94P - Sidedness-dependent prognostic impact of gene alterations in metastatic colorectal cancer in the nationwide cancer genome screening project in Japan (SCRUM-Japan GI-SCREEN)

Background

Treatment strategies and prognoses of patients with metastatic colorectal cancer (CRC) differ according to the sidedness of the primary tumor. Recently, TP53 gain-of-function (GOF) and non-GOF variants have been reported to be differentially associated with prognosis by sidedness. We aimed to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic CRC.

Methods

SCRUM-Japan GI-SCREEN is a comprehensive genome screening project for gastrointestinal cancer that uses next-generation sequencing. Among patients diagnosed with metastatic CRC enrolled from April 2017 to March 2019, 531 who underwent complete gene sequencing were assessed. Patients whose tumor tissues were obtained after chemotherapy and who were enrolled more than six months after the initiation of first-line chemotherapy were excluded.

Results

Overall survival significantly differed between left-sided CRC and right-sided colon cancer (CC) in the TP53 non-GOF variant, KRAS wild-type, NOTCH1 wild-type, NOTCH1 covariant, NOTCH3 sole variant without the covariant of NOTCH1 or NOTCH2, and MYC amplification. Multivariate analysis in each side revealed that TP53 GOF and KRAS variants were independent prognostic factors for poorer prognosis in left-sided CRC [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.04–2.20, P = 0.03, and HR 1.48, 95% CI 1.11–1.96, P < 0.01, respectively], while TP53 non-GOF variant, BRAF V600E, and MYC amplification in right-sided CC (HR 1.56, 95% CI 1.01–2.40, P < 0.05, HR 2.56, 95% CI 1.41–4.64, P < 0.01, and HR 2.29, 95% CI 1.17–4.51, P = 0.02, respectively). NOTCH3 sole variant was an independent prognostic factor for improved prognosis in left-sided CRC (HR 0.30, 95% CI 0.15–0.62, P < 0.01).

Conclusions

The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC. These are candidate stratification factors for clinical trials on the distinct sidedness of metastatic CRC and warrant further investigation.

Clinical trial identification

Editorial acknowledgement

We would like to thank Editage (www.editage.com) for English language editing.

Legal entity responsible for the study

The authors.

Funding

SCRUM-Japan.

Disclosure

T. Kajiwara: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bristol Myers Squibb K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. T. Nishina: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd. R. Yamashita: Financial Interests, Personal, Expert Testimony: Takeda Pharmaceutical Co., Ltd. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health AMEA; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics; Financial Interests, Institutional, Coordinating PI: Seagen. S. Yuki: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Bristol Myers Squibb K.K., Ono Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., MSD K.K., Merck Biopharma Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. H. Taniguchi: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Eli Lilly, Chugai, Taiho, Merck Biopharma; Financial Interests, Institutional, Coordinating PI: Takeda, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Ono. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: Amgen, Astellas, AstraZeneca, Bayel, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX oncology. T. Ohta: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb Japan, Chugai Pharma, Teijin Pharma, Takeda Pharmaceutical Company Limited., Taiho Pharmaceutical Co., Ltd., Eisai Co., Ltd., Yakult Honsha, MSD K.K., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo COMPANY, LIMITED., Merck & Co., Ono Pharmaceutical CO., LTD.; Financial Interests, Personal and Institutional, Coordinating PI: Takeda Pharmaceutical Company Limited. T. Esaki: Financial Interests, Institutional, Research Grant: MSD K.K., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., IQVIA Services Japan K.K., Syneos Health Inc., Chugai Pharmaceutical Co., Ltd., Amgen K.K., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Asahi Kasei Pharma Corporation; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bristol Myers Squibb K.K., MSD K.K. E. Shinozaki: Financial Interests, Personal, Invited Speaker: Guardant Health Japan Corp. A. Takashima: Financial Interests, Institutional, Research Grant: MSD K.K., Amgen K.K., Bristol Myers Squibb K.K., Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd. Y. Yamamoto: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb K.K., Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bayer Yakuhin, Ltd., Taiho Pharmaceutical Co., Ltd., Nihon Servier Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., AstraZeneca K.K., Incyte Biosciences Japan G.K. K. Yamazaki: Financial Interests, Personal, Invited Speaker: Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Lilly, Sanofi, Ono Pharmaceutical, MSD, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd. I. Hyodo: Financial Interests, Personal, Advisory Board: Asahi Kasei Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.