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The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II-III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.0001) and overall survival (OS; HR: 9.68, P < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR: 2.71, P < 0.0001). The significantly shorter DFS in MRD-positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to ACT was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%). True spontaneous clearance rate with no clinical recurrence was 1.9% (2/105). Overall, our findings provide evidence for the utility of ctDNA monitoring for post-resection recurrence and mortality risk stratification that could be used for guiding adjuvant therapy., Competing Interests: Competing interests Y.N. reports advisory roles with Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation and Gilead Sciences, Inc.; speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company and Guardant Health Japan Corp.; research funding from Seagen, Inc., Genomedia, Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd. and Chugai Pharmaceutical Co., Ltd. J.W. reports receiving honoraria for lectures from Johnson & Johnson, Medtronic, Eli Lilly and Takeda Pharmaceuticals and receiving research funding from Medtronic, AMCO, TERUMO and Stryker Japan, all outside the submitted work. N.A. reports nothing to declare. K.H. reports nothing to declare. K. Kataoka reports speakers’ bureau from Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd. and Guardant Health Japan Corp. and research funding from Sysmex. M.Y. reports receipt of personal fees and honoraria for lectures from Medtronic, Johnson & Johnson, INTUITIVE, Eli Lilly, Taiho, Merck KGaA, Takeda and Daiichi Sankyo. K. Kato reports nothing to declare. M.K. reports speakers’ bureau from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Yakult Honsha. Y.K. reports speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. and Ono Pharmaceutical Co., Ltd. K.H.Y. reports payment or honoraria for lectures, presentations and speakers’ bureaus from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd, TTY Biopharm Co. Ltd., OEP Group Co., Ltd., Bristol Myers Squibb, Amgen, Inc., Bayer Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Biopharma Co., Ltd., Novartis Co., Ltd. and CStone Pharmaceuticals Co., Ltd. and advisory roles with Merck & Co., Inc, Pfizer Inc., Pierre Fabre, Ltd. and AstraZeneca. S.M. reports honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Eli Lilly. H.Y. reports nothing to declare. K.A. reports nothing to declare. M. Miyo reports nothing to declare. T.M. reports advisory role with Anaut, Inc. and Fujifilm Corporation and speakers’ bureau from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd. and Miyarisan Pharmaceutical Co., Ltd. K.Y. reports speakers’ bureau from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Yakult Honsha Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., MSD Co., Ltd. and Bristol Myers Squibb and research funding from Taiho Pharmaceutical Co., Ltd. H.E. reports honoraria from Amgen, Chugai Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Incyte Japan Co., Ltd., Merck Serono Co., Ltd., Ono Pharmaceutical Co., Ltd. and Konica Minolta Co, Ltd. and research funding from Astellas Pharmaceutical Co., Ltd. K.O. reports speakers’ bureau from Taiho Pharmaceutical Co., Ltd. A.H. reports receiving honoraria for lectures from Medtronic, Johnson & Johnson, Merck Biopharma Co., Ltd., Eli Lilly and Fujifilm Corporation. H.S. reports nothing to declare. S.K. is a full-time employee of EPS Corporation. G.L., V.N.A., S.S. and A.J. are employees of Natera, Inc., with stock or options to own stock. M.C.L. is an employee of Natera, Inc., with stock or options to own stock, and further reports grants/contracts (funding to institution: Mayo Clinic) from Eisai, Exact Sciences Corporation, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics and Tesaro; travel support reimbursement from AstraZeneca, Genomic Health and Ionis; and ad hoc advisory board meetings (all funds to Mayo Clinic; no personal compensation) from AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics and Syndax. A.A. is an employee of Natera, Inc., with a leadership position and stock or options to own stock. M.R. reports employment, leadership position, stock and other ownership interests and consulting and advisory role at Natera, Inc., MyOme and Marble Therapeutics and research funding, patents/royalties/other intellectual property and travel/accommodations/expenses from Natera, Inc. and MyOme. H.B. reports research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Eli Lilly Japan and Taiho Pharmaceutical. H.T. reports speakers’ bureau from MSD K.K, Merck Biopharma Co., Ltd., Takeda, Taiho, Eli Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharmaceutical, Ono Yakuhin and Amgen and research funding from Takeda and Daiichi Sankyo. I.T. reports speakers’ bureau from Medtronic, Johnson & Johnson, Intuitive, Medicaroid and Eli Lilly and research funding from Medtronic and Sysmex. T.K. reports nothing to declare. D.K. reports honoraria from Takeda, Chugai, Eli Lilly, MSD, Ono Pharmaceutical, Seagen, Guardant Health, Eisai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Pfizer, Merck Biopharma Co., Ltd. and Sysmex and research funding from Ono Pharmaceutical, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, CIMIC and Cimicshiftzero. M. Mori reports nothing to declare. T.Y. reports honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma Co., Ltd., Bayer Yakuhin, Ono Pharmaceutical and MSD K.K; consulting fee from Sumitomo Corp.; and research funding from Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho Pharmaceutical and Takeda Pharmaceutical. E.O. reports speakers’ bureau from Chugai Pharmaceutical Co., Ltd., Bristol Meyers Squibb, Ono Pharmaceutical Co., Ltd., Eli Lilly and Takeda Pharmaceutical Co., Ltd.; research funding from Guardant Health, Inc.; and an advisory role with GlaxoSmithKline., (© 2024. The Author(s).)

