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 » Introduction
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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 228-230
 

Dual mutations and complex mutations in metastatic nonsmall cell lung cancer: A single-institution experience from South India


1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
2 Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. D Koppaka
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_20_17

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 » Abstract 

Wide use and incorporation of newer diagnostic tools in the management of metastatic nonsmall cell lung cancer (NSCLC) has helped in achieving the goal of personalized treatment of this disease. With the wide use of polymerase chain reaction and fluorescence in situ hybridization increasing number of patients are being diagnosed with dual and complex mutations posing a new challenge in the management of patient with metastatic NSCLC. In this article, we would like to bring forth six such cases and the varied responses to the current available treatment in patients with complex and dual mutations. The appropriate management in these groups of patients is yet to be standardized.


Keywords: Dual mutations, complex mutations, nonsmall cell lung cancer, tyrosine kinase inhibitor


How to cite this article:
Kadabur L, Koppaka D, Kanakasetty G B, Usha A, Kuntegowdanahalli L C, Dasappa L, Jacob L A, Babu S, Haleshappa R A, Abhishek A, Rajeev L K. Dual mutations and complex mutations in metastatic nonsmall cell lung cancer: A single-institution experience from South India. Indian J Cancer 2017;54:228-30

How to cite this URL:
Kadabur L, Koppaka D, Kanakasetty G B, Usha A, Kuntegowdanahalli L C, Dasappa L, Jacob L A, Babu S, Haleshappa R A, Abhishek A, Rajeev L K. Dual mutations and complex mutations in metastatic nonsmall cell lung cancer: A single-institution experience from South India. Indian J Cancer [serial online] 2017 [cited 2020 Apr 6];54:228-30. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/228/219564



 » Introduction Top


The past few decades have witnessed a tremendous progress in the management of metastatic nonsmall cell lung cancer (NSCLC) with advent of various targeted therapies such as monoclonal antibodies targeting vascular endothelial growth factor, small molecules targeting epidermal growth factor receptor, anaplastic lymphoma kinase (ALK) tyrosine kinases, and one of the most recent being immunotherapy targeting programmed cell death protein 1. With increasing arsenal of agents against metastatic NSCLC, the need for detecting the potential target is of paramount importance. The availability of various techniques such as polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) in clinical laboratory have helped in detecting EGFR and ALK mutations at affordable costs and leading to the analysis of the target in most patients with metastatic NSCLC.

Wide use of these techniques has proven advantageous as most patients currently undergo target-based therapy, but this has also lead to the dawn of new challenges. In this article, we would like to discuss two new scenarios we face in our practice, i.e., dual mutations and complex mutations. We bring forth four cases of complex mutations and two cases of dual mutations encountered at our institute.


 » Cases Reports Top


Case 1

A 63-year-old male patient presented with complaints of cough, blood in sputum, and shortness of breath for the last 6 months. History reveals a history of ischemic heart disease for which patient underwent bypass grafting. The patient is a chronic cigarette smoker and also gives history of alcohol abuse for more than past 35 years. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 1, and systemic examinations revealed rhonchi in the right supraclavicular, infraclavicular, and axillary regions. Investigations revealed the right upper lobe inhomogeneous opacity and brochoscopy revealed an ulceroproliferative endobronchial growth. Bronchoscopic biopsy from the mass was suggestive of adenocarcinoma primary lung. Positron emission tomography-computed tomography (PET-CT) showed the right upper lobe malignant mass lesion associated with mediastinal lymph nodes and multiple bilateral renal parenchymal lesions. EGFR mutational analysis was positive for G719X Exon 18 mutations and immunohistochemistry (IHC) for echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion was positive. This was further confirmed on FISH. The patient was started on gefitinib (250 mg) and reassessment after 3 months of treatment revealed a progressive disease. The patient was planned for ALK-targeted therapy, but the patient was not affordable for the same following which patient was started on combination chemotherapy with pemetrexed (500 mg/m2) and carboplatin (6 area under the curve [AUC]). After four cycles of chemotherapy, patient achieved a partial response and started on maintenance pemetrexed (500 mg/m2). After six cycles of maintenance chemotherapy imaging revealed a progressive disease and patient opted for best supportive care.

Case 2

A 46-year-old male patient, a known cigarette smoker for the past 30 years, presented with complaints of headache, vomiting, blurring of vision for the last 3 months duration for which patient underwent a neurological evaluation. On imaging, magnetic resonance imaging (MRI) brain revealed multiple metastatic lesions. PET-CT done for the evaluation of the primary revealed a lung lesion. Bronchoscopy revealed an endobronchial mass, biopsy from which was suggestive of adenocarcinoma primary being lung. The patient underwent whole brain radiotherapy thirty gray in ten fractions. ALK testing by IHC was positive and EGFR mutation testing by real-time (RT)-PCR was positive for Exon 19 mutations. Patient was given options for crizotinib treatment upfront, but the patient was not affordable for the same. In view of the above financial constraints, patient was offered options for palliative chemotherapy with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Following three cycles of combination chemotherapy, reevaluation revealed partial response and after four cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) patient was started on maintenance chemotherapy with pemetrexed (500 mg/m2).

