Kif5B & Ccdc6 Ret in Lung Cancer: Clinical Insights and Response to Personalized Based Therapy

Abstract

Aim: Gene analysis became a key factor in managing lung adenocarcinomas (LADC). Rearrangements during transfection (RET) mutations have been reported in 1-2% of LADC, where KIF5B-RET fusion is more common (70-90%) than CCDC6-RET (10-25%). The natural history and the management of RET mutated lung cancer are still unclear. We hereby present a series of eight RET-mutated lung cancer patients, as the first series of lung cancer patients harboring RET fusions out of a clinical study. Methods: This is a multicenter, retrospective report of eight lung cancer patients who harbored RET fusion between May 2009 and July 2014. Results: Four males and four women, mean age of 51 years (range 28-72), four were never and four light smokers. Five harbored the KIF5B-RET variant and three the CCDC6-RET. Five cases had hyper-acute presentation and/or recurrence. Four of them harbored the KIF5B variant. Among them, one patient (KIF5B-RET) treated with cabozantinib and showed a rapid and durable complete response by Response Evaluation Criteria in Solid Tumors for 8 months. Interestingly enough, unique characteristic included bilateral miliary lung metastasis on presentation and early abdominal (liver, ovaries, intestinal) and bone involvement. To our knowledge, this is the first study to report a complete response to cabozantinib for this indication. One patient (with CCDC6-RET mutation) displayed a profound and durable response to cisplatin/pemetrexed/bevacizumab therapy of 8 months. Conclusions: RET-fusion LADC may have an abrupt and acute presentation; in our series, tend to be associated with KIF5B subtype. While some RET-fusion positive LADC patients might benefit from combination chemotherapy, it may also be that the most effective targeted therapy is cabozantinib with a potential long standing complete.