Michal Sarfaty1, Assaf Moore2, Victoria Neiman1, Elizabeth Dudnik2, Maya Ilouze2, Maya Gottfried3, Rivka Katznelson4, Hovav Nechushtan5, Hadas Gantz Sorotsky6, Keren Paz7, Amanda Katz7, Milton Saute8, Mira Wolner9, Mor Moskovitz10, Vincent Miller11, Julia Elvin11, Doron Lipson11, Siraj Ali11, Lior Soussan Gutman12, Addie Dvir12, Noa Gordon2, Nir Peled13. 1. Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 2. Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel. 3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Oncology, Meir Medical Center, Kfar Saba, Israel. 4. Institute of Oncology, Kaplan Medical Center, Rehovot, Israel; Faculty of Medicine, Hebrew University, Jerusalem, Israel. 5. Faculty of Medicine, Hebrew University, Jerusalem, Israel; Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem, Israel. 6. Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem, Israel. 7. Champions Oncology, Baltimore, MD. 8. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Cardiothoracic Surgery, Rabin Medical Center, Petah Tikva, Israel. 9. Institute of Oncology, Rambam Health Care Campus, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel. 10. Institute of Oncology, Rambam Health Care Campus, Haifa, Israel. 11. Foundation Medicine, Cambridge, MA. 12. Teva Pharmaceutical Industries Ltd, Petah Tikva, Israel. 13. Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: nirp@post.tau.ac.il.
Abstract
BACKGROUND: RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. MATERIALS AND METHODS: We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. RESULTS: A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. CONCLUSION: RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.
BACKGROUND:RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. MATERIALS AND METHODS: We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. RESULTS: A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. CONCLUSION:RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.
Authors: Caroline E McCoach; Collin M Blakely; Kimberly C Banks; Benjamin Levy; Ben M Chue; Victoria M Raymond; Anh T Le; Christine E Lee; Joseph Diaz; Saiama N Waqar; William T Purcell; Dara L Aisner; Kurtis D Davies; Richard B Lanman; Alice T Shaw; Robert C Doebele Journal: Clin Cancer Res Date: 2018-03-29 Impact factor: 12.531
Authors: Thereasa A Rich; Karen L Reckamp; Young Kwang Chae; Robert C Doebele; Wade T Iams; Michael Oh; Victoria M Raymond; Richard B Lanman; Jonathan W Riess; Thomas E Stinchcombe; Vivek Subbiah; David R Trevarthen; Stephen Fairclough; Jennifer Yen; Oliver Gautschi Journal: Clin Cancer Res Date: 2019-07-12 Impact factor: 12.531