74 results on '"RET Rearrangement"'
Search Results
52. Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET).
- Author
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Takeuchi S, Yanagitani N, Seto T, Hattori Y, Ohashi K, Morise M, Matsumoto S, Yoh K, Goto K, Nishio M, Takahara S, Kawakami T, Imai Y, Yoshimura K, Tanimoto A, Nishiyama A, Murayama T, and Yano S
- Abstract
Background: Rearranged during transfection ( RET ) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for., Alk: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with., Ret: rearranged NSCLC., Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET -rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib., Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC
0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2., Conclusions: Alectinib exerts limited activity against RET -rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-549). Dr. NY, Dr. YH, and Dr. MM reports personal fees from Chugai Pharma, outside the submitted work. Dr. TS reports grants and personal fees from Chugai Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Eisai, grants and personal fees from Eli Lilly Japan, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Novartis Pharma, grants and personal fees from Pfizer Japan, grants and personal fees from Sanofi, grants and personal fees from Taiho Pharma, personal fees from Daiichi Sankyo, personal fees from Fuji Pharma, personal fees from Hisamitsu Pharma, personal fees from Kyowa Hakko Kirin, personal fees from Mochida Pharma, personal fees from Nippon Kayaku, personal fees from Ono Pharma, personal fees from Roche Diagnostics, personal fees from Showa Yakuhin Kako, personal fees from Sumitomo Dainippon Pharma, personal fees from Takeda Pharma, grants from Astellas Pharma, grants from Bayer Yakuhin, grants from Merck Serono, grants from MSD, grants from Verastem, grants from Yakult, outside the submitted work. Dr. SM reports grants and personal fees from Astellas Pharma, grants and personal fees from Novartis Pharma, grants and personal fees from Eli Lilly Japan, grants from Chugai Pharma, grants from AstraZeneca, grants from Amgen Astellas BioPharma, grants from Eisai, grants from Ono Pharma, grants from Kyowa Hakko Kirin, grants from MSD, grants from Daiichi Sankyo, grants from Taiho Pharma, grants from Takeda Pharma, grants from Pfizer, outside the submitted work. Dr. K Yoh reports grants and personal fees from AstraZeneca, grants and personal fees from Eli Lilly Japan, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Taiho Pharma, personal fees from Bristol-Myers Squibb, personal fees from Ono Pharma, grants from Bayer, grants from Novartis, grants from Takeda Pharma, outside the submitted work. Dr. KG reports grants and personal fees from Chugai, grants and personal fees from Taiho Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Ono Pharma, grants and personal fees from Pfizer, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from Eli Lilly Japan, grants and personal fees from Daiichi Sankyo, grants from MSD, grants from Quintiles, grants from GlaxoSmithKline, grants from OxOnc, grants from Sumitomo Dainippon Pharma, grants from Takeda Pharma, grants from Astellas Pharma, grants from Eisai, grants from Amgen Astellas BioPharma, personal fees from Yakult Honsha, personal fees from Novartis Pharma, personal fees from Bristol-Myers Squibb, outside the submitted work. Dr. MN reports grants and personal fees from Chugai, grants and personal fees from Taiho Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Ono Pharma, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Eli Lilly Japan, grants and personal fees from MSD, personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo Healthcare, personal fees from Merck Serono, personal fees from MSD, personal fees from Pfizer, grants from Astellas, outside the submitted work. Dr. K Yoshimura reports personal fees from Chugai Pharma, personal fees from Astra Zeneca, personal fees from Eli Lilly, outside the submitted work. Dr. SY reports grants from the Japan Agency for Medical Research and Development (AMED), during the conduct of the study; grants and personal fees from Chugai Pharma, grants and personal fees from Boehringer-Ingelheim Japan, grants and personal fees from Novartis, personal fees from AstraZeneca, personal fees from Pfizer, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)- Published
- 2021
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53. The Clinicopathological Results of Thyroid Cancer With BRAFV600E Mutation in the Young Population of Fukushima.
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Iwadate M, Mitsutake N, Matsuse M, Fukushima T, Suzuki S, Matsumoto Y, Ookouchi C, Mizunuma H, Nakamura I, Nakano K, Sakamoto A, Hirokawa M, Ito M, Naganuma H, Hashimoto Y, Shimura H, Yamashita S, and Suzuki S
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- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Thyroid Cancer, Papillary epidemiology, Thyroid Neoplasms epidemiology, Young Adult, Fukushima Nuclear Accident, Proto-Oncogene Proteins B-raf genetics, Thyroid Cancer, Papillary genetics, Thyroid Cancer, Papillary pathology, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology
- Abstract
Background: Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features., Methods: We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC)., Results: The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ± 6.8 mm) than in wild-type BRAF cases (20.9 ± 10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis., Conclusions: The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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54. Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.
