Bo Chen  ( Department of Pathology, Zhejiang Key Laboratory of Diagnosis & Treatment Technology, China. )
Zhiming Jiang  ( Zhejiang Key Laboratory of Diagnosis & Treatment Technology, China. )
Chenghui Li  ( Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, China. )
Hongyang Lu  ( Zhejiang Key Laboratory of Diagnosis & Treatment Technology, China. )

Platinum-based postoperative adjuvant chemotherapy is the standard treatment for stage II-IIIA non-small cell lung cancer (NSCLC). Novel therapeutic modalities are required to improve the outcome of an early stage NSCLC. Patients with advanced NSCLC having anaplastic lymphoma kinase (ALK) fusion protein are sensitive to ALK inhibitors such as crizotinib. This study aimed to further explore the clinicopathological characteristics of postoperative patients with early-stage lung cancer harboring ALK fusion protein and provide a basis to carry out postoperative adjuvant crizotinib treatment. A total of 19 patients were retrospectively reviewed, and the clinicopathological parameters and follow-up data were collected and analysed. ALK rearrangements easily exist in male and in non-smokers patients with adenocarcinoma histology. Brain metastasis occurs easily, and prognosis of patients with stage IIIA is relatively poor. Detection of ALK fusion protein should be a routine testing. Postoperative adjuvant crizotinib treatment for patients with stage IIIA NSCLC harboring ALK fusion protein is promising.

Keywords: ALK, Disease-free survival, Lung cancer.

https://doi.org/10.5455/JPMA.3142

 

 

Introduction

 

Lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), is the most common malignancy and the leading cause of cancer-related mortality worldwide. Previous large-scale studies have established platinum-based chemotherapy as the standard postoperative adjuvant treatment in stage II-IIIA NSCLC. The usefulness of excision repair crosscomplementation group 1 in guiding platinum-based chemotherapy in NSCLC is limited.¹ Negative results were obtained in the randomised phase III trial, studying the role of bevacizumab in adjuvant chemotherapy. Novel therapeutic modalities are required to further improve outcome for patients with early stage NSCLC. Echinoderm microtubule-associated protein-like4 (EML4)- anaplastic lymphoma kinase (ALK) fusion protein is a dominant oncogenic protein present in approximately 4% to 5% of all cases of NSCLC.² Several other fusion partners, except EML4, have also been observed for ALK. The 5-year risk of progression or recurrence has doubled for patients with ALK-positive compared to ALKnegative.³ ALK inhibitors have become the first line of treatment in advanced NSCLC patients with ALK rearrangements. This study aimed to further explore the clinicopathological characteristics of postoperative patients with surgically resected early-stage lung cancer, harboring ALK fusion protein and provide a basis to carry out the postoperative adjuvant crizotinib treatment on these patients. A total of 19 patients were included in this study, and the clinicopathological parameters and followup data were collected and analysed.

 

Case Series

 

A total of 19 patients with lung cancer harboring the ALK fusion protein were reviewed at the Zhejiang Cancer Hospital in China between January 2013 and December 2014. They were diagnosed by immunohistochemistry (IHC) using a highly sensitive anti-ALK (D5F3) rabbit monoclonal primary antibody (Roche, Inc., AZ, USA) with an OptiView Amplification Kit and an OptiView DAB IHC Detection Kit (Roche, Inc.). All specimens were obtained from resected tumors of lung cancer. The pathological diagnosis was based on the standard criteria defined by the World Health Organisation. The stages were defined according to the eighth edition of TNM classification for lung cancer. Specimens were obtained from 8 female and 11 male patients, ranging in age from 33 to 71 years old. The median age of the patients was 57 years and the median pack-years of smoking history was 30. The pathological type, stages and smoking history are shown in Table-1.

This study was approved by the Medical Ethical Committee of the Zhejiang Cancer Hospital. A 66-year old male who was a heavy smoker was diagnosed with SCLC combined with squamous cell carcinomaat stage IA3 (T1cN0M0) who had received four cycles of etoposide combined cisplatin (Figure-1).

Another 44-year old non-smoker female patient with two tumors including lung adenocarcinoma (T1bN0M0, IA2) and lung squamous cell carcinoma (T2aN0M0, IB) received four cycles of adjuvant chemotherapy with gemcitabine combined with cisplatin. ALK positive was detected in both adenocarcinoma and squamous cell carcinoma in this patient (Figure-2).

