Journal of Thoracic Oncology:
Departments of *Medical Oncology, †Pathology, and ‡Nuclear Medicine, Cantonal Hospital, Luzern, Switzerland.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Oliver Gautschi, MD, Medizinische Onkologie, Kantonsspital Luzern, 6000 Luzern, Switzerland. E-mail: firstname.lastname@example.org
Vandetanib, an inhibitor of rearranged during transfection (RET) vascular endothelial growth factor, and EGFR tyrosine kinases, is approved in some countries for the treatment of metastatic medullary thyroid cancer,1 which in many cases harbors RET mutations. Translocations resulting in RET fusion with KIF5B, CCDC6, or NCOA4 were recently discovered in approximately 2% of lung adenocarcinomas, and are associated with younger age (<60 years), never-smoking status and small primary tumors (<3 cm), and N2 disease.2,3 Preclinical studies demonstrated that cell lines with RET fusion had transforming capacity, and enhanced sensitivity to vandetanib and other RET inhibitors.3,4
In 2009, a 58-year-old white man was admitted to our hospital with portal vein thrombosis and an 18-mm nodule in the upper lobe of the left lung, which was evident on chest computed tomography (CT). He had a family history of thromboembolism, was a former smoker (5 pack-years until 1996), and had been exposed to polycyclic aromatic hydrocarbons as a road worker. Surgical staging revealed poorly differentiated adenocarcinoma of the lung (Fig. 1A and B) with involvement of ipsilateral mediastinal lymph nodes (pN2). Brain magnetic resonance imaging and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT did not show distant metastases. After three cycles of neoadjuvant chemotherapy with cisplatin and docetaxel, the CT showed no change. Lobectomy with mediastinal lymphadenectomy revealed ypT1 ypN2 adenocarcinoma. The patient received postoperative radiotherapy of the mediastinum and regular follow-up. In April 2012, the patient had abdominal pain and FDG-PET/CT suggested supraclavicular, retroperitoneal, and inguinal lymph-node metastases. Lymph-node biopsy confirmed relapse of thyroid transcription factor-1-positive lung adenocarcinoma. Sequencing was negative for activating mutations in EGFR, KRAS, BRAF, and HER2. Fluorescence in situ hybridization was negative for ALK or ROS1 fusion and MET amplification. After two cycles of chemotherapy with carboplatin and pemetrexed, abdominal pain increased and CT showed progressive disease. An incident myocardial infarction was treated by coronary stenting, and resolved with normal cardiac function. In December 2012, commercial fluorescence in situ hybridization break-apart assays for RET and KIF5B were performed, and both turned out to be positive (Fig. 1C and D). On the basis of the preclinical rationale, the potential benefits and risks of vandetanib were discussed with the patient. After cardiac assessment, and baseline FDG-PET/CT (Fig. 2A and D), treatment with vandetanib was started at a regular dosage of 300 mg once daily. After 1 week, abdominal pain resolved and FDG-PET/CT showed a decrease in FDG uptake and the size of the metastases (Fig. 2B and E). Vandetanib was tolerated well, treatment was continued, and FDG-PET/CT at 4 weeks confirmed the remission (Fig. 2C and F). To the best of our knowledge, this is the first report of a patient with lung adenocarcinoma and RET fusion responding to vandetanib. The patient provided consent for testing and treatment with a RET inhibitor, which is ongoing at the time of the publishing of this report. Of note, the tumor was refractory to previous chemotherapy. Cabozantinib, another RET inhibitor, is currently being evaluated in patients with advanced non–small-cell lung cancer and RET fusion in a phase II trial (NCT01639508).
We thank the patient for consenting to this publication, Prof. R.K. Thomas (University of Cologne, Germany), Dr. D. Schwarb (Swiss National Accident Insurance Fund SUVA, Luzern), and Dr. M. Frueh (Kantonsspital, St. Gallen) for collaboration, and AstraZeneca for vandetanib.
1. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–141
2. Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352–4359
3. Chao BH, Briesewitz R, Villalona-Calero MA. RET fusion genes in non-small-cell lung cancer. J Clin Oncol. 2012;30:4439–4441
4. Matsubara D, Kanai Y, Ishikawa S, et al. Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol. 2012;7(12):1872–6
5. Wolff DJ, Bagg A, Cooley LD, et al.Association for Molecular Pathology Clinical Practice Committee; American College of Medical Genetics Laboratory Quality Assurance Committee. Guidance for fluorescence in situ hybridization testing in hematologic disorders. J Mol Diagn. 2007;9:134–143