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Tan AC, Seet AOL, Lai GGY, Lim TH, Lim AST, Tan GS, Takano A, Tai DWM, Tan TJY, Lam JYC, Ng MCH, Tan WL, Ang MK, Kanesvaran R, Ng QS, Jain A, Rajasekaran T, Lim WT, Tan EH, Lim TKH, and Tan DSW
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- Adult, Aged, Aged, 80 and over, Female, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Proto-Oncogene Proteins c-ret genetics, Retrospective Studies, Lung Neoplasms genetics, Lung Neoplasms therapy
- Abstract
Introduction: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes., Methods: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected., Results: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009)., Conclusions: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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55. Thyroid Cancer: Role of RET and Beyond
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Francesca Carlomagno
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,endocrine system diseases ,Medullary cavity ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,RET Rearrangement ,Point mutation ,Basic Thyroidology / Review ,medicine.disease_cause ,medicine.disease ,Bioinformatics ,Receptor tyrosine kinase ,Thyroid carcinoma ,biology.protein ,Cancer research ,Medicine ,business ,Carcinogenesis ,Gene ,Thyroid cancer - Abstract
Specific thyroid cancer histotypes, such as papillary and medullary thyroid carcinoma, display genetic rearrangements or point mutations of the RET gene, resulting in its oncogenic conversion. The molecular mechanisms mediating RET rearrangement with other genes and the role of partner genes in tumorigenesis have been described. In addition, the RET protein has become a molecular target for medullary thyroid carcinoma treatment.
- Published
- 2012
56. P2.03b-046 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma
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Yiping Zhang, Zhengbo Song, and Xinmin Yu
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung ,business.industry ,RET Rearrangement ,medicine.disease ,medicine.anatomical_structure ,Internal medicine ,medicine ,Adenocarcinoma ,Genetic variability ,business - Published
- 2017
57. JCES01.19 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma
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Xinmin Yu, Zhengbo Song, and Yiping Zhang
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung ,business.industry ,RET Rearrangement ,medicine.disease ,medicine.anatomical_structure ,Internal medicine ,medicine ,Adenocarcinoma ,Genetic variability ,business - Published
- 2017
58. MA26.03 Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement
- Author
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Rebecca J. Nagy, Dora Dias-Santagata, E. Evans, Jochen K. Lennerz, B. Wolf, C. Clifford, Subba R. Digumarthy, Mari Mino-Kenudson, Zofia Piotrowska, Justin F. Gainor, Hideko Isozaki, Richard B. Lanman, Nicolas Marcoux, Anthony J. Iafrate, L.V. Sequist, Aaron N. Hata, and Mandeep Banwait
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,03 medical and health sciences ,030104 developmental biology ,Oncology ,business.industry ,RET Rearrangement ,Mutant ,Cancer research ,Medicine ,Osimertinib ,business - Published
- 2018
59. Growing thyroid nodules with benign histology and RET rearrangement
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Guido Rossi, Anna Guerra, Elisabetta Campanile, Gianfranco Fenzi, Mario Vitale, Maria Rosaria Sapio, Vincenzo Marotta, Manuela Motta, Marotta, V., Guerra, Anna, Sapio, MARIA ROSARIA, Campanile, E., Motta, M., Fenzi, Gianfranco, Rossi, Guido, and Vitale, Mario
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Adult ,Genetic Markers ,Male ,FNAC ,Thyroid nodules ,endocrine system ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Biopsy, Fine-Needle ,Non malignant ,Polymerase Chain Reaction ,RET/PTC ,Endocrinology ,medicine ,Humans ,Thyroid Neoplasms ,Thyroid Nodule ,Thyroid cancer ,Aged ,Ultrasonography ,Gene Rearrangement ,business.industry ,RET Rearrangement ,Proto-Oncogene Proteins c-ret ,Thyroid ,Thyroidectomy ,Nodule (medicine) ,Histology ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Female ,Nodular goiter ,medicine.symptom ,business - Abstract
Some benign thyroid nodules are stationary in size over time while others grow progressively, indicating that there is a broad individual variability within benign nodules. To date, it is very difficult to predict if a benign thyroid nodule will grow in size and which will be its trend over time. While BRAF(V600E) is a highly specific marker of thyroid cancer, RET rearrangements have been disclosed also in non malignant thyroid lesions and their biological significance is debated. We compared the clinical history of three histologically benign thyroid nodules harboring RET rearrangements with that of 6 benign nodules bearing wild type RET. The nodules negative for RET rearrangements were followed for 10 years by ultrasonographic evaluation, showing a slow, constant enlargement. Three patients with benign nodules diagnosed at FNAC, were followed for 11, 9 and 7 years by annual ultrasonographic evaluation. After several years of latency, the nodules had an unexpected and gradual increase in their dimensions, reaching a large final size. A second FNAC confirmed the previous cytologic diagnosis of benign lesion. Because of the increasing size of the nodules, the patients were advised to surgery. Before undergoing thyroidectomy, we performed molecular diagnostic tests that revealed the absence of BRAF(V600E) and the presence of RET/PTC-1 in one nodule and RET/PTC-3 in the two others. Despite the presence of this oncogene, the samples were histologically classified as benign hyperplastic nodules. These findings lead us to speculate that histologically benign hyperplastic thyroid nodules containing RET rearrangements might represent a subgroup of nodules with a rapid size increase.
