (2019). Long‑term complete response in a patient with postoperative recurrent ALK‑rearranged lung adenocarcinoma treated with crizotinib: A case report. Molecular and Clinical Oncology, 11, 309-312. https://doi.org/10.3892/mco.2019.1892
MLA
Kosaka, T., Yajima, T., Yamaki, E., Nakazawa, S., Tomizawa, K., Onozato, R., Yamazaki, A., Hirato, J., Yatabe, Y., Shimizu, K., Mogi, A., Shirabe, K."Long‑term complete response in a patient with postoperative recurrent ALK‑rearranged lung adenocarcinoma treated with crizotinib: A case report". Molecular and Clinical Oncology 11.3 (2019): 309-312.
Chicago
Kosaka, T., Yajima, T., Yamaki, E., Nakazawa, S., Tomizawa, K., Onozato, R., Yamazaki, A., Hirato, J., Yatabe, Y., Shimizu, K., Mogi, A., Shirabe, K."Long‑term complete response in a patient with postoperative recurrent ALK‑rearranged lung adenocarcinoma treated with crizotinib: A case report". Molecular and Clinical Oncology 11, no. 3 (2019): 309-312. https://doi.org/10.3892/mco.2019.1892