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ORIGINAL ARTICLE
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Concomitant echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearrangement and epidermal growth factor receptor mutation in non-small cell lung cancer patients from eastern India


1 Department of Pulmonary Medicine, AIIMS, Bhubaneswar, Odisha, India
2 Department of Radiotherapy, AIIMS, Bhubaneswar, Odisha, India
3 Department of Pathology, AIIMS, Bhubaneswar, Odisha, India

Correspondence Address:
Prasanta Raghab Mohapatra,
Department of Pulmonary Medicine, AIIMS, Bhubaneswar - 751 019, Odisha
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_678_18

 > Abstract 


Background: In non-small cell lung cancer common driver mutations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are usually mutually exclusive. This study aimed to elucidate the concurrence of EGFR mutation and ALK rearrangement in eastern India patients with primary lung adenocarcinoma and assess the response of EGFR tyrosine kinase inhibitor (TKI) therapy after 6 months in primary lung adenocarcinoma.
Methods: We retrospectively analyzed 198 adenocarcinomas for EGFR and ALK mutations. EGFR and ALK tests were done by real-time polymerase chain reaction and immunohistochemistry (IHC) techniques, respectively. Radiological response was assessed by Response Evaluation Criteria in Solid Tumors (version 1.1).
Results: EGFR/ALK co-alteration was found in 4 adenocarcinoma patients. All were males with advanced disease. Younger patients had exon 19 deletion whereas older ones showed exon 21 mutation. The initial option of ALK-TKI in all four patients was excluded straightaway due to the high-cost burden of ALK-TKI. Two of them showed a partial response while other two had stable disease after 6 months of EGFR TKI therapy.
Conclusion: EGFR/ALK co-alterations in adenocarcinomas albeit rare do exist. The challenge of monetary hurdle in developing countries with ALK TKI therapy can be handled by giving only EGFR TKI in these cases of concomitant mutations. Future perspective in research could be finding an agent with the potential of dual inhibition of ALK and EGFR.

Keywords: Adenocarcinoma, anaplastic lymphoma kinase, concomitant epidermal growth factor receptor anaplastic lymphoma kinase, epidermal growth factor receptor, lung



How to cite this URL:
Mohapatra PR, Sahoo S, Bhuniya S, Panigrahi MK, Majumdar SK, Mishra P, Patra S. Concomitant echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearrangement and epidermal growth factor receptor mutation in non-small cell lung cancer patients from eastern India. J Can Res Ther [Epub ahead of print] [cited 2019 Nov 18]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264706




 > Introduction Top


Over the past few years, the treatment of non-small cell lung cancer (NSCLC) has evolved beyond traditional chemotherapy. Discovery of oncogenic driver mutations along with immune-oncology has revolutionized the treatment approach to advanced NSCLC and has paved the path for individualized therapy. Clinical guidelines recommend routine testing for genetic mutations in all adenocarcinomas, including activating epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 (EML4) – anaplastic lymphoma kinase (ALK) gene rearrangement. The EGFR gene consisting of 28 exons is located in the short arm of chromosome 7. Activating EGFR mutations were identified in 10%–15% of the western population and up to 50% of Asian patients.[1],[2] The rearrangement of ALK with EML4 oncogene on the chromosome 2 short arm is another important therapeutic target. Such aberration is found in about 4%–5% of lung adenocarcinomas in both Asian and Caucasian patients.[3] The coexistence of EGFR mutation and EML4-ALK rearrangement was considered to be mutually exclusive.[4],[5] However, in the past few years, case reports and studies have challenged the dogma of concomitant mutation in both Asian and Caucasian population.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33] However, this occurrence has been a rare observation perhaps due to its low prevalence, the nonavailabilty of diagnostic modalities and cost factor in developing countries like India. We report four cases diagnosed with lung adenocarcinoma, exhibiting concomitant EGFR mutation, and EML4-ALK rearrangement.


 > Methods Top


We retrospectively analyzed data of 198 adenocarcinoma patients from June 2014 to April 2018 who were managed in an institute of national importance in eastern India and whose molecular analysis reports were available. All patients had a confirmed diagnosis of adenocarcinoma by cytology or histopathology. Immediately after establishing diagnosis, the formalin fixed paraffin-embedded (FFPE) histological samples and cell block FFPE samples were sent for molecular analysis. EGFR analysis was done by extracting DNA from the deparaffinized tissue sections using the and tissue kit (Qiagen, Valencia, CA, USA). The mutated EGFR oncogenes were detected using real-time polymerase chain reaction kit. FFPE tissues were stained with an antibody for ALK (mouse monoclonal, D5F3 antibody, Ventana Medical Systems), using a Ventana automated immunostainer. Strong, granular, cytoplasmic staining in tumor cells were taken as positive staining for ALK. The above-mentioned tests for tumour genotyping were done by single-commercial vendor. The radiological response was assessed according to Response Evaluation Criteria in Solid Tumours (version 1.1).