Case 3

A 56-year-old female patient nonsmoker but a habitual tobacco chewer, presented with complaints of cough with expectoration, back pain for the last 2 months. On examination, the patient had an ECOG performance status 1, with normal systemic examination findings. CT Scan Thorax revealed multiple lung nodules in both the lungs largest in the right middle lobe. Bronchoscopy revealed obstruction of the right middle lobe bronchus and biopsy from the mass was performed. Histopathology findings were suggestive of adenocarcinoma lung. Bone scan revealed multiple bone metastases. EGFR mutation analysis using RT-PCR was positive for Exon 18 and Exon 21 L858R mutations. IHC for ALK was negative. The patient was started on palliative chemotherapy with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Reevaluation after three cycles of chemotherapy revealed a progressive disease with increasing bone metastases. In view of progressive disease, the patient was started on tyrosine kinase inhibitor (TKI) gefitinib (250 mg). Patient evaluation after 3 months of gefitinib (250 mg) treatment revealed a stable disease.

Case 4

A 50-year-old nonsmoker female patient presented to the emergency with complaints of cough, breathlessness, and generalized weakness. While patient was being evaluated for the above symptoms patient developed generalized tonic-clonic seizures. MRI brain revealed multiple brain metastases. Evaluation for the primary by PET-CT revealed the right upper lobe lung mass with multiple lung metastases with right pleural effusion. Multiple bone lesions along with multiple renal metastases were also present. CT-guided biopsy from the lung lesion was suggestive of NSCLC, adenocarcinoma. EGFR mutational analysis by RT-PCR was positive for Exon 21 L858R − 2573T>G and Exon 18. ALK testing by IHC was negative. Patient received palliative radiotherapy to the brain thirty gray in ten fractions. In view of poor general condition, patient was started on TKI gefitinib (250 mg). After 3 months of gefitinib (250 mg), no significant improvement in the symptoms was seen and reevaluation revealed a progressive disease. Gefitinib (250 mg) was discontinued and patient was given best supportive care.

Case 5

A 40-year-old woman, a nonsmoker presented to the outpatient department (OPD) with complaints of right-sided chest pain and low back pain for 3 months. On examination, patient had a preserved general condition with tenderness noticed in dorsolumbar spine. Investigations revealed a coin lesion in the right mid zone on chest X-ray. CT scan-guided fine needle aspiration cytology from the lesion was suggestive of adenocarcinoma. IHC staining revealed napsin A, thyroid transcription factor-1, and cytokeratin 7 positive cells suggestive of lung primary. PET-CT evaluation for metastatic workup revealed multiple lung nodules with bilateral mediastinal lymph nodes and multiple skeletal metastases. EGFR mutation testing by Sangers sequencing revealed L858R mutation in Exon 21 and T790M mutation in Exon 20. IHC for ALK was negative. In view of de novo T790M mutation presence in spite of L858R mutation, patient was started on pemetrexed (500 mg/m2) and carboplatin (6 AUC). After three cycles, patient had increase in symptoms and reassessment revealed progressive disease and associated compression fracture of T10 vertebral body. Palliative radiotherapy was given to the spine. Patient refused further chemotherapy and patient was given best supportive care.

Case 6

A 54-year-old chronic cigarette smoker presented to the OPD with complaints of cough with expectoration and difficulty in breathing. Patient is a known hypertensive on medications. ECOG performance status is 1. PET-CT imaging revealed the right upper lobe fluorodeoxy glucose avid mass with significant mediastinal lymphadenopathy along with multiple skeletal, bilateral adrenal metastases. CT-guided biopsy of the lung mass revealed adenocarcinoma arising from the lung. EGFR mutational analysis by PCR revealed complex mutations involving Exon 20 T790M − 2369C>T and Exon 21 L858R − 2573T>G. ALK testing by IHC was negative. In view of de novo mutations involving T790M, patient was started on pemetrexed (500 mg/m2) and cisplatin-(75 mg/m2) based chemotherapy along with zolendronic acid (4 mg). After three cycles of chemotherapy imaging revealed partial response and after four cycles of chemotherapy, patient was started on maintenance chemotherapy with pemetrexed (500 mg/m2). Patient currently received 10th cycle of maintenance pemetrexed (500 mg/m2).


 » Discussion Top


The past decade has witnessed a paradigm shift in the management of metastatic NSCLC. With the advent of newer and more reliable diagnostic techniques currently being used in the clinic, identification of various potential targets is made easier, thus helping in personalized treatment of the patients. However, this has also lead to newer complex scenarios in the management of NSCLC. There is an increase in the evidence of complex and dual mutations observed in patients undergoing EGFR and ALK testing.

