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.

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30–40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC. Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms. Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors. Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival.

Aim: Although MRI has a substantial role in directing treatment decisions for locally advanced rectal cancer, precise interpretation of the findings is not necessarily available at every institution. In this study, we aimed to develop artificial intelligence-based software for the segmentation of rectal cancer that can be used for staging to optimize treatment strategy and for preoperative surgical simulation. Method: Images from a total of 201 patients who underwent preoperative MRI were analyzed for training data. The resected specimen was processed in a circular shape in 103 cases. Using these datasets, ground-truth labels were prepared by annotating MR images with ground-truth segmentation labels of tumor area based on pathologically confirmed lesions. In addition, the areas of rectum and mesorectum were also labeled. An automatic segmentation algorithm was developed using a U-net deep neural network. Results: The developed algorithm could estimate the area of the tumor, rectum, and mesorectum. The Dice similarity coefficients between manual and automatic segmentation were 0.727, 0.930, and 0.917 for tumor, rectum, and mesorectum, respectively. The T2/T3 diagnostic sensitivity, specificity, and overall accuracy were 0.773, 0.768, and 0.771, respectively. Conclusion: This algorithm can provide objective analysis of MR images at any institution, and aid risk stratification in rectal cancer and the tailoring of individual treatments. Moreover, it can be used for surgical simulations.

Aim: In Japan, we have not been able to validate the results of laparoscopic surgery for locally advanced rectal cancer using the universal index “circumferential resection margin (CRM).” Previously, we established a semi‐opened circular specimen processing method and validated its feasibility. In the PRODUCT trial, we aimed to assess CRM in patients with locally advanced rectal cancer who underwent laparoscopic rectal resection.Methods: This was a multicenter, prospective, observational study. Eligible patients had histologically confirmed rectal adenocarcinoma located at or below 12 cm above the anal verge with clinical stage II or III and were scheduled for laparoscopic or robotic surgery. The primary endpoint was pathological CRM. CRM ≤1 mm was defined as positive.Results: A total of 303 patients operated on between August 2018 and January 2020 were included in the primary analysis. The number of patients with clinical stage II and III was 139 and 164, respectively. Upfront surgery was performed for 213 patients and neoadjuvant therapy for 90 patients. The median CRM was 4.0 mm (IQR, 2.1‐8.0 mm), and CRM was positive in 26 cases (8.6%). Univariate and multivariate analyses demonstrated that a predicted CRM from the mesorectal fascia of ≤1 mm on MRI was the significant factor for positive CRM (P = .0012 and P = .0045, respectively).Conclusion: This study showed the quality of laparoscopic rectal resection based on the CRM in Japan. Preoperative MRI is recommended for locally advanced rectal cancer to prevent CRM positivity.

In the paradigm shift related to rectal cancer treatment, we have to understand a variety of new emerging topics to provide appropriate treatment for individual patients as precision medicine. However, information on surgery, genomic medicine, and pharmacotherapy is highly specialized and subdivided, creating a barrier to achieving thorough knowledge. In this review, we summarize the perspective for rectal cancer treatment and management from the current standard‐of‐care to the latest findings to help optimize treatment strategy.