Surgical resection of locally advanced epidermal growth factor receptor (EGFR) mutated lung adenocarcinoma after gefitinib and review of the literature

Abstract

Gefitinib is the current first-line treatment for advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutations. The possibility of using gefitinib as neoadjuvant therapy is interesting because of the low toxicity profile of tyrosine kinase inhibitors. Here we report the case of a 67-year-old nonsmoking woman affected by locally advanced lung adenocarcinoma, in whom one-year treatment with gefitinib rendered the tumor amenable to surgical removal. The results of ongoing clinical trials exploring the ability of preoperative gefitinib to achieve better results than can be obtained with chemotherapy in patients selected on the basis of EGFR mutations are urgently awaited.

Full text

Key words: EGFR gene mutation,
gefitinib, neoadjuvant therapy,
NSCLC.
Correspondence to: Dr Vito Lorusso,
UO Oncologia Medica, Istituto Onco-
logico IRCCS, Via Orazio Flacco 65,
70124 Bari, Italy.
Tel +39-080-5555111;
fax +39-080-5555444;
email vitolorusso@me.com
Received October 15, 2012;
accepted December 4, 2012.
Surgical resection of locally advanced epidermal
growth factor receptor (EGFR) mutated lung
adenocarcinoma after gefitinib and review of the
literature
Ilaria Marech1, Angelo Vacca2, Antonio Gnoni3, Nicola Silvestris1,
and Vito Lorusso1
1National Cancer Center – Istituto Tumori Giovanni Paolo II, IRCCS, Bari; 2Department of Internal
Medicine and Clinical Oncology, University of Bari Medical School, Bari; 3Medical Oncology Unit,
Vito Fazzi Hospital, Lecce, Italy
ABSTRACT
Gefitinib is the current first-line treatment for advanced lung adenocarcinoma with
epidermal growth factor receptor (EGFR) gene mutations. The possibility of using
gefitinib as neoadjuvant therapy is interesting because of the low toxicity profile of ty-
rosine kinase inhibitors. Here we report the case of a 67-year-old nonsmoking woman
affected by locally advanced lung adenocarcinoma, in whom one-year treatment with
gefitinib rendered the tumor amenable to surgical removal. The results of ongoing
clinical trials exploring the ability of preoperative gefitinib to achieve better results
than can be obtained with chemotherapy in patients selected on the basis of EGFR
mutations are urgently awaited.
Introduction
Gefitinib is currently the treatment of choice for advanced lung adenocarcinoma
with mutations of the epidermal growth factor receptor (EGFR) gene within exons 19
and 211-3. EGFR mutations are known to correlate with more favorable clinical pa-
rameters, as does female gender, a nonsmoking status, adenocarcinoma histology,
and Asian ethnicity4.
The potential advantages of neoadjuvant chemotherapy of locally advanced NSCLC
include early treatment of distant micrometastases and downstaging of the tumor5.
However, such treatment is often associated with increased preoperative morbidity
and mortality6,7. In this setting, gefitinib and other tyrosine kinase inhibitors (TKIs) in
patients with activating mutations in the EGFR kinase domain could be used as an al-
ternative to chemotherapy because of their higher activity and better toxicity profile.
Here we report the case of a patient diagnosed with locally advanced lung adeno-
carcinoma rendered amenable to surgery after treatment with gefitinib.
Case report
A 67-year-old nonsmoking woman with idiopathic hypertension and type 2 dia-
betes presented in July 2010 with dyspnea, dry cough and chest pain. Chest x-ray ev-
idenced thickening in the median lobe of the right lung. The patient was admitted to
our department and on 25 July 2010 a computed tomography (CT) scan of the chest
showed 2 nodules in the right upper lobe and 1 in the right lower lobe, measuring 2.4,
2.2 and 1.8 cm, respectively; no pleural effusion or invasion of mediastinal lymph
nodes was noted. Bronchoscopy and BAL were not diagnostic. PET/CT scan was not
performed before surgery because the multidisciplinary group discussing the case
considered the patient not amenable to radical surgery given the multiple tumor nod-
Tumori, 99: e241-e244, 2013

