Published papers

IMPORTANCE: Amplification of ERBB2 (formerly referred to as HER2) is present in nearly 3% of patients with metastatic colorectal cancer overall and 5% of patients with KRAS and NRAS wild-type tumors. Despite the availability of several ERBB2-targeted therapeutic options for patients with ERBB2-positive breast and gastric/gastroesophageal tumors, to date, there are currently no approved therapies for patients with ERBB2-positive metastatic colorectal cancer, although ERBB2-targeted therapies are recommended in National Comprehensive Cancer Network guidelines. Recent evidence indicates that anti-ERBB2 therapeutic strategies are active in patients with ERBB2-positive metastatic colorectal cancer and could potentially represent a new standard-of-care. OBSERVATIONS: The protein ERBB2 is a member of a family of epidermal growth factor receptors that also includes epidermal growth factor receptor (ERBB1), ERBB3, and ERBB4. Amplification of ERBB2 leads to overexpression of the ERBB2 tyrosine kinase receptor, resulting in aberrant signaling and cell migration, growth, adhesion, and differentiation. Colorectal tumors that harbor ERBB2 amplification are more likely to originate on the left side of the colon, are associated with primary and acquired resistance to anti-epidermal growth factor receptor therapies, and have increased incidence of central nervous system metastases. Using immunohistochemistry, fluorescence in situ hybridization, next-generation sequencing, and liquid biopsy techniques, several randomized clinical trials have evaluated the efficacy of ERBB2-targeted therapies in patients with ERBB2-positive metastatic colorectal cancer. These therapies include monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors, many of which were associated with favorable efficacy and safety profiles when treating patients with ERBB2-positive metastatic colorectal cancer. CONCLUSIONS AND RELEVANCE: The results of this review suggest the ERBB2 receptor is a promising target for patients with metastatic colorectal cancer; however, to date, no therapies are approved for use in this patient population. Therefore, it is imperative to continue to work to address this unmet need so that patients with ERBB2-positive metastatic colorectal cancer have therapeutic options should they become refractory to treatment with standard therapies.

The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis.We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations.Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence.Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

(-)-Epigallocatechin-3-O-gallate (EGCg), the major catechin responsible for the health-enhancing and disease-preventive effects of green tea, is susceptible to auto-oxidation at physiological pH levels. However, whether the oxidized EGCg resulting from its oral consumption possesses any bioactive functions remains unclear. This study presents a differential analysis of intact and oxidized EGCg regarding their interactions with phosphatidylcholine liposomes, serving as a simple biomembrane model. In the presence of ascorbic acid, pre-oxidized EGCg induced liposomal aggregation in a dose-dependent manner, whereas intact EGCg did not. Toxicity evaluation using calcein-loaded liposomes revealed that liposomal aggregation is associated with minimal membrane damage. Through fractionation of the oxidized EGCg sample, the fraction containing theasinensins showed high liposomal aggregation activity. Overall, these results suggest that oxidatively condensed EGCg dimers may stimulate various cells by altering the plasma membrane in a manner different from that of EGCg monomers.

BACKGROUND: Cancer progression following chemotherapy is a significant barrier to effective cancer treatment. We aimed to evaluate the role of drug-exposed cancer-associated fibroblasts (CAFs) in the growth and progression of drug-exposed gastric cancer (GC) cells and to explore the underlying molecular mechanism. METHODS: The human GC cell line 44As3 and CAFs were treated with 5-fluorouracil and oxaliplatin (5FU + OX). 5FU + OX-pretreated 44As3 cells were then cultured in a conditioned medium (CM) from 5FU + OX-pretreated CAFs, and the growth and migration/invasion ability of the cells were evaluated. We also compared the clinicopathological characteristics of the GC patients treated with S1 + OX in accordance with the properties of their resected specimens, focusing on the number of CAFs. Changes in gene expression in CAFs and 44As3 cells were comprehensively analyzed using RNA-seq analysis. RESULTS: The CM from 5FU + OX-pretreated CAFs promoted the migration and invasion of 5FU + OX-pretreated 44As3 cells. Although the number of cases was relatively small (n = 21), the frequency of positive cases of lymphovascular invasion and the recurrence rate were significantly higher in those with more residual CAF. RNA-seq analysis revealed 5FU + OX-pretreated CAF-derived glycoprotein 130 (gp130) as a candidate factor contributing to the increased migration of 5FU + OX-pretreated 44As3 cells. Administration of the gp130 inhibitor SC144 prevented the increased migration ability of 5FU + OX-pretreated 44As3 cells owing to drug-treated CAFs. CONCLUSIONS: Our findings provide evidence regarding the interactions between GC cells and CAFs in the tumor microenvironment following chemotherapy, suggesting that ligands for gp130 may be novel therapeutic targets for suppressing or preventing metastasis in GC.