- Published
- 2010
60. Association Between RET Fusions and Efficacy of Pemetrexed-based Chemotherapy for Patients With Advanced NSCLC in China: A Multicenter Retrospective Study.
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Shen T, Pu X, Wang L, Yu Z, Li J, Zhang Y, Liang X, Chen H, Xu C, Song Z, and Wang W
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- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics, Adult, Aged, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Follow-Up Studies, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Male, Middle Aged, Paclitaxel administration & dosage, Pemetrexed administration & dosage, Prognosis, Proto-Oncogene Mas, Retrospective Studies, Survival Rate, Gemcitabine, Adenocarcinoma of Lung pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung pathology, Gene Rearrangement, Lung Neoplasms pathology, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins c-ret genetics
- Abstract
Background: Rearranged during transfection (RET) proto-oncogene gene fusions are rare in non-small-cell lung cancer (NSCLC). We compared the efficacy of pemetrexed-based chemotherapy with other chemotherapy regimens in patients with NSCLC with different RET fusion subtypes., Patients and Methods: A retrospective, multicenter study of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas was conducted. RET rearrangements were detected using next generation sequencing. We analyzed the clinical characteristics of patients with RET-rearranged NSCLC and the efficacy of chemotherapy regimens. We also evaluated the efficacy between groups of patients with and without KIF5B-RET-rearranged lung cancer., Results: We evaluated 62 patients with NSCLC and RET rearrangements, including 41 with KIF5B-RET, 15 with CCDC6-RET, and 6 with other rare fusion subtypes. Of these 62 patients, 50 had stage IIIB/IV. We also evaluated 40 patients with first-line chemotherapy information available. The median progression-free survival was significantly different between those receiving pemetrexed-based chemotherapy and those receiving other chemotherapy regimens (9.2 vs. 5.2 months; P = .007). The median progression-free survival for patients with KIF5B-RET fusion and non-KIF5B-RET fusion was not significantly different statistically (7.8 vs. 11.2 months; P = .847). For second-line chemotherapy, a statistically significant difference was found between the chemotherapy regimens (4.9 vs. 2.8 months; P = .049). Survival follow-up data were available for 38 patients with advanced NSCLC. The median overall survival was 26.4 months. The overall survival of the patients with RET-rearranged NSCLC who had received pemetrexed-based chemotherapy versus no pemetrexed-based chemotherapy was 35.2 versus 22.6 months (P = .052). No difference in survival was observed between the patients with KIF5B-RET and non-KIF5B-RET rearrangements., Conclusions: Pemetrexed-based treatment should be considered first when selecting the chemotherapy regimen for patients with NSCLC and RET rearrangements., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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61. Characteristics and outcomes of RET-rearranged Korean non-small cell lung cancer patients in real-world practice.
