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CASE REPORT
A Patient With BRAF V600E Lung Adenocarcinoma
Responding to Vemurafenib
Oliver Gautschi, MD,* Chantal Pauli, MD,† Klaus Strobel, MD,‡ Astrid Hirschmann,†
Gert Printzen, MD,§ Stefan Aebi, MD,* and Joachim Diebold, MD†
V
emurafenib is active against metastatic melanoma with
BRAF V600E mutation.1,2 BRAF mutations were reported
in 3% to 5% of non–small-cell lung cancers (NSCLC) by the
US Lung Cancer Mutation Consortium and by Italian investigators.3,4 In vitro, MEK inhibition in lung cancer cell lines with
V600E induced apoptosis, but clinical experience with drugs
targeting the RAS/RAF/MEK pathway in ­V600E-NSCLC is
limited.5
CASE REPORT
An 80-year-old man was admitted to our hospital with
a history of shortness of breath and hoarseness. He was a former smoker and received torasemide (a diuretic) for hypertensive heart disease. Computed tomography (CT) scan showed a
central tumor in the left lung, mediastinal lymph node metastases, and left pleural effusion (Fig. 1A). Drainage of pleural
and pericardial effusion was performed, followed by pericardial instillation of bleomycin and talc slurry of the left pleura.
Cytology revealed thyroid transcription factor-1 positive cancer cells, consistent with the diagnosis of NSCLC stage M1a
(Fig. 2A). Polymerase chain reaction and direct sequencing
showed BRAF V600E mutation (Fig. 2B). Sequencing of epidermal growth factor receptor exon 18 to 21, KRAS exon 2,
and human epidermal growth factor receptor 2 exon 19 to 20
was negative. Anaplastic lymphoma kinase fluorescence in situ
hybridization was also negative. The performance status was 4,
the prognosis was very poor, chemotherapy was not recommended, and the patient was ineligible for a clinical trial with
an MEK inhibitor. After exclusion of contraindications, the
patient was offered vemurafenib off-label use. Pretreatment
fluorodeoxyglucose–positron emission tomography/CT was
performed (Fig. 1B), vemurafenib was initiated at the regular dose of 960 mg bid, and the patient left the hospital in a
stable condition supported by family and professional home
care. After 1 week of vemurafenib, his clinical and laboratory parameters were stable, and he decided to continue.
Departments of *Medicine, †Pathology , ‡Nuclear Medicine, and §Laboratory
Medicine, Luzerner Kantonsspital, Luzern, Switzerland.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Oliver Gautschi, MD, Medical Oncology,
Luzerner Kantonsspital, 6000 Luzern, Switzerland. E-mail: oliver.
[email protected]
Copyright © 2012 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/12/0710-e23
FIGURE 1. A, CT scan at diagnosis with a tumor in the left
lung (long arrow), mediastinal lymph node metastases (short
arrow), left pleural effusion (arrowheads), and pericardial
effusion; (B) pretreatment FDG-PET/CT with increased FDG
uptake (SUV max. 13.3) in the lung tumor (long arrow) and
the mediastinal nodes (SUV max. 15.0, short arrow), and
pleural effusion (arrowheads); and (C ) follow-up FDG-PET/
CT after 2 weeks of vemurafenib with decreased uptake in the
lung tumor (SUV max. 5.5, long arrow) and in the mediastinal
nodes (SUV max. 6.2, short arrow). CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography; SUV max., maximum standardized uptake value.
Journal of Thoracic Oncology • Volume 7, Number 10, October 2012
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Gautschi et al.
Journal of Thoracic Oncology • Volume 7, Number 10, October 2012
FIGURE 2. A, Diagnostic cytology with thyroid transcription factor-1–positive cancer cells and (B) Sanger sequencing read with
heterozygous T-A mutation (arrow) in codon 600 of BRAF. C Autopsy with macroscopic appearance of tumor fibrosis in the left
lung (arrow) and (D) representative histopathology section with residual tumor cell islet (arrow) surrounded by fibrotic tissue
(arrowheads), consistent with significant tumor regression after vemurafenib therapy.
After 2 weeks, follow-up fluorodeoxyglucose–positron
emission tomography/CT showed good metabolic response
(Fig. 1C). The condition of the patient was stable, and he
remained on treatment. Three days later, he was admitted to
the emergency room with worsening of dyspnoe, and clinical
examination revealed progressive bilateral pleural effusions.
Vemurafenib was stopped, the patient received terminal care,
and died. Autopsy showed massive bilateral pleural effusions,
global heart dilatation, and severe biventricular hypertrophy.
Cytology showed near complete absence of cancer cells in
pleural fluid, and histology showed massive tumor regression
with fibrosis and few residual cancer cell islets (Fig. 2C, D).
N-terminal B-type natriuretic peptide in archived pretreatment serum was 1880 pg/ml, consistent with chronic cardiac
failure. To the best of our knowledge, this is the first report
of a patient with V600E-NSCLC responding to vemurafenib.
Unfortunately, the patient did not obtain clinical benefit
because he died from a comorbidity without evidence of drug
toxicity. We hope that this report may encourage further study
on vemurafenib in V600E-NSCLC.
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ACKNOWLEDGMENTS
We thank the patient for consenting before his death to
release medical information and images. We thank Drs. Schwizer,
Schlaepfer, and Allelein from our institution for collaboration, and
Dr. Juerg Aebi from Roche Switzerland for providing vemurafenib.
REFERENCES
1. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant
advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:
707–714.
2.Chapman PB, Hauschild A, Robert C, et al.; BRIM-3 Study Group.
Improved survival with vemurafenib in melanoma with BRAF V600E
mutation. N Engl J Med 2011;364:2507–2516.
3.Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver
mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin
Oncol 2011;29 (Suppl): abstr CRA7506.
4. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome
of patients with non-small-cell lung cancer harboring BRAF mutations.
J Clin Oncol 2011;29:3574–3579.
5.Pratilas CA, Hanrahan AJ, Halilovic E, et al. Genetic predictors of MEK
dependence in non-small cell lung cancer. Cancer Res 2008;68:9375–9383.
Copyright © 2012 by the International Association for the Study of Lung Cancer