|Year : 2018 | Volume
| Issue : 6 | Page : 527-529
Concomitant expression of exon 19 mutation epidermal growth factor receptor and anaplastic lymphoma kinase gene rearrangement in metastatic adenocarcinoma lung responsive to crizotinib
Abhishek Purkayastha1, Amul Kapoor2, Harinder Pal Singh2, Arti Sarin3, Prasanta Sengupta4, Sankalp Singh1, Niharika Bisht1, Azhar Husain5
1 Department of Radiation Oncology, Command Hospital (Southern Command), Pune, Maharashtra, India
2 Department of Medical Oncology, Command Hospital (Southern Command), Pune, Maharashtra, India
3 Department of Radiation Oncology, INHS Asvini, Mumbai, Maharashtra, India
4 Department of Pathology and Molecular Sciences, Command Hospital (Southern Command), Pune, Maharashtra, India
5 Department of Nuclear Medicine, Command Hospital (Southern Command), Pune, Maharashtra, India
|Date of Web Publication||30-Oct-2018|
Dr. Abhishek Purkayastha
Department of Radiation Oncology, Command Hospital (Southern Command), Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Purkayastha A, Kapoor A, Singh HP, Sarin A, Sengupta P, Singh S, Bisht N, Husain A. Concomitant expression of exon 19 mutation epidermal growth factor receptor and anaplastic lymphoma kinase gene rearrangement in metastatic adenocarcinoma lung responsive to crizotinib. Lung India 2018;35:527-9
|How to cite this URL:|
Purkayastha A, Kapoor A, Singh HP, Sarin A, Sengupta P, Singh S, Bisht N, Husain A. Concomitant expression of exon 19 mutation epidermal growth factor receptor and anaplastic lymphoma kinase gene rearrangement in metastatic adenocarcinoma lung responsive to crizotinib. Lung India [serial online] 2018 [cited 2019 May 23];35:527-9. Available from: http://www.lungindia.com/text.asp?2018/35/6/527/244504
Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements usually are mutually exclusive and such occurrence are extremely rare in adenocarcinoma lung., ALK rearrangements correlate with specific clinical and pathological features and may cause potential resistance to anti-EGFR tyrosine-kinase inhibitors (TKIs). Use of EGFR-TKIs gefitinib or erlotinib,,,, and ALK-TKI crizotinib, in a concomitant lung adenocarcinoma has shown mixed results with few progressing,,,, and few responding.,, Patients housing both mutations have shown an objective response and increased sensitivity to ALK-TKI alone, but can also be sensitive to both targeted therapies, thus suggesting a variable dependence on EGFR and ALK oncogenes. Patients with double mutations have a higher incidence of brain metastases and also renal dissemination as seen in our case, indicating their aggressive nature.
A 36-year-old male, nonsmoker presented with nonproductive cough, weight loss, and headache with vomiting. Magnetic resonance imaging (MRI) brain showed multiple intracranial metastatic lesions. Computed tomography (CT) scan chest showed irregularly marginated 5.8 cm × 4.9 cm × 5.9 cm lesion involving the posteromedial basal segments of the right lower lobe (RLL), biopsy from which showed adenocarcinoma histology with immunohistochemistry (IHC) positive for cytokeratin-7 (CK7), thyroid transcription factor-1 while negative for P63. Whole-body positron emission tomography (WB-PET) scan showed mass lesion RLL with a standard uptake value (SUV) of 16.45. Multiple skeletal lesions were seen involving whole spine, right scapula, sternum, ribs, and pelvic bones with SUV of 10.0–15.99. The left kidney showed a hypermetabolic focus of SUV 13.19 suggestive of metastasis. Evaluation for EGFR with real-time polymerase chain reaction assay was positive for exon 19 deletion mutation. IHC for ALK stained positive which was further confirmed with fluorescent in situ hybridization [Figure 1].
