554P - Novel clinical decision support (CDS) system optimizing adjuvant chemotherapy (ACT) for colorectal cancer (CRC) by integrating deep learning and circulating tumor DNA (ctDNA) molecular residual disease (MRD): GALAXY histotyping

Background

Deep learning-based markers and ctDNA MRD analysis have been developed independently to predict survival of patients (pts) with resectable CRC. Here, we developed a novel CDS system based on both technologies to facilitate individualized selection of ACT.

Methods

The GALAXY, a large-scale prospective observational study, monitored ctDNA MRD status in pts with clinical stage II–IV CRC following surgery (UMIN000039205). ctDNA was analyzed using a tumor-informed MRD assay (Signatera). We integrated an established CDS system combining DoMore-v1-CRC, a deep learning-based biomarker, pathological tumor/nodal stage, and number of lymph nodes sampled, with ctDNA MRD in pts with curatively resected pathological stage II–III CRC and available scanned hematoxylin and eosin-stained sections.

Results

Of 5581 pts with CRC enrolled between May 2020 and June 2023, 1082 with a median follow-up of 22.5 months were included in this analysis. Based on DoMore-v1-CRC and pathological stage, 537 (50%), 302 (28%), and 243 (22%) pts were classified as low, intermediate, and high-risk groups, respectively. Positive ctDNA at MRD window (2–10 weeks post-surgery) was more frequently observed in high (26%) or intermediate-risk (15%) groups compared to low-risk (10%) group. Even in ctDNA-negative pts, high-risk and intermediate-risk groups had significantly worse relapse-free survival (RFS) (high vs. low: 24-month RFS, 80.9% vs. 92.9%; HR 2.96, 95% CI 1.72–5.11; intermediate vs. low: 24-month RFS, 88.7% vs. 92.9%; HR 1.88, 95% CI 1.08–3.27). Adjustment by the propensity score revealed a significant benefit of ACT in high or intermediate-risk pts (HR 0.52, 95% CI 0.35–0.79). Low-risk groups also received a significant benefit of ACT if ctDNA at MRD window was positive (HR 0.36, 95% CI 0.17–0.76), while no clear benefit of ACT was observed in low-risk and ctDNA negative pts (HR, 0.85, 0.36–2.00).

Conclusions

Integrating DoMore-v1-CRC, pathological stage, and ctDNA MRD enable a new paradigm in which pts with CRC will receive truly personalized adjuvant chemotherapy.

Clinical trial identification

UMIN000049638.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Japan Agency for Medical Research and Development.

Disclosure

Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health Pte Ltd, MSD K.K, Eisai, Zeria Pharmaceutical, Miyarisan pharmaceutical, CareNet, Inc., Hisamitsu Pharmaceutical, Taiho Pharmaceutical, DAIICHI SANKYO Co., Ltd., Becton Dickinson, Guardant Health Japan Corp.; Financial Interests, Personal, Advisory Board: Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., DAIICHI SANKYO Co., Ltd., Takeda, Exact Sciences, Gilead Sciences, Guardant Health Pte Ltd; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics, Guardant Health AMEA, Inc., Tempus; Financial Interests, Institutional, Coordinating PI: Seagen. T. Misumi: Financial Interests, Personal, Invited Speaker: Miyarisan, Chugai. J. Watanabe: Financial Interests, Personal, Invited Speaker: Medtronic, Johnson and Johnson, Eli Lilly, Takeda Pharmaceutical Company Limited; Financial Interests, Institutional, Funding: Medtronic, TERUMO, AMCO, Stryker Japan. D. Kotani: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eli lilly, MSD, MerckBiopharma, Ono pharma, Pfizer, Taiho pharma, Takeda, Sysmex, Nihonkayaku, Novartis, Guardant Health; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Local PI: Ono pharma, MSD, Servier, Novartis, Janssen pharma, IQVIA, Syneos health, CIMIC shiftzero, CIMIC; Financial Interests, Institutional, Funding: Ono pharma. H. Bando: Financial Interests, Institutional, Research Grant: Ono pharmaceutical; Other, Lecture fee: Ono pharmaceutical, Taiho pharmaceutical, Eli Lilly Japan. H. Taniguchi: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Eli Lilly, Chugai, Taiho, Merck Biopharma, Amgen, MSD K.K, Bristol-Myers Squibb Japan, Roche Diagnostics; Financial Interests, Institutional, Coordinating PI: Takeda, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Ono. T. Kato: Financial Interests, Personal, Invited Speaker: CHUGAI PHARMACEUTICAL CO., LTD, Eli Lilly and Company, ONO Pharmaceutical Co, Takeda Pharmaceutical Company Limited; Financial Interests, Institutional, Research Grant: CHUGAI PHARMACEUTICAL CO; Financial Interests, Personal, Coordinating PI: ASAHIKASEI. E. Oki: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly, Bristol-myers squibb, MSD, Takeda Pham; Financial Interests, Institutional, Research Grant: Guardant Health. 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., Merus N.V., Bristol-Myers Squibb K.K., Medical & Biological Laboratories Co., LTD., Takeda Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.