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Lee J, Ku BM, Shim JH, La Choi Y, Sun JM, Lee SH, Ahn JS, Park K, and Ahn MJ
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- Adult, Aged, Aged, 80 and over, Brain Neoplasms genetics, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, ErbB Receptors genetics, Female, Genome, Human, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Male, Middle Aged, Pemetrexed therapeutic use, Piperidines therapeutic use, Quinazolines therapeutic use, Republic of Korea, Treatment Outcome, Carcinoma, Non-Small-Cell Lung genetics, Gene Rearrangement, Lung Neoplasms genetics, Proto-Oncogene Proteins c-ret genetics
- Abstract
Objective: Since the first discovery of rearranged during transfection (RET) fusion in lung adenocarcinoma in 2011, two tyrosine kinase inhibitors, namely vandetanib and cabozantinib, are currently available. Despite favorable outcomes in systemic control, the intracranial therapeutic response remains insufficient. In this study, the clinical characteristics and outcomes of non-small cell lung cancer (NSCLC) patients with RET rearrangements were analyzed., Methods: Patients with NSCLC harboring RET fusion who received treatment between January 2006 and January 2018 were analyzed. RET rearrangement was identified by FISH or NGS., Results: A total of 59 patients were identified. About half of the patients were female (47.5%) and never smokers (50.9%). Most patients had adenocarcinoma (89.8%). A total of 17 patients (28.8%) had an intracranial lesion at the initial diagnosis of stage IV disease, and 11 additional patients (18.6%) developed intracranial metastases during follow-up. The median time to development of intracranial metastases was 19.0 months (95% CI: 9.6-28.5), resulting in a >60% cumulative incidence of brain metastasis at 24 months. The systemic efficacy of pemetrexed-based regimens was favorable with progression-free survival of 9.0 (95% CI: 6.9-11.2) and OS of 24.1 (95% CI: 15.2-33.0) months. The median progression-free survival for vandetanib and immunotherapy was 2.9 (95% CI: 2.0-3.8) and 2.1 (95% CI: 1.6-2.6) months, respectively., Conclusions: Given the likelihood of RET-rearranged NSCLC progressing to intracranial metastases and the absence of apparent clinical benefit of currently available targeted or immunotherapeutic agents, development of novel treatment with higher selectivity and better penetration of the blood-brain barrier remains a priority., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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62. Incidentally simultaneous occurrence of RET/PTC, H4–PTEN and BRAF mutation in papillary thyroid carcinoma
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Jiucun Wang, Yong Xue Zhu, Qinghai Ji, Ling Zhang, Yi Wu, Cai Ping Huang, Duan Shu Li, Qiang Shen, and Yu-Long Wang
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Adult ,Male ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Adolescent ,endocrine system diseases ,Thyroid carcinoma ,Humans ,PTEN ,Medicine ,Thyroid Neoplasms ,Target therapy ,neoplasms ,Gene Rearrangement ,biology ,business.industry ,RET Rearrangement ,Proto-Oncogene Proteins c-ret ,PTEN Phosphohydrolase ,Gene rearrangement ,Middle Aged ,Predictive value ,Cytoskeletal Proteins ,Young age ,Oncology ,Mutation ,Mutation (genetic algorithm) ,Cancer research ,biology.protein ,Female ,business - Abstract
Because interaction existed between PTEN and RET-RAS-RAF-MAPK pathway, H4-PTEN (a newly identified gene rearrangement), RET/PTC and BRAF mutation were scanned in 125 Chinese patients with papillary thyroid carcinoma (PTC). H4-PTEN were detected in 9.6% of PTC and the frequency of the occurrence of BRAF mutation and/or RET/PTC in H4-PTEN positive tumors was extremely high (75%). On the other hand, age has an important effect on the aberration formation and young age renders more prone to multi-genetic events. A combinational scanning of these involved changes will improve the predictive value of molecular aberrations in the treatment of PTC.
- Published
- 2008
63. Identification of nicotinamide aminonaphthyridine compounds as potent RET kinase inhibitors and antitumor activities against RET rearranged lung adenocarcinoma.
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Wang, Modi, Naganna, N., and Sintim, Herman O.
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NICOTINAMIDE , *ANAPLASTIC lymphoma kinase , *KINASE inhibitors , *LUNGS - Abstract
• A series of nicotinamide naphthyridine analogs identified as potent RET inhibitors. • HSN608, a lead compound, inhibited various mutant RET enzymes better than Alectinib, Vandetanib and Apatinib in vitro. • HSN608 inhibited the growth of RET-driven LC-2/ad cell line with IC50 of ~3 nM. RET rearrangement is a recently identified oncogenic mutation in lung adenocarcinoma (LADC) that accounts for approximately 2% of all NSCLCs. More than six fusion partners have been identified in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1 and ERC1. Many RET inhibitors have been reported and some have progressed to the clinic. Similar to most kinase inhibitors, patients often respond to current RET inhibitors but relapse can occur due to the emergence of mutant RET kinases, such as RET (S904F) and (V804L/M), which are resistant to inhibition. Our group previously reported that the benzamide aminonaphthyridine HSN356, a multikinase inhibitor, also inhibited RET. In this study, we prepared various nicotinamide analogs of HSN356 and investigated RET inhibition to uncover the salient moieties on HSN356 that are important for kinase inhibition and to also evaluate if HSN356 and analogs thereof could inhibit mutant RET kinases, such as RET (S904F) and (V804L/M). Compound 3 (HSN608), the nicotinamide analog of HSN356, inhibits RET and mutant forms better than reported RET inhibitors such as Alectinib, Sorafenib, Vandetanib and Apatinib, and comparable to BLU667. HSN608 inhibited the growth of CCDC6-RET driven LC-2/ad cell line with IC50 of ~3 nM. Under similar conditions, BLU667 and vandetanib (two drugs being evaluated against RET-driven cancers in the clinic) inhibited the growth of LC-2/ad with IC50 values of ~10 and 328 nM respectively. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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64. Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients
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Christian Grohé, Jürgen Wolf, Lukas C. Heukamp, Walburga Engel-Riedel, Oliver Gautschi, Michaela Angelika Ihle, Lukas Bubendorf, Clemens Müller-Naendrup, Franziska Aebersold, Anne Adams, Jana Fassunke, Christian Mattonet, Winfried Randerath, Rebecca Hein, Stefan Krüger, Georg Pall, Matthias Scheffler, Joachim Diebold, Hans-Ulrich Schildhaus, Helen Künstlinger, Sabine Merkelbach-Bruse, Sebastian Michels, Ullrich Graeven, Carina Heydt, Heike Lüders, Monika Serke, Wolfgang Hartmann, Andreas H. Scheel, Rieke Fischer, Britta Kaminsky, Susanne Schulze-Olden, Ulrich Gerigk, Karl-Otto Kambartel, Sacha I. Rothschild, Anne M. Schultheis, Wolfgang Schulte, Lucia Nogova, Reinhard Büttner, and Andreas Draube
- Subjects
0301 basic medicine ,Oncology ,Male ,Pathology ,Lung Neoplasms ,endocrine system diseases ,Oncogene Proteins, Fusion ,Smoking history ,NSCLC ,medicine.disease_cause ,Clinicopathological characteristics ,0302 clinical medicine ,TP53 ,In Situ Hybridization, Fluorescence ,Aged, 80 and over ,Gene Rearrangement ,medicine.diagnostic_test ,Middle Aged ,Prognosis ,Europe ,Proto-Oncogene Proteins c-ret ,030220 oncology & carcinogenesis ,Cohort ,Carcinoma, Squamous Cell ,Adenocarcinoma ,Female ,KRAS ,Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,RET rearrangement ,03 medical and health sciences ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Lung cancer ,neoplasms ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Retrospective cohort study ,Gene rearrangement ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,business ,Fluorescence in situ hybridization ,Follow-Up Studies - Abstract
Introduction Rearrangements of RET are rare oncogenic events in patients with non–small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. Methods Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. Results Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53 . The median age at diagnosis was 62 years (range, 39–80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). Conclusions Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear.