|Figure 1: (a) Image-guided biopsy from the lung mass showing adenocarcinoma histology (H and E, ×100). (b) Immunohistochemistry staining positive for thyroid transcription factor-1 (×100). (c) Immunohistochemistry staining positive for cytokeratin-7 (×100). (d) Real-time polymerase chain reaction showing epidermal growth factor receptor mutation at exon 19. (e) Immunohistochemistry staining positive for anaplastic lymphoma kinase (×100). (f) Tumor cells staining positive for echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase translocation by fluorescent in situ hybridization method|
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He was diagnosed with metastatic adenocarcinoma lung with concomitant EGFR and ALK positivity. The patient was treated with palliative whole-body radiation therapy to a dose of 30 Gy/10 fractions for his brain metastasis and then started on oral crizotinib 250 mg twice/day monthly schedule. Response assessment after 3 months with CT scan and WB-PET showed a significant reduction in size and metabolic activity of lung and skeletal lesions [Figure 2]. He was continued on monthly crizotinib with WB-PET after 12 months showed near complete morphological and metabolic resolution of the lung, skeletal, and kidney lesions [Figure 3].
|Figure 2: (a) Initial computed tomography scan of the patient at presentation showing an irregularly marginated mix-density lesion involving the posteromedial basal segments of the right lower lobe. (b) Initial positron emission tomography scan image showing the lung lesion. (c) Computed tomography scan 3 months after starting crizotinib showing significant resolution of the lung lesion. (d) Positron emission tomography scan also showing similar resolution of the pulmonary lesion|
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|Figure 3: Comparison of (a) initial whole-body positron emission tomography scan at presentation showing lung lesion right lower lobe and multiple skeletal lesions. (b) Response assessment after 6 months of starting oral crizotinib with whole-body positron emission tomography showing a significant reduction in size and metabolic activity of lung and skeletal lesions. (c) Initial positron emission tomography scan. (d) Positron emission tomography scan at 12 months showing near-complete metabolic resolution of the lung and skeletal lesions|
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The advent of molecular characteristics in non-small cell lung cancer (NSCLC) like mutations in exons 18–21 of tyrosine kinase EGFR has made possible the precise treatment with EGFR-TKIs such as gefitinib, erlotinib, and afatinib. Rearrangement of ALK with echinoderm microtubule-associated protein-like-4 oncogene on the chromosome-2 short arm in approximately 3%–7% NSCLC adenocarcinoma cases specific for ALK-TKIs such as crizotinib and ceritinib. EGFR mutations have been known to predominate in well-differentiated while ALK in poorly differentiated adenocarcinomas, in young Asian nonsmokers. However, around 100 cases of concomitant presence have been reported in the world and only one case in India. Regarding such coexistence, few have described it to be about 1%, 1.3%, 1.6%, and even 0.3%.
With around 100 such concomitant cases reported in the world, Kamath et al. have reported the only case in India, while we report the second case in an upfront metastatic patient. Kamath et al. used gefitinib 250 mg/day, however, the disease progressed after 3 months. The patient was upfront metastatic which prompted the use of crizotinib 250 mg twice/day. The patient showed a dramatic response with near complete metabolic resolution of the primary lung mass, skeletal lesions, and renal metastasis over a period of 9 months after starting crizotinib. Exhaustive review of Indian,, and world literature revealed no similar case has shown such an excellent therapeutic response to crizotinib in a widely disseminated state.
EGFR mutations have been reported as a resistance mechanism with ALK translocations treated with ALK-TKIs while concomitant ALK rearrangements an acquired resistance mechanism for EGFR-TKIs. EGFR-TKIs such as geftinib and erlotinib,,,, and ALK-TKI crizotinib, have shown mixed results. Few patients progressed,,,, while few responded.,, In double-mutated cases, ALK-TKIs have been found to more effective than EGFR-TKIs,, but can also be sensitive to both targeted therapies, thus suggesting a variable dependence on EGFR and ALK oncogenes. Double-positive patients are resistant to EGFR-TKIs and sensitive to ALK-TKIs; therefore, these patients may be treated with first-line ALK-inhibitors than with first-line EGFR-inhibitors., Newer generation TKIs have also been reported to be of relevant intracranial efficacy. Clinical trials testing the safety and efficacy of co-inhibition of both ALK and EGFR could be an interesting preposition in the near future.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We would like to thank the patient for allowing us to publish the case report and use the images taken during his stay in the hospital.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ulivi P, Chiadini E, Dazzi C, Dubini A, Costantini M, Medri L, et al.