e242 I MARECH, A VACCA, A GNONI ET AL
ules. On 20 August 2010, in order to obtain histological
proof of neoplasia, double trans-segmental resection of
the right inferior apical lobe segment and right superior
anterior lobe segment was performed. Histological ex-
amination revealed moderately differentiated infiltrat-
ing lung adenocarcinoma with a peripheral bronchi-
oloalveolar pattern and initial intravascular infiltration
in both areas. Mediastinal lymphadenectomy was not
performed during this intervention because of its only
diagnostic intent.
Direct sequencing and real-time PCR-based ap-
proaches were employed to assess the mutational status
of EGFR in the specimens. EGFR mutation analysis in
exons 18, 19 and 21 showed a specific mutation in exon
19 (E746-A750del). Macro-dissection of the tumor from
the paraffin block was performed to enrich the final
amount of tumor DNA and eliminate the nonmutated
DNA from nonneoplastic cells in order to avoid compe-
tition in the amplification of the final PCR product. In
addition, pyrosequencing analysis, which was also per-
formed to detect the presence of resistance mutations
such as T790M, showed an activating point mutation at
L861Q in exon 21.
PET/CT scan performed 1 month after surgery
showed a pathological increase in 18F-FDG uptake in the
posterior segment of the right upper lobe lesion (SUV
max 9.5) adherent to the pleura (Figure 1) and uptakes
in the lower right lobe and ipsilateral mediastinal lymph
nodes (SUV max 4.1 and 3.5, respectively). Serum bio-
chemistry revealed a slightly elevated level of carci-
noembryonic antigen (CEA) (18.4 ng/mL).
The patient was considered to be in stage IIIB
(T4N2M0) and treatment with gefitinib at a dose of 250
mg per day was started on 5 October 2010. Clinical
symptoms such as breathlessness and chest pain were
significantly reduced within 2 weeks. The only side ef-
fect experienced by the patient in the first 2 months of
treatment was a single episode of facial rash. No other
side effects were reported.
PET/CT scans on 20 December 2010 showed a signifi-
cant reduction in 18F-FDG uptake (SUV max 2.2 versus
previous 9.5) from the posterior segment of the right
upper lobe and no uptake from either the second lesion
in the lower lobe or the mediastinal lymph nodes (Fig-
ure 2).
PET/CT scans were performed again in March and
October 2011 and showed further reduction in the up-
take from the right upper lobe lesion (SUV max 1.9 and
1.2, respectively, versus initial 2.2) (Figure 3). Moreover,
serum CEA had decreased to 6.3 ng/mL.
Treatment with gefitinib was continued until Novem-
ber 2011, when the patient urgently requested surgery
and underwent excision of the upper lobe of the right
lung and lymphadenectomy of the 7th, 10th and 11th me-
diastinal stations. Histopathological examination con-
firmed the presence of a single lesion of 1.5 cm in diam-
eter showing a pattern of moderately differentiated ade-
nocarcinoma. The 5 resected lymph nodes were nega-
tive.
After surgery the patient remained free of gefitinib
therapy. In February 2012 and June 2012 2 PET/CT scans
demonstrated the absence of disease. At the time of
writing, she was alive and well.
Discussion
Gefitinib is an orally bioavailable, synthetic anilino-
quinazoline that selectively and reversibly binds the in-
tracellular ATP-binding site of the EGFR tyrosine kinase.
Several randomized clinical trials have shown its effica-
cy as first-line treatment in patients with tumors har-
Figure 1 - PET/CT performed on 21 September 2010 showing in-
creased metabolic activity in the posterior segment of the right up-
per lobe lesion (SUV max 9.5) adherent to the pleura.
Figure 2 - PET/CT performed on 20 December 2010: initial 18F-FDG
uptake reduction (SUV max 2.2) in the posterior segment of the right
upper lobe lesion.

