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Classical Case

Successful treatment of lung cancer with FBXW7 mutations

Case Summary: The patient is a 63-year-old female with a history of smoking, diagnosed with lung adenocarcinoma. Common lung cancer driver gene mutations were negative. She underwent chemotherapy, targeted therapy, surgical treatment and radiotherapy multi-line treatment but disease relapsed within 1 year after treatments. Using high-throughput sequencing (NGS), FBXW7 inactivating mutations were identified and mTOR inhibitor temsirolimus was prescribed. The treatment demonstrated remarkable efficacy in this patient.

Molecular Mechanism: FBXW7 is a tumor-suppressor gene that inhibits the mTOR signal pathway. When inactivating FBXW7 mutation occurs, the mTOR pathway is activated and leads to tumor formation and invasion. The use of mTOR inhibitor restores the inhibition of mTOR oncogenic pathway and therefore inhibits tumor cell proliferation.

Detailed Treatment History:

Patient Information: 63 years old; female; Stage IV adenocarcinoma with a history of smoking

Timeline of treatments:

2010 Patient was diagnosed with metastatic lung adenocarcinoma in left upper lobe, left hilum and right adrenal gland.

· March 2010-November 2010: combination treatment of carboplatin, paclitaxel and cetuximab. Disease progressed 7 months later.

· November 2010-March 2011: Erlotinib (EGFR mutation status was unknown) was prescribed and disease  progressed in five months.

· May 2011: Cervical mediastinoscopy, left pneumonectomy, extrapleural dissection, intrapericardial dissection and pericardial reconstruction

· July 2011: Right adrenalectomy

· July 2011: Genetic testing was performed on dissected adrenal mass. Testing of activating mutations for EGFR, KRAS and BRAF, ALK rearrangement and c - MET amplification were all negative.

· May 2012: Multiple nodules in lower lobe of the right lung were found. Biopsy confirmed the recurrence of lung adenocarcinoma.

· Chemotherapy with carboplatin and pemetrexed. Disease progressed and metastasized to mediastinal lymph node in January 2013.

· February 2013 Radiotherapy, tumor progression slowed down.

· Feb 2013: NGS genetic testing on the right adrenal tumor identified FBXW7 p.R465H inactivating mutation.

· March 2013: Targeted therapy temsirolimus was performed, and CT scan was performed every two cycles of treatment. The treatment lasted for 8 cycles as of publication.

· Imaging results: Disease was in remission for more than 32 weeks since temsirolimus treatment.

Comment: Comprehensive genomic sequencing for the identification of putative oncogenic drivers for which targeted therapies may be effective. In particular implicates FBXW7 mutated lung adenocarcinoma as a novel molecular NSCLC subtype.