Nonsquamous, non-small-cell lung cancer patients who carry a double mutation of EGFR, EML4-ALK or KRAS: Frequency, clinical-pathological characteristics, and response to therapy. Clin Lung Cancer 2016;17:384-90.
Santelmo C, Ravaioli A, Barzotti E, Papi M, Poggi B, Drudi F, et al.
Coexistence of EGFR mutation and ALK translocation in NSCLC: Literature review and case report of response to gefitinib. Lung Cancer 2013;81:294-6.
Tiseo M, Gelsomino F, Boggiani D, Bortesi B, Bartolotti M, Bozzetti C, et al.
EGFR and EML4-ALK gene mutations in NSCLC: A case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 2011;71:241-3.
Kamath MP, Lokesh KN, Babu KG, Lakshmaiah KC, Babu SM, Amirtham U. A case report of a metastatic adenocarcinoma of lung with dual positivity for EGFR mutation and ALK fusion. J Nucl Med Radiat Ther 2015;6:262.
Popat S, Vieira de Araújo A, Min T, Swansbury J, Dainton M, Wotherspoon A, et al.
Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol 2011;6:1962-3.
Kuo YW, Wu SG, Ho CC, Shih JY. Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol 2010;5:2039-40.
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.
Tanaka H, Hayashi A, Morimoto T, Taima K, Tanaka Y, Shimada M, et al.
A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. BMC Cancer 2012;12:558.
Schmid S, Gautschi O, Rothschild S, Mark M, Froesch P, Klingbiel D, et al.
Clinical outcome of ALK-positive non-small cell lung cancer (NSCLC) patients with de novo
EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKIs). J Thorac Oncol 2017;12:681-8.
Sahnane N, Frattini M, Bernasconi B, Zappa F, Schiavone G, Wannesson L, et al.
EGFR and KRAS mutations in ALK-positive lung adenocarcinomas: Biological and clinical effect. Clin Lung Cancer 2016;17:56-61.
Won JK, Keam B, Koh J, Cho HJ, Jeon YK, Kim TM, et al.
Concomitant ALK translocation and EGFR mutation in lung cancer: A comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor. Ann Oncol 2015;26:348-54.
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;368:2385-94.
Lee JK, Kim TM, Koh Y, Lee SH, Kim DW, Jeon YK, et al.
Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation. Lung Cancer 2012;77:460-3.
Lo Russo G, Imbimbo M, Corrao G, Proto C, Signorelli D, Vitali M, et al.
Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: A literature review of 100 cases. Oncotarget 2017;8:59889-900.
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al.
Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.
Xu L, Lei J, Wang QZ, Li J, Wu L. Clinical characteristics of patients with non-small cell lung cancers harboring anaplastic lymphoma kinase rearrangements and primary lung adenocarcinoma harboring epidermal growth factor receptor mutations. Genet Mol Res 2015;14:12973-83.
Yang JJ, Zhang XC, Su J, Xu CR, Zhou Q, Tian HX, et al.
Lung cancers with concomitant EGFR mutations and ALK rearrangements: Diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 2014;20:1383-92.
Bal A, Singh N, Agarwal P, Das A, Behera D. ALK gene rearranged lung adenocarcinomas: Molecular genetics and morphology in cohort of patients from North India. APMIS 2016;124:832-8.
Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al.
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14:4275-83.
Rossing HH, Grauslund M, Urbanska EM, Melchior LC, Rask CK, Costa JC, et al.
Concomitant occurrence of EGFR (epidermal growth factor receptor) and KRAS (V-ki-ras2 kirsten rat sarcoma viral oncogene homolog) mutations in an ALK (anaplastic lymphoma kinase)-positive lung adenocarcinoma patient with acquired resistance to crizotinib: A case report. BMC Res Notes 2013;6:489.
Imamura F, Inoue T, Kimura M, Nishino K, Kumagai T. A long-term survivor of non-small-cell lung cancer harboring concomitant EGFR mutation and ALK translocation. Respir Med Case Rep 2016;19:137-9.
Dempke WC, Edvardsen K, Lu S, Reinmuth N, Reck M, Inoue A, et al.
Brain metastases in NSCLC-are TKIs changing the treatment strategy? Anticancer Res 2015;35:5797-806.
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