Skip Navigation LinksHome > November 2011 - Volume 6 - Issue 11 > Lung Adenocarcinoma with Concurrent Exon 19 EGFR Mutation an...
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e31822eec5e
Case Report

Lung Adenocarcinoma with Concurrent Exon 19 EGFR Mutation and ALK Rearrangement Responding to Erlotinib

Popat, Sanjay MRCP, PhD*†; Vieira de Araújo, Alexandra MD‡; Min, Toon PhD*; Swansbury, John FRCPath*; Dainton, Melissa BSc*; Wotherspoon, Andrew FRCPath*; Lim, Eric MD, FRCS§; Nicholson, Andrew G. FRCPath†§; O'Brien, Mary E. R. MD, FRCP*

Free Access
Article Outline
Collapse Box

Author Information

*Royal Marsden Hospital, London and Surrey, United Kingdom; †National Heart and Lung Institute, Imperial College London, London, United Kingdom; ‡Portuguese Institute of Oncology, Oporto, Portugal; and §Royal Brompton Hospital, London, United Kingdom.

Disclosure: Sanjay Popat, MRCP, PhD, and Mary E.R. O'Brien, MD, FRCP, have received research funds and honoraria from Roche.

Address for correspondence: Sanjay Popat, Royal Marsden Hospital, London, SW3 6JJ, UK. E-mail:

Sanjay Popat is a recipient of a Clinical Senior Lecturer Award from the Higher Education Funding Council for England.

A 65-year-old Caucasian female never-smoker (<100 lifetime cigarettes) was found to have elevated carcinoembryonic antigen (CEA) after protracted gastrointestinal symptoms and underwent right lower lobectomy with systematic nodal dissection and pleural lavage for an asymptomatic 58-mm moderately differentiated TTF1-positive lung adenocarcinoma with acinar pattern and nodal metastasis (pT2N2M0, stage IIIA). CEA normalized after surgery and she completed four cycles of adjuvant carboplatin and vinorelbine without major toxicities. Nine months after surgery, she developed a new 1.3-cm right upper lobe nodule and right hilar nodes with elevated CEA. Genotyping identified KRAS wild-type and EGFR exon 19 deletion in the primary tumor. She commenced systemic treatment with erlotinib at 150 mg daily and continued on this for 25 months with normalized CEA levels and a complete metabolic response on positron emission tomography-computed tomography (Figure 1). ALK rearrangement tested by fluorescence in situ hybridization (FISH) using the commercially available break-apart probe set (Abbott Molecular, Des Plaines, IL) demonstrated loss of the ALK 5′ (centromeric) probe (Figure 2A). ALK immunohistochemistry (clone ALK1, Dako UK Ltd, DM828) was negative (Figure 2B).

Figure 1
Figure 1
Image Tools
Figure 2
Figure 2
Image Tools
Back to Top | Article Outline


Four previous cases have been described of lung adenocarcinomas with concurrent EGFR mutation and ALK translocation. Two are described in series for prevalence analysis with scarce clinical information.1,2 The remaining two are case reports detailing a 72-year-old East Asian woman (with adenocarcinoma treated with first-line gefitinib for 232 days with an initial excellent response, before progression),3 and a 48-year-old Caucasian man (mixed adenosquamous carcinoma treated with second-line erlotinib for 2 months, before dying from disease progression).4 All had classical ALK translocations with probe break-apart. In all cases, the EGFR mutation was an exon 19 deletion.

ALK rearrangement is considered a potential resistance mechanism to EGFR-tyrosine kinase inhibitors (TKIs)1 and is thought to occur mutually exclusively to other somatic mutations. Of the three patients (including our own) harboring simultaneous EGFR and ALK molecular aberration in which outcome data are reported, one was refractory to EGFR-TKI treatment but had mixed squamous/adenocarcinoma histology,4 while the other two (both older and female) demonstrated very good responses. To our knowledge, our patient presents the most durable response to an EGFR-TKI in this setting and is the first such case with an ALK rearrangement characterized by an isolated 3′ FISH signal. In addition, this case demonstrates no ALK expression by immunohistochemistry. Whether this is due to aberrant expression due to ALK 5′ loss or another mechanism such as variability in expression detection due to differences in antibody clone used5 remains unclear.

