TY - JOUR
T1 - Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer
AU - Jogo, Tomoko
AU - Nakamura, Yoshiaki
AU - Shitara, Kohei
AU - Bando, Hideaki
AU - Yasui, Hisateru
AU - Esaki, Taito
AU - Terazawa, Tetsuji
AU - Satoh, Taroh
AU - Shinozaki, Eiji
AU - Nishina, Tomohiro
AU - Sunakawa, Yu
AU - Komatsu, Yoshito
AU - Hara, Hiroki
AU - Oki, Eiji
AU - Matsuhashi, Nobuhisa
AU - Ohta, Takashi
AU - Kato, Takeshi
AU - Ohtsubo, Koushiro
AU - Kawakami, Takeshi
AU - Okano, Naohiro
AU - Yamamoto, Yoshiyuki
AU - Yamada, Takanobu
AU - Tsuji, Akihito
AU - Odegaard, Justin I.
AU - Taniguchi, Hiroya
AU - Doi, Toshihiko
AU - Fujii, Satoshi
AU - Yoshino, Takayuki
N1 - Funding Information:
We would like to thank the Translational Research Support Section of the National Cancer Center Hospital East for study management and data center support; Geneticlab Co., Ltd. and Thermo Fisher Scientific, Inc. for data analysis; and Mari Takahashi and Yuka Nakamura for their excellent technical assistance. This work was supported by grants from the Japan Agency for Medical Research and Development (20ck0106447h0002 to T. Yoshino).
Funding Information:
Y. Nakamura reports grants from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Guardant Health, Inc., Genomedia, Inc., and Seagen, Inc. outside the submitted work. K. Shitara reports grants and personal fees from Astellas Pharma, Eli Lilly and Company, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, and Merck Pharmaceutical; personal fees from Bristol-Myers Squibb, Takeda Pharmaceuticals, Pfizer Inc., Novartis, AbbVie Inc., Yakult, GlaxoSmithKline, Amgen, and Boehringer Ingelheim; and grants from Dainippon Sumitomo Pharma, Chugai Pharma, Medi Science, and Eisai outside the submitted work. H. Bando reports personal fees from Eli Lilly Japan and Taiho Pharmaceutical outside the submitted work. H. Yasui reports grants from MSD, Ono Pharmaceutical; grants and personal fees from Daiichi Sankyo; and personal fees from Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb Japan, TERUMO, Eli Lilly Japan, Merck Bio-pharma, and Yakult Honsha outside the submitted work. T. Esaki reports grants and personal fees from MSD, Ono, Daiichi Sankyo, and Merck Serono; grants from Novartis, Dainippon Sumitomo, Astellas, AstellasAmgenBiopharma, BeiGene, Pierre Fabre Medicament, Ignyta, and Array BioPharma; and personal fees from Bayer, Eli Lilly, Taiho, Chugai, Sanofi, and Takeda outside the submitted work. T. Satoh reports grants and personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha, Eli-Lilly, MSD, Daiichi-Sankyo, and Taiho Pharmaceutical, as well as grants from Gilead, BeiGene, and Astellas outside the submitted work. T. Nishina reports grants and personal fees from Taiho Pharmaceutical Co., Chugai Pharmaceutical Co., Ono Pharmaceutical Co., Bristol-Myers Squibb, and Lilly Pharma, as well as grants from MSD, Sumitomo Dainippon Pharma Co., and AstraZeneca outside the submitted work. Y. Sunakawa reports grants and personal fees from Takeda, Sanofi, Chugai Pharmaceutical, and Taiho Pharmaceutical; personal fees from Bristol-Myers Squib, Merck Biopharma, and Lilly Japan; and grants from Otsuka Pharmaceutical outside the submitted work. H. Hara reports grants from Astellas, AstraZeneca, Eisai, Elevar, GSK, Incyte, Pfizer, and BeiGene; grants and personal fees from Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Merck, MSD, Ono, and Taiho; and personal fees from BMS, Kyowa Hakko Kirin, Sanofi, Takeda, and Yakult outside the submitted work. E. Oki reports other support from Taiho Pharm during the conduct of the study, as well as other support from Eli Lilly, Bayer, Chugai Pharm, and Ono Pharm outside the submitted work. T. Ohta reports personal fees from Bristol-Myers Squibb Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd, and Eisai Co., Ltd. outside the submitted work. T. Kawakami reports personal fees from Bayer, Taiho Pharmaceutical, Takeda, Ono Pharmaceutical, and Bristol-Myers Squibb outside the submitted work. N. Okano reports personal fees from Taiho Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, Eisai, Bayer Yakuhin, Chugai, J-Pharma, Ono Pharmaceutical, Takeda, and GSK outside the submitted work. T. Yamada reports personal fees from Johnson and Johnson, Taiho, Ono, and Nippon Kayaku outside the submitted work. A. Tsuji reports personal fees from Takeda Pharmaceutical Company Limited, Sanofi Corporation, and Pfizer Japan Inc.; grants and personal fees from Merck Serono Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd., Ono Pharmaceutical Co.,
Publisher Copyright:
©2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/10/15
Y1 - 2021/10/15
N2 - Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number. Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.
AB - Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number. Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=85117439498&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-1414
DO - 10.1158/1078-0432.CCR-21-1414
M3 - Article
C2 - 34376535
AN - SCOPUS:85117439498
VL - 27
SP - 5619
EP - 5627
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 20
ER -
