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.

The prognostic role of circulating-tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk-stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear. Patients with CLM without extrahepatic disease from GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex mPCR-NGS assay. ctDNA-based MRD status was evaluated 2 to 10 weeks after curative surgery, before the start of ACT. Among 6,061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 (1-48) months. ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT (33.3% vs. not reached, adjusted HR: 0.07, P <0.0001); whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% vs. 62.2%, adjusted HR: 0.68, P =0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P =0.031) was prognostic of DFS in the MRD-positive group. However, in the MRD-negative group, none of the clinicopathological factors were prognostic of DFS. Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk-stratification could be potentially incorporated in future clinical trials for CLM.

Background Whether tumour side affects the anatomical extent and distribution of lymph node metastasis in colon cancer is unknown. The impact of tumour side on the anatomical pattern of lymphatic spread in colon cancer was assessed. Methods Patients with stage III colon cancer from a Japanese multi‐institutional database who underwent extensive (D3) lymphadenectomy, which is similar in concept to complete mesocolic excision with central venous ligation, were divided into groups with right‐ and left‐sided tumours. Based on location, mesenteric lymph nodes were categorized as paracolic (L1), intermediate (L2) or central (L3). The Kaplan–Meier method was used to evaluate disease‐free survival (DFS) and overall survival (OS), and multivariable Cox models were used to evaluate the association between anatomical lymph node level, metastatic pattern and outcome. Results A total of 4034 patients with stage III colon cancer (right 1618, left 2416) were included. Unadjusted OS was worse in patients with right colon cancer (hazard ratio 1·23, 95 per cent c.i. 1·08 to 1·40; P = 0·002), but DFS was similar. Right‐sided tumours more frequently invaded L3 nodes than left‐sided lesions (8·5 versus 3·7 per cent; P < 0·001). The proportion of patients with a skipped pattern of lymphatic spread was higher in right than in left colon cancer (13·7 versus 9·0 per cent; P < 0·001). In multivariable analysis, invasion of L3 nodes was associated with worse OS in left but not in right colon cancer. The presence of skipped metastasis was associated with worse DFS in left, but not right, colon cancer. Conclusion There are significant differences in the pattern of lymph node invasion between right‐ and left‐sided stage III colon cancer, and in their prognostic significance, suggesting that tumour side may dictate the operative approach.

155 Background: Although the impact of postoperative complications, especially infectious complications (IC), on long-term survival after transthoracic esophagectomy remains controversial to date, we hypothesized that postoperative IC may affect tumor recurrence and survival of the patients (pts) undergoing transthoracic esophagectomy. Methods: The data from JCOG9907 (Ando N; Ann Surg Oncol 2012) was used to estimate the influence of IC on the outcome of current standard preoperative chemotherapy followed by surgery for clinical stage II/III squamous cell carcinoma of the thoracic esophagus. IC were classified into three: pneumonia, anastomotic leakage, and the others. OS and PFS were estimated by landmark method at 6 months from randomization. Univariate and multivariate analyses using Cox proportional hazard model were performed to assess the impact of postoperative complications on the survival after right-transthoracic esophagectomy with extended lymphadenectomy. Results: Among the 152 analyzed pts, the incidence of overall IC was 36%, among which pneumonia and anastomotic leakage were observed both in 14%. OS of pts with any IC (n=54) was shorter than that of pts without IC (HR 1.66, 95%CI [1.02-2.71]) and PFS also tended to be shorter in pts with any IC (HR 1.44, [0.92-2.23]). OS of pts with pneumonia (n=22) was shorter than that of pts without pneumonia (HR 1.82, [1.01-3.29]), and PFS also tended to be shorter in pts with pneumonia (HR 1.50, [0.85-2.62]). OS of pts with anastomotic leakage (n=21) were nearly identical to that for pts without leakage (HR 1.06, [0.52-2.13]) and PFS was slightly shorter in pts with leakage (HR 1.28, [0.71-2.32]). Multivariate analysis revealed that pneumonia tended to compromise OS and PFS (HR 1.66, [0.87-3.17] and HR 1.37, [0.75-2.51]). Conclusions: This study reveals that postoperative morbidity, especially pneumonia may deteriorate the survival of pts undergoing esophagectomy after preoperative chemotherapy. Achieving esophagectomy without postoperative complications might prolong OS and PFS. Clinical trial information: NCT00190554.