Background/aim: The immune microenvironment in cancer correlates with cancer progression and patient prognosis. Cancer immune microenvironment evaluation, based on CD3 + and CD8 + T cell infiltration at the center and invasive margin of the tumor, is defined as the immunoscore. An international multicenter analysis revealed that the immunoscore can accurately predict the prognosis of patients with colorectal cancer (CRC) (stage I, II, and III). However, no markers are currently available to predict the prognosis in patients with stage IV CRC. We thus aimed to analyze the immune microenvironment in patients with stage IV CRC in this study., Patients and Methods: We analyzed the immune microenvironment of patients with stage IV CRC using immunohistochemical (IHC) staining. We evaluated the expressions of CD8 and the cases were divided into CD8 high (CD8 Hi ) and CD8 low (CD8 Low ) groups according to median CD8 expression. HLA class 1 (HLA1) expression was also evaluated using IHC staining and the cases were divided into HLA1 Hi group and HLA1 Low group according to 50% of HLA1 expression rate. CD8×HLA1 score was defined by the combination of CD8 and HLA1 expressions., Results: CD8 Hi and HLA1 Hi cases were associated with better prognosis compared with CD8 Low and HLA1 Low cases according to a log-rank test, respectively. We defined a novel biomarker by combining CD8 + T-cell infiltration and HLA1 expression, referred to as the CD8×HLA1 score. We found that CD8×HLA1 Hi cases predicted patient prognosis better than CD8×HLA1 Int and CD8×HLA1 Low according to a log-rank test., Conclusion: The combination of CD8 + T cell infiltration and HLA1 expression is crucial for cancer immune microenvironment evaluation in CRCs., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Folate plays a pivotal role in the one-carbon metabolism needed for methylation reactions, nucleotide synthesis, and DNA repair. Although folate metabolism was recently shown to be associated with carcinogenesis in some solid tumors, the importance of folate metabolism in colorectal cancer remains unclear. In the present investigation we found that expression of three mitochondrial folate metabolic enzymes, serine hydroxymethyl transferase (SHMT2), methylenetetrahydrofolate dehydrogenase (MTHFD2) and aldehyde dehydrogenase 1 family member L2 (ALDH1L2), were upregulated in human colorectal tumor tissues compared to normal tissues. Colorectal cancer tissue samples were obtained from 117 consecutive patients. We evaluated the expression of the enzymes with immunohistochemical analysis and determined their relevance to clinicopathological characteristics and prognosis. Rates of recurrence-free survival (RFS) and overall survival (OS) in patients with high expression of SHMT2, MTHFD2 and ALDH1L2 tended to be lower than in patients with low expression of SHMT2, MTHFD2 and ALDH1L2 (P=0.446 and P=0.337, P=0.099 and P=0.064, P=0.178 and P=0.257, respectively). Notably, the combined high expression of SHMT2, MTHFD2 and ALDH1L2 (triple high) was more highly associated with poor prognosis than the individual expression levels (RFS; P=0.004 and OS; P=0.037). A multivariate analysis showed that triple high expression was independently associated with RFS (P=0.017). These findings suggested that mitochondrial folate metabolic enzymes could provide a potential therapeutic strategy for treating colorectal cancer.

Tumor cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone. Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions. Furthermore, we identified pivotal roles of GLUD1 and SLC25A13 in nutritional stress. GLUD1 and SLC25A13 were associated with tumor aggressiveness and poorer prognosis of colorectal cancer. In conclusion, GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments., Competing Interests: Institutional endowments were partly received from Taiho Pharmaceutical Co., Ltd. (http://www.taiho.co.jp/english/), the Evidence Based Medical (EBM) Research Center (http://ebmrce.co.jp/index.html), Chugai Co., Ltd. (http://www.chugai-pharm.co.jp/english/index.html), Yakult Honsha Co., Ltd. (http://www.yakult.co.jp/english/index.html), and Merck Co., Ltd. (http://www.merck.co.jp/en/index.html). Those funders had no role in the main experimental equipment, supply expenses, study design, data collection and analysis, decision to publish, or preparation of the manuscript for this work.

Purpose: One of the main reasons for cancer treatment resistance is the existence of cancer stem-like cells (CSCs). Here, we elucidated the relationship between low proteasome activity cells (LPACs) and CSCs., Experimental Design: The human colorectal cancer cell lines HCT116, SW480, DLD1, and KM12SM were engineered to stably express a green fluorescent molecule fused to the degron of ornithine decarboxylase, resulting in an accumulation of the fluorescence in LPACs. LPACs were isolated by flow cytometry. Treatment resistance (radio- and chemotherapy) and the capacity of LPACs to act as CSCs were analyzed. Microarray analysis was performed to reveal genes related to treatment resistance. The prognostic impact of potent genes was examined in 190 patients with colorectal cancer., Results: LPACs had a significantly increased capacity for radioresistance and chemoresistance (5-fluorouracil and oxaliplatin), significantly lower reactive oxygen species activity, and significantly increased sphere formation capacity compared with non-LPACs. The number of cells in the G 0 -G 1 phase was significantly higher among LPACs. Subcutaneous injection of as few as 20 LPACs led to tumor formation in immunologically incompetent mice. Microarray analysis revealed that the expression of EP300-interacting inhibitor of differentiation 3 (EID3) was significantly increased in LPACs. In vitro assay revealed that EID3 positively controlled cell proliferation and treatment resistance. The high expression of EID3 was an adverse prognostic indicator in patients with colorectal cancer (P = 0.0400)., Conclusions: LPACs have characteristic treatment resistance and act as CSCs in colorectal cancer. In addition, EID3 is one of the potential regulators of treatment resistance in colorectal cancer and may be a potential therapeutic target. Clin Cancer Res; 22(21); 5277-86. ©2016 AACR., (©2016 American Association for Cancer Research.)