Conversion Therapy of RAS/BRAF Wild-Type Right-Sided Colon Cancer Patients With Initially Unresectable Liver Metastases
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2696397 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The prognosis of patients with metastatic right-sided colon cancer is worse than that of patients with metastatic left-sided cancer. Different guidelines have different recommendations on specific conversion therapy for colorectal liver metastases. The United States NCCN guidelines do not recommend standard chemotherapy combined with anti EGFR monoclonal antibody for patients with right colon cancer. The European ESMO guidelines recommend that patients with Ras / BRAF wild-type right-sided colon cancer should first consider three drugs ± bevacizumab, but considering the objective response rate results, standard chemotherapy + anti EGFR monoclonal antibody is still one of the choices. China CSCO guidelines recommend standard chemotherapy ± bevacizumab, and also recommend standard chemotherapy + cetuximab for patients with right-sided colon cancer.
Therefore, the targeted therapy for RAS / BRAF wild-type metastatic right colon cancer is still controversial. Therefore, we are ready to carry out the clinical trial of cetuximab and bevacizumab in conversion therapy for RAS / BRAF wild-type metastatic right colon cancer. The conversion resection rate is the primary point, and the objective response rate, perioperative safety and long-term survival are the secondary points.
| 2349751 | ecrin-mdr-crc
Project description:Interventions: FOLFOXIRI plus Cetuximab:FOLFOXIRI plus Cetuximab;FOLFOXIRI plus Bevacizumab:FOLFOXIRI plus Bevacizumab
Primary outcome(s): conversion-to-resection rate
Study Design: Parallel
| 2698094 | ecrin-mdr-crc
Project description:Evidence suggests that the addition of cetuximab or bevacizumab to doublet regimens could improve response rate and resectability rate of liver metastases and survival in colorectal liver metastases (CRLM). Moreover, it is observed that FOLFOXIRI yields higher response and resection rates compared with doublet regimens. However, which is better in conversion therapy of RAS/BRAF wild-type initially unresectable CRLM, FOLFOXIRI plus cetuximab or bevacizumab, remains unknown.
In this study, RAS/BRAF wild-type colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab and mFOLFOXIRI plus bevacizumab. Patient imaging will be reviewed for resectability by MDT, consisting of at least one radiologist and three liver surgeons every assessment. MDT review will be performed prior to randomization as well as during treatment, as described in the protocol.
| 2362223 | ecrin-mdr-crc
Project description:Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.
| S-EPMC8187652 | biostudies-literature
Project description:BackgroundLimited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.MethodsWe conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.ResultsIn comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer.ConclusionsMucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.
| S-EPMC8895744 | biostudies-literature
Project description:BackgroundDoublets plus anti-epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI-bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI-bevacizumab versus doublets plus anti-EGFRs is available in left-sided RAS/BRAF wild-type mCRC.Materials and methodsWe selected patients with left-sided RAS and BRAF wild-type mCRC treated with first-line FOLFOX-panitumumab or FOLFOXIRI-bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score-based analysis was performed to compare FOLFOXIRI-bevacizumab with FOLFOX-panitumumab.ResultsA total of 185 patients received FOLFOX-panitumumab and 132 received FOLFOXIRI-bevacizumab. Median progression-free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI-bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX-panitumumab group (propensity score-adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64-1.04; p = .11; propensity score-adjusted HR for OS, 0.80; 95% CI, 0.59-1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI-bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI-bevacizumab and FOLFOX-panitumumab are valuable treatment options in left-sided RAS/BRAF wild-type mCRC.Implications for practiceA propensity score-based analysis of five trials was performed to compare FOLFOX-panitumumab versus FOLFOXIRI-bevacizumab in left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI-bevacizumab achieved numerically superior survival outcomes versus FOLFOX-panitumumab. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group. These observations suggest that although doublet chemotherapy plus anti-EGFRs remains the preferred treatment in patients with left-sided RAS/BRAF wild-type mCRC, FOLFOXIRI-bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients' preference and potential impact on quality of life.