Concurrent EGFR mutation and ALK rearrangement remain rare. However, future larger planned collaborative group studies will inform better on clinical and molecular demographics of ALK rearrangement. Our case suggests that EGFR mutation when concordant with ALK rearrangement retains TKI sensitivity and that a common molecular event may underpin both exon 19 EGFR deletion and ALK rearrangement.

Back to Top | Article Outline


Sanjay Popat, MRCP, PhD, Toon Min, PhD, John Swansbury, FRCPath, Melissa Dainton, BSc, and Andrew Wotherspoon, FRCPath, acknowledge NHS funding to the Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre.

Back to Top | Article Outline


1. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14:4275–4283.

2. Zhang X, Zhang S, Yang X, 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.

3. Kuo YW, Wu SG, Ho CC, et al. Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol 2010;5:2039–2040.

4. Tiseo M, Gelsomino F, Boggiani D, et al. EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 2011;71:241–243.

5. Camidge DR, Hirsch FR, Varella-Garcia M, et al. Finding ALK-positive lung cancer: what are we really looking for? J Thorac Oncol 2011;6:411–413.

Cited By:

This article has been cited 8 time(s).

Biomedical Papers-Olomouc
Non-small cell lung cancer - genetic predictors
Koudelakova, V; Kneblova, M; Trojanec, R; Drabek, J; Hajduch, M
Biomedical Papers-Olomouc, 157(2): 125-136.
Clinical Cancer Research
ALK Rearrangements Are Mutually Exclusive with Mutations in EGFR or KRAS: An Analysis of 1,683 Patients with Non-Small Cell Lung Cancer
Gainor, JF; Varghese, AM; Ou, SHI; Kabraji, S; Awad, MM; Katayama, R; Pawlak, A; Mino-Kenudson, M; Yeap, BY; Riely, GJ; Iafrate, AJ; Arcila, ME; Ladanyi, M; Engelman, JA; Dias-Santagata, D; Shaw, AT
Clinical Cancer Research, 19(): 4273-4281.
Bmc Cancer
A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene
Tanaka, H; Hayashi, A; Morimoto, T; Taima, K; Tanaka, Y; Shimada, M; Kurose, A; Takanashi, S; Okumura, K
Bmc Cancer, 12(): -.
ARTN 558
Bmc Cancer
Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4-ALK-rearranged non-small-cell lung cancer harbored coexisting EGFR mutation
Miyanaga, A; Shimizu, K; Noro, R; Seike, M; Kitamura, K; Kosaihira, S; Minegishi, Y; Shukuya, T; Yoshimura, A; Kawamoto, M; Tsuchiya, S; Hagiwara, K; Soda, M; Takeuchi, K; Yamamoto, N; Mano, H; Ishikawa, Y; Gemma, A
Bmc Cancer, 13(): -.
ARTN 262
Lung Cancer
Coexistence of EGFR mutation and ALK translocation in NSCLC: Literature review and case report of response to gefitinib
Santelmo, C; Ravaioli, A; Barzotti, E; Papi, M; Poggi, B; Drudi, F; Mangianti, M; Salvi, M; Crino, L
Lung Cancer, 81(2): 294-296.
Lung Cancer
A case of lung adenocarcinoma harboring exon 19 EGFR deletion and EML4-ALK fusion gene
Chen, XX; Zhang, J; Hu, Q; Li, XF; Zhou, CC
Lung Cancer, 81(2): 308-310.
Expert Review of Anticancer Therapy
Anaplastic lymphoma kinase: a glimmer of hope in lung cancer treatment?
Franco, R; Rocco, G; Marino, FZ; Pirozzi, G; Normanno, N; Morabito, A; Sperlongano, P; Stiuso, P; Luce, A; Botti, G; Caraglia, M
Expert Review of Anticancer Therapy, 13(4): 407-420.
Expert Opinion on Pharmacotherapy
PROFILing non-small-cell lung cancer patients for treatment with crizotinib according to anaplastic lymphoma kinase abnormalities: translating science into medicine
Pilotto, S; Peretti, U; Novello, S; Rossi, G; Milella, M; Levra, MG; Ciuffreda, L; Massari, F; Brunelli, M; Tortora, G; Bria, E
Expert Opinion on Pharmacotherapy, 14(5): 597-608.
Back to Top | Article Outline

© 2011International Association for the Study of Lung Cancer


Article Tools



Other Ways to Connect



Visit on your smartphone. Scan this code (QR reader app required) with your phone and be taken directly to the site.

 For additional oncology content, visit LWW Oncology Journals on Facebook.