Figure 3 - PET/CT scans performed in March (A) and October (B) 2011 showing further reduction in the uptake from the right upper lobe le-
sion (SUV max 1.9 and 1.2, respectively).
PREOPERATIVE GEFITINIB FOR LUNG ADENOCARCINOMA e243
boring EGFR gene mutations1. The IPASS study and the
First-SIGNAL study were undertaken in Asian patients
selected on the basis of clinical factors8,9. The WJTOG
3405 study and the NEJ002 study were undertaken in
patients with activating mutations in the EGFR gene10,11.
These trials have confirmed a significant increase in
progression-free survival when patients with EGFR-mu-
tated advanced NSCLC were treated with gefitinib com-
pared to platinum-based chemotherapy. Treatment
with gefitinib was also associated with evidence of a
high objective response rate, better quality of life, and
more favorable toxicity profile8. Trials evaluating the ef-
ficacy and tolerability of gefitinib – either as neoadju-
vant therapy or in combination with radiotherapy – in
patients with locally advanced NSCLC and EGFR muta-
tions are still ongoing and thus its preoperative efficacy
remains to be established12,13. Only a few cases of surgi-
cal resection of residual disease after treatment with
gefitinib have been reported. Takamochi et al.14 de-
scribed 2 cases of surgical resection of residual disease
after gefitinib treatment in patients with initially large
N2 disease who failed to respond to conventional
chemotherapy. Liu et al.15 reported a case of bilateral
NSCLC with mediastinal involvement which, after 1
month of treatment with gefitinib, showed absence of
metabolic activity in the left lung nodule and mediasti-
nal lymph nodes at PET/CT scan. The patient was then
successfully treated with surgery.
In this paper we report the case of a patient with ini-
tially locally advanced adenocarcinoma of the lung. Af-
ter 1 year of treatment with gefitinib, PET/CT scan
showed a reduction of the NSCLC to a single nodule in
the right lung, which led the patient to undergo suc-
cessful surgical treatment.
It is noteworthy that in our case we found 2 activating
mutations: E746-A750 deletion in exon 19 and L861Q
mutation in exon 21. In the literature, the rates of E746-
A750 deletion and L861Q mutation are 24-44% and 3%,
respectively16-18. In this regard, Yamamoto et al.19 re-
ported that not all EGFR activating mutations are equal,
and that exon 19 and 21 mutations are the most likely to
predict response: 81% and 71%, respectively. Moreover,
Ong et al.20 in a recent case report showed that a female
patient with locally advanced papillary adenocarcino-
ma of the lung, not candidable to chemoradiation be-
cause of a poor performance status but carrying the
L861Q mutation, successfully underwent surgery after 3
months of therapy with erlotinib, another TKI20.
In conclusion, as our knowledge of the mechanism of
action of TKIs in adenocarcinoma of the lung improves,
it has been definitely established that the presence of an
activating mutation of the EGFR gene is a prerequisite
for obtaining a clinical response. The possibility to use
these drugs in the neoadjuvant setting for patients har-
boring EGFR mutations is an intriguing field of research
that warrants further investigation, and studies are al-
ready ongoing. The aim of these studies will be not only
to demonstrate the feasibility of this neoadjuvant ap-
proach, but also to define the optimal timing and dura-
tion of gefitinib in the neoadjuvant setting.
References
Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J,1.
Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L,
Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ,
Strawn JR, Trent D, Giaccone G: American Society of Clini-
cal Oncology clinical practice guideline update on chemo-
therapy for stage IV non-small-cell lung cancer. J Clin On-
col, 27: 6251-6266, 2009.
Hammerman PS, Janne PA, Johnson BE: Resistance to2.
EGFR TKIs in NSCLC. Clin Cancer Res, 15: 7502-7509,
2009.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M,3.
Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisa-
AB