| S-EPMC8018298 | biostudies-literature
Project description:Growing evidence indicates that primary tumor location of metastatic colorectal cancer (mCRC) can affect response to specific therapy. This study aimed to assess the impact of primary tumor location on efficacy of cetuximab in Chinese patients with mCRC. We included patients with RAS wild-type liver-limited mCRC treated with first-line cetuximab plus chemotherapy or chemotherapy alone between June 2008 and December 2016. All patients were categorized as having left-sided tumors or right-sided tumors. Progression free survival (PFS), overall survival (OS), objective response rate (ORR) and conversion rate of surgery for liver metastases was analyzed according to tumor location and treatment. Right-sided tumors were characterized with larger primary tumor, poorer differentiation, more lymph node metastases and larger and more liver metastases. For patients with left-sided tumors (N=233), addition of cetuximab to chemotherapy significantly improved ORR (68.9% vs. 30.6%, OR=5.01, P < 0.001), conversion rate of liver surgery (33.5% vs. 10.8%, OR=4.18, P < 0.001), PFS (12.1 months vs. 6.1 months, HR=0.42, P < 0.001), and OS (not evaluable vs. 23.1 months, HR=0.31, P < 0.001). Among patients with right-sided tumors (N=85), cetuximab plus chemotherapy, compared with chemotherapy alone, also significantly improved ORR (56.8% vs. 29.3%, OR=3.18, P=0.010), PFS (9.3 months vs. 5.1 months, OR=0.57, P=0.012) and OS (25.3 months vs. 16.8 months, HR=0.56, P=0.032) but conversion rate of liver surgery (20.5% vs. 9.8%, HR=2.38, P=0.171). Our results demonstrated differential effect of cetuximab on efficacy outcomes based on tumor sidedness. Also, we found that patients with right-sided tumors also benefit from cetuximab plus chemotherapy but not as great as left-sided tumors and in general, did worse. In conclusion, findings of previous studies about differential effect of anti-EGFR therapy based on tumor sidedness are applicable to an Asian population.
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Project description:To compare protein expression levels, gene mutation and survival among Right-Sided Colon Cancer (RSCC), Left-Sided Colon Cancer (LSCC) and rectal cancer patients, 57 cases of RSCC, 87 LSCC and 145 rectal cancer patients were included retrospectively. Our results demonstrated significant differences existed among RSCC, LSCC and rectal cancer regarding tumor diameter, differentiation, invasion depth and TNM stage. No significant difference was identified in expression levels of MLH1, MSH2, MSH6, PMS2, β-Tubulin III, P53, Ki67 and TOPIIα, and gene mutation of KRAS and BRAF among three groups. Progression Free Survival (PFS) of RSCC was significantly lower than that of LRCC and rectal cancer. In univariate analyses, RSCC, preoperative chemoradiotherapy, poor differentiation, advanced TNM stage, elevated serum CEA and CA19-9 level, tumor deposit, perineural and vascular invasion were found to be predictive factors of shorter PFS. In multivariate analyses, only differentiation and TNM stages were found to be independent predictors of PFS. In conclusion, compared with LSCC and rectal cancer, RSCC has larger tumor size, poor differentiation, advanced TNM stage and shorter survival. The shorter survival in RSCC might be attributed to the advanced tumor stage caused by its inherent position feature of proximal colon rather than genetic difference.
| S-EPMC5554205 | biostudies-other
Project description:For patients with initially unresectable colorectal liver metastasis (IU-CRLM) receiving effective conversion therapy, disease relapse after conversion hepatectomy is common due to the extensive tumor load. Yet, few studies have focused on the assessment and management of relapse after conversion hepatectomy for IU-CRLM. This study aimed to investigate the impact of surgical management for relapse after conversion hepatectomy in IU-CRLM.
| 2742045 | ecrin-mdr-crc
Project description:Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutant-type. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.
| S-EPMC7160543 | biostudies-literature