Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II–IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49–24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT.

BackgroundStandard treatment for unresectable esophageal squamous cell carcinoma (ESCC) without distant metastasis is definitive chemoradiotherapy (dCRT), in which the incidence of esophageal fistula (EF) is reported to be 10–12%. An ad hoc analysis of JCOG0303, a phase II/III trial of dCRT for patients with unresectable ESCC (including non-T4b), suggested that esophageal stenosis is a risk factor for EF. However, risk factors for EF in patients limited to T4b ESCC treated with dCRT have yet to be clarified. The aim of this study was to investigate risk factors for EF in T4b thoracic ESCC treated with dCRT.MethodsWe retrospectively analyzed the data of consecutive T4b thoracic ESCC patients who were treated with dCRT (cisplatin and fluorouracil) at Shizuoka Cancer Center between April 2004 and September 2015.ResultsExcluding 8 patients with esophageal fistula clearly attributable to other iatrogenic interventions, the data of 116 patients who met the inclusion criteria were analyzed. Esophageal fistula was observed in 28 patients (24%). Although the fistula was closed in 5 patients, overall survival was significantly shorter in patients who experienced esophageal fistula (8.0 vs. 26.8 months; p < 0.0001). Among four potential variables extracted in univariate analysis, namely, total circumferential lesion, elevated CRP level, elevated white blood cell count, and anemia, the first two were revealed as risk factors for esophageal fistula in multivariate analysis.ConclusionsThis study demonstrated that total circumferential lesion and CRP ≥1.00 mg/dL are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT.Trial registrationThis study was retrospectively registered.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4486-3) contains supplementary material, which is available to authorized users.

9 Background: Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) has the potential to select patients who may benefit more from standard-of-care (SOC) adjuvant chemotherapy (ACT) by accurately assessing recurrence-risk post-surgery and by evaluating ACT efficacy. Here we present an analysis from GALAXY study, an observational study monitoring MRD, to evaluating the association of ctDNA dynamics with a short-term clinical outcome and ACT efficacy. Methods: A personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) was used for post-surgical MRD detection in colorectal cancer (CRC) patients. Six-month disease-free survival (6M-DFS) rates were analyzed excluding patients enrolled in associated phase III trials (VEGA and ALTAIR). Results: Total 1,365 CRC patients enrolled between June 2020 and April 2021 were included in this analysis; 116 pStage I, 478 pStage II, 503 pStage III, and 268 oligomet resectable pStage IV (16% [42/268] received neoadjuvant chemotherapy). 6M-DFS rate by ctDNA dynamics from 4w to 12w were 98% in ‘negative to negative’ group (N = 618), 59% in ‘negative to positive’ (N = 32), 100% in ‘positive to negative’ (N = 58), and 45% in ‘positive to positive’ (N = 78), with a significant difference between ‘positive to negative’ and ‘positive to positive’ groups with hazard ratio (HR) of 52.3 (95% CI: 7.2-380.5; p < 0.001), with a median follow-up time of 6.6 months. Further, out of 188 patients who were MRD+ at 4w with available MRD status at 12w, 95 received SOC ACT (80/95 received fluoropyrimidine [FP] + oxaliplatin and 15 received FP alone) by an investigator’s decision. ctDNA clearance rate at 12w was significantly higher in ACT vs. non-ACT; 57% (54/95) vs. 8% (7/93) in pStage I-IV (p < 0.001), and 58% (42/72) vs. 11% (4/37) in pStage II-III (p < 0.001). In addition, ctDNA clearance rate at 24w was also significantly higher in ACT vs. non-ACT; 26% (7/27) vs. 0% (0/30) in pStage I-IV (p = 0.003), and 33% (7/21) vs. 0% (0/15) in pStage II-III (p = 0.03). Cumulative incidence of ctDNA clearance was significantly higher in ACT vs. non-ACT (67% vs. 7% by 24w; cumulative HR = 17.1; 95% CI: 6.7-43.4, p < 0.001). Among 4w-MRD+ patients, 6M-DFS rate was significantly higher in ACT vs. non-ACT; 84% vs. 34% (HR = 0.15; 95% CI: 0.078-0.25; p < 0.001), which was seen in all stages, including pStage II. Conclusions: This analysis from the GALAXY study, is the largest MRD study to date, demonstrating the association of ctDNA dynamics with improved clinical outcomes in MRD+ patients. Our study shows that stratifying post-surgical treatment decisions using the assay can identify patients likely to benefit from ACT across all stages, including pStage II. ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies and will be presented in the future conferences. Clinical trial information: jRCT1031200006.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE‐Japan including three clinical trials. The GALAXY study is a prospectively conducted large‐scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high‐risk stage II or low‐risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double‐blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor–positive status in the GALAXY study. Therefore, CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for ctDNA‐negative and ‐positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA‐guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.

Background. KRAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising activities for corresponding advanced solid tumors, including metastatic CRC (mCRC). However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC. Materials and Methods. We retrospectively reviewed medical records of patients with mCRC who received first-line chemotherapy between January 2005 and December 2017 at four large oncology facilities in Japan. Survival outcomes were compared between patients with KRAS G12C and those with non-G12C mutations. Results. Among 2,457 patients with mCRC, 1,632 met selection criteria, and of these, 696 had KRAS exon 2 mutations, including 45 with KRAS G12C mutation tumors. Patient characteristics were not significantly different between the KRAS G12C and non-G12C groups. At a median follow-up of 64.8 months, patients with the KRAS G12C mutation showed significantly shorter first-line progression-free survival (PFS; median, 9.4 vs. 10.8 months; p = .015) and overall survival (OS; median, 21.1 vs. 27.3 months; p = .015) than those with non-G12C mutations. Multivariate analysis also showed that KRAS G12C mutation was significantly associated with shorter PFS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.04-1.96, p = .030) and OS (HR, 1.42; 95% CI, 1.01-2.00; p = .044). Conclusion.We demonstrate that, compared with non-G12C mutations, KRAS G12C mutation is significantly correlated with shorter first-line PFS and OS. These findings indicate the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.