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Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 119-120

Coexistence of epidermal growth factor receptor mutation and anaplastic lymphoma kinase translocation in non-small cell lung cancer: Do we know the treatment sequence?

1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radio diagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication9-Sep-2019

Correspondence Address:
Vanita Noronha
HBB 304, 3rd Floor, Tata Memorial Hospital, Mumbai, - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_26_19

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How to cite this article:
Talreja VT, Noronha V, Joshi A, Patil V, Mahajan A, Prabhash K. Coexistence of epidermal growth factor receptor mutation and anaplastic lymphoma kinase translocation in non-small cell lung cancer: Do we know the treatment sequence?. Cancer Res Stat Treat 2019;2:119-20

How to cite this URL:
Talreja VT, Noronha V, Joshi A, Patil V, Mahajan A, Prabhash K. Coexistence of epidermal growth factor receptor mutation and anaplastic lymphoma kinase translocation in non-small cell lung cancer: Do we know the treatment sequence?. Cancer Res Stat Treat [serial online] 2019 [cited 2021 Feb 28];2:119-20. Available from: https://www.crstonline.com/text.asp?2019/2/1/119/266448

Gainor et al. tested epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase, (ALK), and KRAS in 1683 non-small cell lung cancer (NSCLC) patients and found that no patient had both EGFR and ALK mutations.[1] However, as the depth and breadth of genetic testing increase, the incidence of two or more genetic alterations increases significantly. The Lung Cancer Mutation Consortium tested 1007 lung adenocarcinoma specimens for at least one genomic alteration. They reported that the incidence of two or more gene mutations was as high as 3%, including three cases of ALK and EGFR double-mutations, resulting in an incidence of double EGFR/ ALK mutations of 0.3%.[2] More recent reports have placed the incidence of dual EGFR/ ALK mutations higher at 1.3%[3] to as high as 15.4%.[4] Treatment options for these mutations are known separately at present.

We report the case of a 55-year-old hypertensive non-smoker female patient with a left axillary mass diagnosed to have metastatic adenocarcinoma lung from a biopsy of the axillary node which was positive for CK7, TTF-1, and napsin A. Subsequently, the tumor cells were positive for ALK-1 amplification on immunohistochemistry by D5F3 Ventana antibody clone and fluorescent in situ hybridization. Positron emission tomography confirmed primary lung cancer with thyroid and axillary node metastases. Her serum tumor markers were within normal range; carcinoembryonic antigen test (CEA) was 1 ng/ml, serum CA-15.3 was 21.8 U/ml, serum thyroglobulin level was 0.75 U/ml, serum CA-125 was 10.2 U/ml, and serum CA-19.9 was 8.35 U/ml. TaqMan probe-based endpoint genotyping mutation analysis by real-time polymerase chain reaction on the LC 480 II platform was positive for exon 19 EGFR deletion. She was started on crizotinib 250 mg orally twice daily, and her response assessment suggested stable disease with an ill-defined left infrahilar paramediastinal lesion which measured 2.9 cm × 1.9 cm as compared to the previous size of 3.2 cm × 2.4 cm. She has a sustained response which is persisting for 12 months at the time of writing of this article [Figure 1].
Figure 1: Ill-defined soft tissue mass noted in the lower lobe of the left lung (a and c) which post crizotinib suggests a decrease in the size of the mass (b and d)

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The demographic characteristics of the patients with dual EGFR/ ALK mutations are broadly similar to those of patients with individual mutations, i.e., there is a prevalence of women, Asians, and never-smokers.[5] Patients with dual EGFR/ ALK mutations may have a more aggressive clinical course, with an increased propensity to early metastases and a higher incidence of brain metastases.[5],[6] These dual-mutated patients have a worse prognosis; Lou et al. reported median survival times of 18.5, 21.3, and 23.7 months (P = 0.06) in 11 double-mutations, 84 EGFR mutations, and 23 ALK-positive patients, respectively, suggesting that the survival time of the double-mutation patients was the shortest. There was a statistically significant difference in the median overall survival of patients with ALK mutation compared to those with dual EGFR/ ALK mutation, hazard ratio (HR), 0.43; 95% confidence interval (CI), 0.2–0.93; P= 0.03; while there was no significant difference in the overall survival between patients with EGFR mutations and EGFR/ ALK dual-mutations, HR, 0.71; 95% CI, 0.37–1.35; P= 0.29.[7] Sweis et al.[6] reported that patients with dual-mutations have poor response to first-line platinum-based chemotherapy. Baldi et al.,[8] Sweis et al.,[6] and Kadabur et al.[9] had reported that response to the first-line EGFR tyrosine kinase inhibitor (TKI) is poor and that patients have a better outcome with ALK-directed therapy. In the case report by Galetta et al.,[3] the patient had no response to ALK-directed therapy when used in the third-line setting, after first-line chemotherapy and second-line EGFR oral TKI, whereas Baldi et al.[8] reported a sustained response to an ALK-inhibitor in the third line. Conversely, a case series by Shin et al.[10] reported that therapy with an EGFR TKI may be more efficacious that ALK inhibitors in patients with dual-mutations. Thus, the data in the literature are conflicting. Lo Russo et al. in a study comprising 100 patients with dual EGFR and ALK mutations recommended that ALK TKI may be a reasonable choice for the first-line therapy.[5] Data on the use of concomitant EGFR and ALK-inhibitor therapy are not available, and toxicity may be an issue.

Due to the rarity of this condition, it would be difficult to conduct a randomized study. These case reports provide unique insight into the behavior and outcome of these patients and emphasize the importance of testing patients with NSCLC for all actionable mutations.

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.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Gainor JF, Varghese AM, Ou SH, Kabraji S, Awad MM, Katayama R, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: An analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013;19:4273-81.  Back to cited text no. 1
Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006.  Back to cited text no. 2
Galetta D, Catino A, Misino A. Concomitant EGFR mutations/ALK rearrangements: Beyond a simple dual target. Transl Lung Cancer Res 2016;5:143-4.  Back to cited text no. 3
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. 4
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.  Back to cited text no. 5
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. 6
Lou NN, Zhang XC, Chen HJ, Zhou Q, Yan LX, Xie Z, et al. Clinical outcomes of advanced non-small-cell lung cancer patients with EGFR mutation, ALK rearrangement and EGFR/ALK co-alterations. Oncotarget 2016;7:65185-95.  Back to cited text no. 7
Baldi L, Mengoli MC, Bisagni A, Banzi MC, Boni C, Rossi G, et al. Concomitant EGFR mutation and ALK rearrangement in lung adenocarcinoma is more frequent than expected: Report of a case and review of the literature with demonstration of genes alteration into the same tumor cells. Lung Cancer 2014;86:291-5.  Back to cited text no. 8
Kadabur L, Koppaka D, Kanakasetty GB, Usha A, Kuntegowdanahalli LC, Dasappa L, et al. 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.  Back to cited text no. 9
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Shin HJ, Kho BG, Kim MS, Park HY, Kim TO, Kim YI, et al. Co-alteration of EGFR mutation and ALK rearrangement in non-small cell lung cancer: Case series. Medicine (Baltimore) 2019;98:e14699.  Back to cited text no. 10


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