Case 1

In September 2017, a 58-year-old never-smoker male with rheumatic heart disease presented with a 5 months' history of breathlessness. He had no complaints of cough, wheeze, chest pain, or hemoptysis. Chest radiograph showed homogeneous opacity over left middle and lower zones with blunting of costophrenic angle and meniscus sign along with increased cardiothoracic ratio suggestive of pleuropericardial effusion. Echocardiography ruled out any regional wall motion abnormalities. Contrast-enhanced computed tomography (CECT) of thorax showed a soft tissue density lesion in the apicoposterior segment of the left upper lobe with pleural tag (size 15 mm × 17 mm) and enlarged, necrotic right lower paratracheal, bilateral hilar, aortopulmonary and subcarinal lymph nodes, largest measuring 10 mm × 13 mm. The analysis of cell block preparation of pleural fluid showed atypical cells which were diffusely positive for TTF-1, Napsin, and CD15 while negative for WT1 suggestive of metastatic adenocarcinoma, primary from lung (T1N3M1a; Stage IV according to 8th edition lung cancer staging by IASLC). Molecular study showed positivity to both EGFR and ALK mutations. The patient maintained a stable disease (SD) after completion of six cycles of platinum doublet chemotherapy (pemetrexed and carboplatin) following which he was switched to erlotinib 150 mg daily. The patient had SD for almost 7 months when suddenly he succumbed of cerebrovascular accident complicated with sepsis and disseminated intravascular coagulation in August 2018.

Case 2

A 40-year-old male smoker, on 2 months of anti-tubercular therapy for right-sided pleural effusion, presented in November 2017 with persistent right-sided dull aching chest pain unrelieved by analgesics. Serial chest radiographs were suggestive of increasing right-sided pleural effusion. CECT of thorax showed gross right-sided pleural effusion and mediastinal and diaphragmatic pleura nodularity and thickening of >1 cm with sclerosis of 8th and 9th dorsal vertebral body suggestive of metastases. Straw color pleural fluid on analysis turned out to be exudative with adenosine deaminase of 17 U/ml. The pleural fluid was negative for malignant cells on many occasions. Intercostal chest tube was inserted, and pleural fluid was drained out. Bronchoscopic-guided biopsy of mucosal irregularities at right lower lobe opening was positive for TTF-1 and napsin (while negative for WT1) suggestive of adenocarcinoma (Stage IV). The patient was administered four cycles of platinum doublet chemotherapy (pemetrexed and carboplatin). The molecular study showed the presence of EGFR exon 19 deletion mutation within the tumor specimen with concomitant ALK rearrangement. The patient was started with gefitinib (250 mg) daily from March 2018 with good response and has shown no signs of progression at 6 months of follow-up.

Case 3

A 39-year-old never smoker male with a history of 3 months of progressive dyspnea and chest pain presented our outpatient department in December 2017. Chest radiograph showed mass lesion with pleural effusion. CECT of thorax confirmed right upper lobe mass of 6.7 cm × 6.1 cm × 6.8 cm with multiple nodules bilaterally, pleural effusion multiple sclerotic bone metastases in dorsolumbar spine. Bronchoscopic biopsy revealed adenocarcinoma diffusely positive for TTF-1 and napsin (Stage IV). The FFPE tissue was sent for molecular analysis. The molecular study showed positivity to both EGFR (Exon 19 deletion) and ALK rearrangement. The patient had an SD after receiving four cycles of chemotherapy with platinum doublets (pemetrexed and carboplatin). He was switched to gefitinib (250 mg daily) and has shown a partial response (PR) after 6 months of gefitinib.