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

PURPOSE: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). MATERIALS AND METHODS: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. RESULTS: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). CONCLUSION: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.

KRAS gene mutations can predict prognosis and treatment response in patients with metastatic colorectal cancer (mCRC).We undertook a meta-analysis of three randomized, placebo-controlled trials (RECOURSE, TERRA and J003) to investigate the impact of KRAS mutations in codons 12 or 13 on overall survival (OS) and progression-free survival in patients receiving trifluridine/tipiracil (FTD/TPI) for refractory mCRC.A total of 1375 patients were included, of whom 478 had a KRAS codon 12 mutation and 130 had a KRAS codon 13 mutation. In univariate analyses, the absence of a KRAS codon 12 mutation was found to significantly increase the OS benefit of FTD/TPI relative to placebo compared with the presence of the mutation {hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.53-0.72] versus 0.86 (0.70-1.05), respectively; interaction P = 0.0206}. Multivariate analyses showed that taking confounding factors into account reduced the difference in treatment effect between the presence and the absence of KRAS codon 12 mutations, confirming that treatment benefit was maintained in patients with [HR, 0.73 (95% CI: 0.59-0.89)] and without [HR, 0.63 (95% CI: 0.54-0.74)] codon 12 mutations (interaction P = 0.2939). KRAS mutations in codon 13 did not reduce the OS benefit of FTD/TPI relative to placebo, and, furthermore, KRAS mutations at either codon 12 or codon 13 did not affect the progression-free survival benefit.Treatment with FTD/TPI produced a survival benefit, relative to placebo, regardless of KRAS codon 12 or 13 mutation status in patients with previously treated mCRC.

Background: HER2-amplified metastatic colorectal cancer (mCRC) is a clinically relevant subgroup for HER2-targeted therapy. The TRIUMPH and MyPathway studies demonstrated the activity of pertuzumab plus trastuzumab (PER + TRA) in that population. Our integrated analysis assessed the effect of prior anti-epidermal growth factor receptor (EGFR) therapy on PER + TRA efficacy and explored the role of baseline circulating tumor DNA (ctDNA) profiling. Materials and methods: The analysis enrolled patients with HER2-amplified mCRC from TRIUMPH and MyPathway who had baseline ctDNA available. Anti-EGFR resistance alterations were defined as RAS, BRAF, or PIK3CA mutations; EGFR ectodomain mutation; or MET amplification. Clinical outcomes with PER + TRA were analyzed in patients who had tissue-based RAS wild-type tumors, stratified by prior anti-EGFR therapy and the presence of resistance alterations. Results: Of 66 enrolled patients, 47 had received prior anti-EGFR therapy. Prior anti-EGFR therapy was associated with inferior overall survival (OS) [median: 10.9 versus 19.7 months; hazard ratio (HR): 2.01] and numerically shorter progression-free survival. ctDNA profiling identified anti-EGFR resistance alterations in 18 patients (27.3%), with an associated absence of objective response (0% versus 31.3%) and a significantly shorter OS (median: 7.6 versus 16.5 months; HR: 2.15). Outcomes were markedly poorer (including shorter OS and lower response rates) in patients with either prior anti-EGFR therapy or resistance alterations than in patients with neither factor. Conclusions: Prior anti-EGFR therapy and resistance alterations detected by baseline ctDNA profiling are associated with reduced efficacy of PER + TRA in HER2-amplified mCRC. Integrating treatment history with baseline ctDNA profiling might enable improved patient selection for dual HER2-targeted therapy.

PURPOSELow concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology.MATERIALS AND METHODSWe investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315).RESULTSOf 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS/BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P <.001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%).CONCLUSIONPatients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection.