RET fusions have been identified as a therapeutic target in non-small cell lung cancer (NSCLC). The establishment of molecular diagnostics for RET fusions is required for the development of molecular-targeted therapies for fusion-positive patients. We have operated molecular testing for various actionable gene alterations, including RET fusions, in our nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan).
Since 2013, RET fusions were analyzed by multiplex RT-PCR, and fusion-positive samples were confirmed by break-apart FISH. Since 2015, an amplicon-based next generation sequencing (NGS) system, Oncomine™ Comprehensive Assay was also applied in our genomic screening.
As of February 2017, 244 institutions across Japan were participating, and a total of 4015 lung cancer patients including 3392 non-squamous (Non-Sq) NSCLCs were enrolled into the LC-SCRUM-Japan. Of the Non-Sq NSCLCs, available samples for multiplex RT-PCR and NGS were 94% (3186/3392) and 90% (1671/1852), respectively. RET fusions were detected in 89 samples (2.8%), including 54 detected by NGS. The types of variants found were KIF5B-RET (n = 50, 56%), CCDC6-RET (n = 20, 22%) and undetermined (n = 19, 21%). Of the 54 RET fusion-positive samples by NGS, the positivity was confirmed using break-apart FISH in 35 (92%) of 38 available samples. Among the 1335 samples available for both RT-PCR and NGS, the concordance rate between the two assays for the detection of RET fusions were 0.99. The detection sensitivity and specificity of the fusions in NGS assay were 0.98 and 0.99.
Our nation-wide screening results revealed that this amplicon-based NGS assay showed high sensitivity and specificity for the detection of RET fusions and is clinically applicable for diagnosis of RET fusions in lung cancer.
Clinical trial identification
Legal entity responsible for the study
National Cancer Center
Astra Zeneka, Eisai, Chugai Pharmaceutical, Pfizer, DAIICHI SANKYO, Astellas Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Kyowa Hakko Kirin, Eli Lilly Japan, Takeda Pharmaceutical, Novartis Pharma, Amgen Astellas BioPharma, MSD, Merck Serono.
S. Matsumoto: Astra Zeneka, Eisai, Chugai Pharmaceutical, Pfizer, Daiichi Sankyo, Astellas Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Kyowa Hakko Kirin, Eli Lilly Japan, Takeda Pharmaceutical, Novartis Pharma, Amgen Astellas BioPharma, MSD, Merck Serono. Y. Ohe: Honorarium/Consultant/Expert Testimony/Research Funding (Institution); AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer, Bayer, Pfizer, MSD, Taiho, Clovis, Sanofi, Novartis, Kyorin, Dainippon-Sumitomo, Merck. M. Nishio: Novartis, Ono Pharmaceutical, Bristol-Myers Squibb, TAIHO Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, AstraZeneca and Honoraria, Pfizer, Bristol-Myers Squibb, Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca. T. Seto: AstraZeneca, Astellas Pharma, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Merck Serono, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Bristol-Myers Squibb, Kissei, Kyowa Hakko Kirin, Nippon Kayaku, Ono, Roche Singapore Pte, Taiho, Yakult. K. Yoh: AstraZeneca, Chugai Pharma, Boehringer Ingelheim, Lilly Japan, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Pfizer. K. Goto: Astellas Pharma, Astra Zeneka, Amgen Astellas BioPharma, Eisai, Ono, Kyowa Hakko Kirin, Daiichi Sankyo, Taiho, Takeda, Chugai, Novartis, Pfizer, MSD, Eli Lilly, Merck Serono, Bristol-Myers Squibb, Life Technologies. All other authors have declared no conflicts of interest.