Case 4

A 69-year-old smoker (40 pack-year) male presented in January 2018 with 6 months' history of progressive breathlessness. A 1 cm × 1 cm chest wall nodule, mobile, and firm in consistency was palpable. Chest radiograph showed features suggestive of massive pleural effusion. Pleural fluid was negative for malignant cells on multiple occasions. In view of rapid accumulation of pleural fluid intercostal chest tube was inserted in the right pleural space. CECT of thorax showed an ill-defined heterogeneously enhancing mass lesion in the right perihilar location with ipsilateral deviation of mediastinum. Enlarged necrotic subcarinal and right paratracheal lymph nodes were also seen. CECT abdomen revealed multiple well-defined hypoenhancing lesions in both lobes of liver, bulky left adrenal, and prominent paraaortic lymph nodes suggestive of metastases. MRI of the brain revealed multiple nodular ring-enhancing lesions suggestive of metastasis. Bone scan showed multifocal skeletal metastases at sternum, left scapula, left shoulder joint, right 10th rib, right iliac bone, right acetabulum, and left proximal femur. The endobronchial biopsy had features of adenocarcinoma, immunopositive for TTF-1 and napsin. Biopsied chest wall nodule evidenced metastatic adenocarcinoma, immunopositive for CK7 and napsin (T4N2M1c stage IV). EGFR (exons 18-21), ALK, and ROS1 mutations were performed on the biopsy specimen demonstrating the classic missense mutation in exon 21 (L858R; base change 2573T>G). Interestingly, it showed strong expression of ALK protein by immunohistochemistry method. Based on the molecular study and poor performance status, he was put on EGFR tyrosine kinase inhibitor (TKI) (Erlotinib 150 mg) daily along with 10 fractions of whole brain radiotherapy, 8 Gy in single fraction to fourth lumbar vertebrae and zoledronic acid. The patient has shown PR after 8 months of EGFR TKI.


 > Results Top


Of 251 patients with NSCLC, 198 had established diagnosis of adenocarcinoma. We investigated the course of the diseases with the efficacy of targeted therapy in EGFR/ALK coaltered adenocarcinomas. EGFR ALK coalterations were found in 4 of 251 (1.6%) NSCLC patients. This incidence was 2% (4/198) in adenocarcinoma patients. Out of EGFR mutations, two of them were mutation positive for exon 19 and other two for exon 21. All the four patients' mutation was detected from initial FFPE sample, 1 from cell block and rest from tissue. All the four patients were negative for ROS1. All were male with advanced stages of lung cancer. In our series, younger patients (with age 39 and 40 years) had exon 19 deletions whereas older ones (with age 58 and 69 years) had exon 21 mutation. Two of them were actively smoking at the time of diagnosis whereas the other two were never-smokers. Three patients had bone metastases at diagnosis. Three patients had received platinum doublet followed by EGFR-TKI and one patient received erlotinib straightaway. No one has received crizotinib yet. None of our patients had shown signs of disease progression after 6 months of EGFR TKI [Table 1].
Table 1: Characteristics of patients with concomitant epidermal growth factor receptor/anaplastic lymphoma kinase alteration