Complex mutations are defined as more than one mutation per sample.[1] The current incidence of these mutations in NSCLC varies from 3.2% to 15% in various studies.[1],[2],[3] The exact frequency and response to EGFR TKI for these complex mutations has not been clarified in various studies. Complex mutations having co-occurring Del-19 + L858R mutations have response rates that seem to be similar or sometimes greater than to patients having single sensitive mutation.[1] Patients with complex mutations with T790M have poorer response to the EGFR TKI therapy as seen in most studies while some reports have shown responses that are as similar to patients with classical mutations. Contrary to the earlier reports that tumors acquire secondary T790M mutations while on TKI treatment increasing reports show patient may upfront present with de novo T790M mutations.[1] In our patients with complex mutations with T790M, both patients were started on palliative chemotherapy. One patient had progressive disease on therapy while the other patient is currently on maintenance chemotherapy after 10 months of follow-up, the patient has a partial response to chemotherapy. The presence of complex mutation with Exon 18 is reported in very few studies. Most of these patients with complex mutations had stable disease when treated with TKI.[1],[4] In our study, one patient with this complex mutation progressed on TKI after 3 months of therapy. Other patient had progressive disease after 3 months of pemetrexed-based chemotherapy and has stable disease on imaging with TKI treatment when evaluated at 3 months.

Data from the initial studies revealed, EGFR mutations, and ALK gene rearrangements are mutually exclusive and as mutual causes of resistance to EGFR-TKIs or ALK-TKIs. However, this mutual exclusivity is being challenged with the increasing evidence showing the coexistence of both EGFR and ALK. In the earlier studies, the rates of dual mutations ranged from 1.3% to 3% while the frequency of these dual mutations detection in metastatic NSCLC using the newer techniques as mutant-enriched next generation sequencing is as high as 4.4%–15.4%.[5] Thus, testing for one of these mutations or sequential testing for these mutations precludes identification of dual altered tumors. We have earlier published similar case as mentioned above (Case 1) having dual mutations.[6] While the clinicopathological features of dual positive tumors are similar to other metastatic NSCLC patients, the optimal treatment for patients presenting with dual EGFR and ALK mutations is still controversial. The benefit of platinum-based doublets is questioned in this group of patients. Earlier studies have shown either a short duration of response or no response to treatment. Even in our setting, the first case had a very brief period of response while the second patient is currently on maintenance chemotherapy. While earlier studies of pemetrexed revealed benefit in patients with EML4-ALK mutations;[7] however, this was not seen in patients with dual mutations.[8] Studies have failed to show superiority of EGFR TKI therapy in earlier studies. One study showed responses in 46% patients with TKI.[8] In many studies, significant benefit of crizotinib in this group of patients is seen. One study by Yang et al.[9] suggested that the relative activation status of EGFR and ALK, as determined by phosphorylated EGFR and ALK, could be predictive of inhibitor efficacy. Another study revealed minor clone of EGFR mutant may have little influence on the responsiveness to ALK inhibitors in dual-positive patients.[10] The current role of EGFR and ALK inhibitor in dual-positive patients is not straightforward, thus further study on the appropriate management of dual-positive NSCLC patients is needed.


 » Conclusion Top


With the advent of target-based treatment approaches in the management of NSCLC increasing number of patients are being diagnosed with complex and dual mutations. The use of more sensitive techniques in clinic might increase the number of patients being presenting with these rare scenarios. The optimal management of patient with dual and complex continues to pose a constant challenge in the management of patients of metastatic NSCLC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Hata A, Yoshioka H, Fujita S, Kunimasa K, Kaji R, Imai Y, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol 2010;5:1524-8.  Back to cited text no. 1
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2.
Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:45-51.  Back to cited text no. 2
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3.
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812-21.  Back to cited text no. 3
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4.
Baek JH, Sun JM, Min YJ, Cho EK, Cho BC, Kim JH, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: A retrospective analysis in Korea. Lung Cancer 2015;87:148-54.  Back to cited text no. 4
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5.
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.  Back to cited text no. 5
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6.
Kamath MP, Lokesh KN, Lakshmaiah K, Amirtham SB. 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.  Back to cited text no. 6
    
7.
Camidge DR, Kono SA, Lu X, Okuyama S, Baron AE, Oton AB, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 2011;6:774-80.  Back to cited text no. 7
    
8.
Sweis RF, Thomas S, Bank B, Fishkin P, Mooney C, Salgia R. Concurrent EGFR mutation and ALK translocation in non-small cell lung cancer. Cureus 2016;8:e513.  Back to cited text no. 8
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9.
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.  Back to cited text no. 9
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10.
Kim HS, Sung JS, Yang SJ, Kwon NJ, Jin L, Kim ST, et al. Predictive efficacy of low burden EGFR mutation detected by next-generation sequencing on response to EGFR tyrosine kinase inhibitors in non-small-cell lung carcinoma. PLoS One 2013;8:e81975.  Back to cited text no. 10
[PUBMED]    




 

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