- Published
- 2015
65. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma
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Corvi, R, Berger, N, Balczon, R, and Romeo, G
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- 2000
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66. 1p/19q codeletion and RET rearrangements in small-cell lung cancer
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Na Han, Weimin Mao, Hongyang Lu, Yun Fan, Fa-Jun Xie, Haimiao Xu, and Jing Qin
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Pathology ,medicine.medical_specialty ,RET rearrangement ,medicine.medical_treatment ,1p/19q Codeletion ,OncoTargets and Therapy ,03 medical and health sciences ,0302 clinical medicine ,FISH ,small-cell lung cancer ,medicine ,Pharmacology (medical) ,Oligodendroglial Tumor ,Lung cancer ,neoplasms ,Original Research ,Chemotherapy ,Temozolomide ,1p/19q codeletion ,medicine.diagnostic_test ,business.industry ,RET Rearrangement ,Cancer ,medicine.disease ,respiratory tract diseases ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,business ,030217 neurology & neurosurgery ,Fluorescence in situ hybridization ,medicine.drug - Abstract
Hongyang Lu,1,2 Haimiao Xu,3 Fajun Xie,2 Jing Qin,2 Na Han,2 Yun Fan,1,2 Weimin Mao1 1Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Diagnosis& Treatment Technology on Thoracic Oncology (Lung and Esophagus), 2Department of Thoracic Medical Oncology, 3Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China Abstract: The prognosis of small-cell lung cancer (SCLC) is poor despite reports suggesting modest improvement in survival. To date, chemotherapy remains the cornerstone treatment for SCLC patients, and many studies have focused on identifying the molecular characteristics of SCLC, which serve as the basis for precision treatments that improve the prognosis of SCLC. For instance, the therapeutic effect of temozolomide, recommended for patients with relapsed SCLC, is linked to 1p/19q codeletion in anaplastic oligodendroglial tumors. A subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. In order to identify 1p/19q codeletion and RET rearrangement in SCLC patients, 32 SCLC resected specimens were retrospectively collected between 2008 and 2014 from the Zhejiang Cancer Hospital in People’s Republic of China. Fluorescence in situ hybridization was used to detect 1p/19q codeletion and RET rearrangement in the specimens. A 1p single deletion was detected in eight specimens, 19q single deletion was detected in three specimens, and only three specimens had a 1p/19q codeletion. None of the specimens had a RET rearrangement. The three patients whose specimens had a 1p/19q codeletion were alive after 58, 50, and 30 months of follow-up care. There was a trend toward prolonged overall survival for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (P=0.113, 0.168, 0.116, and 0.122, respectively). Our data showed that RET rearrangement may be not an ideal molecular target for SCLC therapies in People’s Republic of China. Instead, 1p/19q codeletion is a promising marker for a good prognosis and treatment with temozolomide in SCLC. Keywords: small-cell lung cancer, 1p/19q codeletion, RET rearrangement, FISH
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- 2016
67. Papillary carcinoma of the breast lacks evidence of RET rearrangements despite morphological similarities to papillary thyroid carcinoma
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Xiaopei Zhu, Omar Hameed, Arie Perry, Ruma Banerjee, and John D. Pfeifer
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,Oncogene Proteins, Fusion ,Breast Neoplasms ,In situ hybridization ,Biology ,Pathology and Forensic Medicine ,Breast Neoplasms, Male ,Thyroid carcinoma ,Carcinoma ,medicine ,Humans ,Thyroid Neoplasms ,In Situ Hybridization, Fluorescence ,Aged ,Aged, 80 and over ,Gene Rearrangement ,Reverse Transcriptase Polymerase Chain Reaction ,RET Rearrangement ,Chromosome ,Nuclear Proteins ,Gene rearrangement ,Middle Aged ,medicine.disease ,Carcinoma, Papillary ,DNA-Binding Proteins ,Female ,Papillary carcinoma ,Nested polymerase chain reaction - Abstract
Rare breast neoplasms resembling the tall-cell variant of papillary thyroid carcinoma have been reported. In addition, papillary carcinoma of the breast occasionally displays nuclear features reminiscent of papillary thyroid carcinoma. In this study, we evaluated 33 intraductal/intracystic papillary carcinomas of the breast for the presence and extent of nuclear overlap, grooves, clearing, and inclusions, as well as features of the tall-cell or columnar-cell variants of papillary thyroid carcinoma. RET rearrangements were assessed in a subset of these cases. Paired probes localizing to the centromeric and telomeric ends of the RET gene on chromosome 10 were used for FISH using a break-apart approach. Single round and nested PCR was performed to detect RET/PTC1, RET/PTC2, RET/PTC3 and ELKS-RET fusion transcripts. Nuclear overlap, grooves, stratification, and clearing were identified in 24 (73%), 14 (42%), 11 (33%), and 9 (27%) cases respectively, whereas nuclear inclusions and 'tall-cell' features were each seen in only one (3%) and two (6%) cases, respectively. Four of 19 tested cases displayed split FISH signals in a low percentage of cells and were considered borderline for RET rearrangement. All 19 tested cases with amplifiable RNA were negative for the four RET fusion transcripts evaluated by RT-PCR. Although papillary carcinomas of breast often display one or more cytoarchitectural features of papillary thyroid carcinoma, there is no evidence that RET rearrangements are involved.
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- 2009
68. Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers.