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 > Discussion Top


The discovery of EGFR and ALK molecular alterations has radically changed the clinical history of two specific subgroups of patients (EGFR-mutated and EML4-ALK-rearranged patients). In the 1st year, after its discovery, the presence of ALK rearrangement was described as mutually exclusive.[4],[5] To find relevant data, we searched the MEDLINE database. The following search terms and criteria were used: concomitant EGFR and ALK mutation and lung neoplasm. Search results were filtered to include only English language articles and case reports. With this methodology, we found over 100 cases with the double mutation translocation with varying responses to EGFR/ALK TKI.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33] These observations demonstrated that the concomitant presence of EML4-ALK rearrangements and EGFR mutations albeit rare is not irrelevant. The study done by Yang et al. showed that the frequency of this concomitant driver mutation was 1.3% (13/977) in NSCLCs.[6] Similar to our experience, their study showed that patients with exon 19 deletion were nearly a decade younger (average 53.6 years) than those with exon 21 mutation (average 62.7 years). Of 13 patients in their study 10 had received EGFR TKI as first-line treatment. Of these ten patients, eight (4 erlotinib, 3 gefitinib, and 1 afatinib) achieved PR, one patient had SD with afatinib while other progressed while on being erlotinib. Similar response to EGFR TKIs was observed by Ulivi et al. where 6 of 380 NSCLC patients (1.6%) harboring coalteration were put on EGFR TKI with complete response in one, 3 had PR and 2 had progressive disease (PD).[7] Sasaki et al., Zhang et al. and Xu et al. also experienced similar results with EGFR TKI.[8],[9],[10] However, the same was not evidenced by studies done by Won et al. and Sahnane et al.[11],[12] Won et al. screened 1458 patients with lung cancer. Of these 1445 has NSCLC of which 91 were ALK positive by FISH and 4 were having simultaneous EGFR and ALK mutations. However, their detection rate for EGFR positivity increased to 8, 11, and 14 cases with peptide nucleic acid-clamping RT PCR, targeted next-generation sequencing (NGS), and mutant-enriched NGS assays respectively. Of these 14 patients with concomitant mutations detected by mutant-enriched NGS, three patients were prescribed gefitinib (1 had SD, 2 had PD) and eight patients were given ALK TKI (7 had PR). The rationale behind treating 7 of 8 patients with ALK TKI was the low EGFR tumor burden which could only be detected by highly sensitive assays.[11] Of three patients having this coalteration in Sahnane et al. work, two patients had a better response to crizotinib.[12] Lo Russo et al. did a literature search where they screened 923 papers of which they included 58 in their review analysis and finally selected 33 for qualitative synthesis making a total of 100 cases including their own two patients. Both of their patients were treated with EGFR TKI upfront. One of them did not respond to EGFR TKI but maintained a long SD with ALK TKI (crizotinib) whereas the other achieved a PR with gefitinib and long SD with erlotinib followed by an excellent response to ceritinib.[13] Tang et al. searched the database of Clinical Cytogenetics Laboratory at the University of Texas MD Anderson Cancer Center for cases of lung carcinoma assessed by FISH method for ALK, ROS1, RET, and MET mutations. They could identify 15 cases having more than 1 mutation for ALK, ROS1, RET, and MET. Five of these 15 had EGFR mutation also and of this only 1 was ALK positive who was a female with a PR to EGFR TKI.[14] The cutoffs used for ROS1 and RET FISH tests were low from what is advised in guidelines and other papers; however, the ALK FISH cutoff was consensual in comparison with others.[15] Jakobsen et al. looked for concomitant driver mutations in EGFR-mutated tumor samples from erlotinib-treated patients. They found 36 patients harboring EGFR mutation in 514 NSCLC patients of which 33 had locally advanced or advanced disease and had received first-line erlotinib treatment. Although they could get TP53, CTNNB1, KRAS, MET, and other driver mutations coexisting to surprise none were positive for ALK rearrangement.[16] In a similar study by Mao and Wu, 421 EGFR-mutated patients on EGFR TKIs were examined for ALK and ROS1 mutation. They found 10 cases with concomitant ALK rearrangement and 3 with ROS1. Of 10 patients with coexistent EGFR ALK mutation 5 achieved PR, 3 maintained SD, and 2 had PD while on being EGFR TKI. Three out of 5 patients who were switched to ALK TKI (crizotinib) after ineffective EGFR TKI had obtained PR, while other ones had PD and SD They concluded that although the progression-free survival was longer in patients with single EGFR mutation than those with concomitant mutations no difference was elicited in overall survival.[17] Fan et al. reported a case of multifocal lung adenocarcinomas exhibiting concomitant ALK EGFR mutation who experienced a PD after 3 months of EGFR TKI but showed a PR with 2 months of crizotinib.[18] The dominance of one oncogenic alteration over other could be explained by mutation tumor burden and phosphorylation of single-mutated proteins. Often small biopsies and cytologies represent a small portion of the entire tumor and mutation burden which probably explain the inconsistent response to TKIs. Histologically, NSCLC has been highly heterogeneous. Molecular heterogeneity could be a reflection of morphological heterogeneity or vice versa. Marino et al. screened 509 surgically resected NSCLC cases and selected 105 mixed adenocarcinomas and 17 adenosquamous carcinomas for mutational studies. They got two males with concomitant ALK EGFR mutation. Both showed intratumor heterogeneity of ALK rearrangement while homogeneous expression of EGFR mutations in all patterns.[19],[20] We preferred to give chemotherapy in three of our four patients with good performance status as we did not have tests to quantify the EGFR tumor burden which could guide us the better TKI as in study done by Won et al.[11] Unfortunately, we had excluded the option of crizotinib in all four patients due to cost factor advantages of EGFR-TKI over crizotinib. There is no existing guideline regarding initial treatment choices in such concomitant mutations. None of our patients experienced progression of disease while on being EGFR TKI for at least 6 months. In other words, our patients better responded to first-generation EGFR-TKI.


 > Conclusion Top


In spite of extensive research on molecular therapy in lung cancer, concomitant oncogenic driver mutations have emerged as a big challenge raising queries regarding the optimal treatment approach in these dual mutation patients especially in developing countries where cost factor still remains a big hindrance. The molecular characteristics of these patients are different. The response to EGFR-TKIs or ALK-TKIs is expected to be different from patients with either oncogenic driver. In the target-based therapy, treating one target and sparing the other remains challenges due to the further activation of untreated driver mutation.

In our series, younger patients had exon 19 deletions whereas older ones had exon 21 mutation. With these four reports in a short span of 2 years in a single center the coexistence of EGFR mutations and EML4-ALK rearrangements may be low but is higher than other geographical areas. Since the two alterations may coexist from the beginning of diagnosis, future perspective in management could be finding an agent with the potential of dual inhibition of ALK and EGFR.

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.

Acknowledgment

We would like to thank team of core diagnostics for molecular test confirmations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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