All other patients with stages IA and IB lung adenocarcinoma did not receive adjuvant chemoradiotherapy. Patients with stages IIA, IIB and IIIA received three or four cycles of adjuvant chemotherapy with gemcitabine combined with cisplatin, or pemetrexed combined with cisplatin, including one patient with stage IIIA who received adjuvant thoracic radiotherapy. At the follow-up deadline of May 10, 2018, no patients had been lost. The survival time was calculated from the date of pathological diagnosis. ALK-positive lung cancer easily occurred in males, and non-smokers patients with adenocarcinoma. The followup results of all the patients are given in Table-2.

Six patients relapsed, of which three of them due to brain metastasis:one patient with lung adenocarcinoma (pT1bN0M0, IA2) had brain metastasis 23 months after surgery; another patient with adenocarcinoma and squamous cell carcinoma had lung metastasis 23 months after surgery; the third patient with lung adenocarcinoma (pT2aN1M0, IIB) had lymph node metastasis 39 months after surgery; one patient with lung squamous cell carcinoma (pT2aN1M0, IIB) had brain metastasis 5 months after surgery; another patient with lung adenocarcinoma (pT3N1M0, IIIA) had adrenal metastasis 7 months after surgical resection, and the sixth patient with lung adenocarcinoma (pT2aN2M0, IIIA) had brain metastasis 9 months after surgical resection.

 

Discussion

 

In the present cohort, IHC (Ventana) was used in all the patients with lung cancer to detect the status of ALK. Most of the patients enrolled in our study were adenocarcinoma and non-smokers, which is consistent with literature.⁴ Gender percentage and median age in the cohort were consistent with Li's report.⁵ A case of SCLC combined with adenocarcinoma harboring EML4- ALK fusion protein and an exon 19 EGFR mutation in each histological component was reported.⁶ In the present cohort, one patient with SCLC combined with squamous cell carcinoma harbored ALK rearrangement. ALKrearranged squamous cell lung carcinomas are rare tumors that can also respond to anti-ALK-targeted therapy.⁷ It may be imperative to identify all patients with NSCLC harboring ALK translocations because the ALK TKI crizotinib is highly effective in ALK-translocated patients, especially in those who have never smoked. Patients with lung cancer having ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib and ceritinib, than with chemotherapy. Crizotinib was superior compared to the standard first-line pemetrexed-plus-platinum chemotherapy performed on patients with previously untreated advanced ALK-positive NSCLC.⁸ Compared with chemotherapy, crizotinib demonstrated a significantly higher intracranial disease control rate in patients with brain metastasis.⁹ The overall survival of patients with ALK-positive NSCLC is less than that of ALK-negative patients following surgical resection.³ In our retrospective study, two of three patients with ALKpositive stage IIIA lung cancer relapsed quickly and early, despite receiving adjuvant chemotherapy. The administration of gefitinib following pemetrexed and carboplatin adjuvant therapy showed significant improvement in disease-free survival (DFS) in patients with resected stage IIIA-N2 NSCLC harboring EGFR mutations (39.8 vs 27.0 months, P=0.014).¹⁰ It was speculated that the use of crizotinib could result in an improvement in DFS and decrease in brain metastasis for ALK positive NSCLC with stage IIIA. In addition, the main limitation of our study is the relatively small sample size enrolled due to the low frequency of ALK rearrangement in lung cancer. Owing to the retrospective nature of this study, a constructed prospective trial may be needed in the future.

 

Conclusion

 

In conclusion, all lung adenocarcinomas and lung squamous cell carcinomas should be examined for ALK fusion protein. Brain metastasis occurs easily and the prognosis for patients with stage IIIA is not satisfactory. The use of ALK inhibitor in patients with ALK-positive NSCLC following surgical resection is a potential therapeutic option to improve the outcome. Postoperative adjuvant crizotinib treatment for patients with NSCLC, especially those with stage IIIA harboring the ALK fusion protein, is promising and needs further evaluation.

 

Disclaimer: None to be declared.

Declaration of Interest: The authors declare no potential or real conflicts of interest.

Sources of Funding: This work was supported by Zhejiang province public welfare and technology application project of China (2016C33118), and the 1022 Talent Training Program of Zhejiang Cancer Hospital. Financial sponsors played no role in the design, execution, analysis and interpretation of data or writing of the study.

 

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