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Drilon A, Lin JJ, Filleron T, Ni A, Milia J, Bergagnini I, Hatzoglou V, Velcheti V, Offin M, Li B, Carbone DP, Besse B, Mok T, Awad MM, Wolf J, Owen D, Camidge DR, Riely GJ, Peled N, Kris MG, Mazieres J, Gainor JF, and Gautschi O
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- Adult, Aged, Aged, 80 and over, Brain Neoplasms genetics, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Mas, Treatment Outcome, Brain Neoplasms secondary, Lung Neoplasms genetics, Protein Kinase Inhibitors therapeutic use
- Abstract
Introduction: In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized., Methods: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined., Results: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months)., Conclusions: Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2018
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69. Characterization of Computed Tomography Imaging of Rearranged During Transfection-rearranged Lung Cancer.
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Saiki M, Kitazono S, Yoshizawa T, Dotsu Y, Ariyasu R, Koyama J, Sonoda T, Uchibori K, Nishikawa S, Yanagitani N, Horiike A, Ohyanagi F, Oikado K, Ninomiya H, Takeuchi K, Ishikawa Y, and Nishio M
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- Adenocarcinoma diagnostic imaging, Adenocarcinoma genetics, Adult, Aged, Carcinoma, Non-Small-Cell Lung diagnostic imaging, Carcinoma, Non-Small-Cell Lung genetics, Female, Follow-Up Studies, Humans, Lung Neoplasms diagnostic imaging, Lung Neoplasms genetics, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Retrospective Studies, Transfection, Adenocarcinoma secondary, Carcinoma, Non-Small-Cell Lung pathology, Gene Rearrangement, Lung Neoplasms pathology, Proto-Oncogene Proteins c-ret genetics, Tomography, X-Ray Computed methods
- Abstract
Background: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented., Patients and Methods: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics., Results: In 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%)., Conclusion: Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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70. Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer.
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Ferrara R, Auger N, Auclin E, and Besse B
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- Carcinoma, Non-Small-Cell Lung genetics, Humans, Lung Neoplasms genetics, Proto-Oncogene Mas, Proto-Oncogene Proteins c-ret antagonists & inhibitors, Carcinoma, Non-Small-Cell Lung drug therapy, Gene Rearrangement, Lung Neoplasms drug therapy, Molecular Targeted Therapy, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-ret genetics
- Abstract
Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores the clear need for development of more selective and potent RET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2018
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71. Basic: Searching a New Molecular Targets
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Seiji Yano
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business.industry ,RET Rearrangement ,Cancer therapy ,Cancer ,ROS1 Rearrangement ,Hematology ,medicine.disease ,Oncology ,Egfr mutation ,Cancer research ,Molecular targets ,Medicine ,ALK Rearrangement ,business ,Lung cancer - Abstract
Recent advances in molecular biology have led to the identification of new molecular targets for solid tumors, which were considered refractory to conventional cancer therapy, and efficacious molecular targeted drugs are being developed. For example, oncogenic drivers such as EGFR mutations, ALK rearrangement, ROS1 rearrangement, and RET rearrangement have been found in lung cancer, and dramatic therapeutic effects have been achieved with corresponding drugs in lung cancer expressing these driver oncogenes. On the other hand, patients who have responded to those inhibitors will acquire resistance within a few years and experience the recurrence of cancer, and several molecular targets for overcoming the resistance have also been identified. Using lung cancer as an example, new molecular targets will be introduced in this session.
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- 2012
72. Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients.