wa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF: Clini-
cal and biological features associated with epidermal
growth factor receptor gene mutations in lung cancers. J
Natl Cancer Inst, 97: 339-346, 2005.
Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA,4.
Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Ia-
cona RB, Krebs AD, Johnson DH, Giaccone G, Herbst RS,
Manegold C, Fukuoka M, Kris MG, Baselga J, Ochs JS, Ha-
ber DA: Epidermal growth factor receptor mutations and
gene amplification in non small cell lung cancer: molecu-
lar analysis of IDEAL/INTACT gefitinib trials. J Clin Oncol,
23: 8081-8092, 2005.
Depierre A, Westeel V, Jacoulet P: Preoperative chemothe-5.
rapy for non small cell lung cancer. Cancer Treat Rev, 27:
119-127, 2001.
Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E,6.
Lebeau B, Braun D, Breton JL, Lemarié E, Gouva S, Paillot
N, Bréchot JM, Janicot H, Lebas FX, Terrioux P, Clavier J,
Foucher P, Monchâtre M, Coëtmeur D, Level MC, Leclerc P,
Blanchon F, Rodier JM, Thiberville L, Villeneuve A, Westeel
V, Chastang C; French Thoracic Cooperative Group: Preo-
perative chemotherapy followed by surgery compared
with primary surgery in resectable stage I (except T1N0),
II, and IIIa non small cell lung cancer. J Clin Oncol, 20: 247-
253, 2002.
Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L,7.
Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger
M, Visseren-Grul C, Torri V: Randomized phase III study of
surgery alone or surgery plus preoperative cisplatin and
gemcitabine in stages IB to IIIA non-small-cell lung can-
cer. J Clin Oncol, 2: 172-178, 2012.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N,8.
Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwa-
ki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL,
Watkins CL, Armour AA, Fukuoka M: Gefitinib or carbo-
platin-paclitaxel in pulmonary adenocarcinoma. New
Engl J Med, 361: 947-957, 2009.
Lee JS, Park K, Kim SW: A randomized phase III study of9.
gefitinib (IRESSA) versus standard chemotherapy (gemci-
tabine plus cisplatin) as a first-line treatment for never-
smokers with advanced or metastatic adenocarcinoma of
the lung. In: Proceedings of the World Conference on Lung
Cancer 2009; abstract no. PRS.4.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsu-10.
rutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K,
Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S,
Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M;
West Japan Oncology Group: Gefitinib versus cisplatin
plus docetaxel in patients with non-small-cell lung cancer
harbouring mutations of the epidermal growth factor re-
ceptor ( WJTOG3405): an open label, randomised phase 3
trial. Lancet Oncol, 11: 121-128, 2010.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi11.
S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I,
Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogu-
ra T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K,
Morita S, Nukiwa T; North-East Japan Study Group: Gefiti-
nib or chemotherapy for non-small-cell lung cancer with
mutated EGFR. New Engl J Med, 362: 2380-2388, 2010.
Epidermal growth factor receptor (EGFR) status based ge-12.
fitinib neoadjuvant therapy in non small cell lung cancer
(NSCLC). ClinicalTrials.gov Identifier: NCT00986284.
Phase 2 study of neoadjuvant IRESSA treatment in stage 113.
NSCLC. ClinicalTrials.gov Identifier: NCT00188617.
Takamochi K, Suzuki K, Sugimura H, Funai K, Mori H, Ba-14.
shar AH, Kazui T: Surgical resection after gefitinib treat-
ment in patients with lung adenocarcinoma harboring
epidermal growth factor receptor gene mutation. Lung
Cancer, 58: 149-155, 2007.
Liu M, Jiang G, He W, Zhang P, Song N: Surgical resection of15.
locally advanced pulmonary adenocarcinoma after gefiti-
nib therapy. Ann Thorac Surg, 92: 11-12, 2011.
Shigematsu H, Gazdar AF: Somatic mutations of epider-16.
mal growth factor receptor signalling pathway in lung can-
cers. Int J Cancer, 118: 257-262, 2006.
Murray S, Dahabreh IJ, Linardou H, Manoloukos M, Bafa-17.
loukos D, Kosmidis P: Somatic mutations of the tyrosine
kinase domain of epidermal growth factor receptor and ty-
rosine kinase inhibitor response to TKIs in non-small cell
lung cancer: an analytical database. J Thorac Oncol, 3: 832-
839, 2008.
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jan-18.
ne PA, Joshi VA, McCollum D, Evans TL, Muzikansky A, Ku-
hlmann GL, Moon H, Goldberg JS, Settleman J, Iafrate AJ,
Haber DA, Johnson BE, Lynch TJ: First-line gefitinib in pa-
tients with advanced non-small-cell lung cancer harboring
somatic EGFR mutations. J Clin Oncol, 26: 2442-2449, 2008.
Yamamoto H, Toyooka S, Mitsudomi T: Impact of EGFR19.
mutation analysis in non-small cell lung cancer. Lung
Cancer, 63: 315-321, 2009.
Ong M, Kwan K, Kamel-Reid S, Vincent M: Neoadjuvant er-20.
lotinib and surgical resection of a stage IIIa papillary ade-
nocarcinoma of the lung with an L861Q activating EGFR
mutation. Curr Oncol, 19: e22-26, 2012.
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