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Michels S, Scheel AH, Scheffler M, Schultheis AM, Gautschi O, Aebersold F, Diebold J, Pall G, Rothschild S, Bubendorf L, Hartmann W, Heukamp L, Schildhaus HU, Fassunke J, Ihle MA, Künstlinger H, Heydt C, Fischer R, Nogovà L, Mattonet C, Hein R, Adams A, Gerigk U, Schulte W, Lüders H, Grohé C, Graeven U, Müller-Naendrup C, Draube A, Kambartel KO, Krüger S, Schulze-Olden S, Serke M, Engel-Riedel W, Kaminsky B, Randerath W, Merkelbach-Bruse S, Büttner R, and Wolf J
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- Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell pathology, Europe, Female, Follow-Up Studies, Humans, In Situ Hybridization, Fluorescence, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Oncogene Proteins, Fusion genetics, Prognosis, Retrospective Studies, Adenocarcinoma genetics, Biomarkers, Tumor genetics, Carcinoma, Squamous Cell genetics, Gene Rearrangement, Lung Neoplasms genetics, Proto-Oncogene Proteins c-ret genetics
- Abstract
Introduction: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC., Methods: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected., Results: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%)., Conclusions: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2016
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73. A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies
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Laura Blockley, Richard De Boer, Jessica Read, Neil Gray, Graham Bigley, James Vasselli, Qunsheng Ji, Jin Soo Lee, Angela Dale, J. Stevens, Carl John Cresswell, Victoria Williams, John Edward Norris Morten, Haihua Fu, Paul Elvin, Shuqiong Fan, Amanda Gladwin, Tianwei Zhang, Emma Donald, Chris Womack, Roy S. Herbst, Qingqing Ye, Grace Harrod, Amanda Davies, Xinying Su, Li Zheng, and Adam Platt
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Oncology ,Male ,medicine.medical_specialty ,Pathology ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Cancer Research ,Lung Neoplasms ,endocrine system diseases ,RET rearrangement ,Population ,Phases of clinical research ,Vandetanib ,Translocation, Genetic ,Piperidines ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Carcinoma ,Prevalence ,Genetics ,Humans ,education ,Lung cancer ,neoplasms ,Aged ,Retrospective Studies ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Proto-Oncogene Proteins c-ret ,Gene Amplification ,Middle Aged ,medicine.disease ,Treatment Outcome ,Quinazolines ,Female ,Erlotinib ,business ,Non-small-cell lung cancer ,medicine.drug ,Fluorescence in situ hybridization ,Research Article - Abstract
To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3–1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4–6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).
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74. Establishment of a non-tumorigenic papillary thyroid cell line (FB-2) carrying the RET/PTC1 rearrangement
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Riccardo Giannini, Fulvio Basolo, Piero Berti, Pinuccia Faviana, Rossella Elisei, Carmen Monaco, Paolo Miccoli, Antonio Toniolo, Alfredo Fusco, Marina N. Nikiforova, Furio Pacini, Monica Fedele, R. Casalone, Yuri E. Nikiforov, Giovanna Maria Pierantoni, Lisa Fiore, Massimo Santoro, Basolo, F., Giannini, R., Toniolo, A., Casalone, R., Nikiforova, M., Pacini, F., Elisei, R., Miccoli, P., Berti, P., Faviana, P., Fiore, L., Monaco, C., Pierantoni, GIOVANNA MARIA, Fedele, M., Nikiforov, Y. E., Santoro, Massimo, and Fusco, Alfredo
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Cancer Research ,Oncogene Proteins, Fusion ,endocrine system diseases ,Cellular differentiation ,medicine.medical_treatment ,Thyroid Gland ,Mice, SCID ,Mice ,Cell Movement ,Tumor Cells, Cultured ,Paired Box Transcription Factors ,HMGA1a Protein ,Thyroid ,biology ,Nuclear Proteins ,Cell Differentiation ,cell line ,Protein-Tyrosine Kinases ,DNA-Binding Proteins ,medicine.anatomical_structure ,Phenotype ,Oncology ,Female ,Cell Division ,Adult ,medicine.medical_specialty ,endocrine system ,RET rearrangement ,Proto-Oncogene Proteins c-myc ,PAX8 Transcription Factor ,Thyroid peroxidase ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Thyroid Neoplasms ,Oncogene ,Interleukin-6 ,HMGA2 Protein ,Interleukin-8 ,Gene rearrangement ,Neoplasms, Experimental ,Carcinoma, Papillary ,Endocrinology ,Cell culture ,Karyotyping ,biology.protein ,Cancer research ,Trans-Activators ,Thyroglobulin ,PAX8 ,Neoplasm Transplantation ,papillary carcinoma - Abstract
A novel human thyroid papillary carcinoma cell line (FB-2) has been established and characterized. FB-2 cells harbor the RET/PTC1 chimeric oncogene in which the RET kinase domain is fused to the H4 gene. FB-2 cells neither formed colonies in semisolid media nor induced tumors after heterotransplant into severe combined immunodeficient mice. However, HMGI(Y), HMGI-C and c-myc genes, which are associated to thyroid cell transformation, were abundantly expressed in FB-2 cells but not in normal thyroid cells. FB-2 cells only partially retained the differentiated thyroid phenotype. In fact, the PAX-8 gene, which codes for a transcriptional factor required for thyroid cell differentiation, was expressed, while thyroglobulin, TSH-receptor and thyroperoxidase genes were not. Moreover, FB-2 cells produced high levels of interleukin (IL)-6 and IL-8.
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