Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15547-e15547
Author(s):  
Jianwei Zhang ◽  
Cailu Shen ◽  
Jianxia Li ◽  
Zehua Wu ◽  
Huabin Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Systemic Treatment ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinicopathologic Features ◽  
Significant Difference ◽  
The Impact ◽  
Braf Mutant

e15547 Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P < 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P < 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.

scholarly journals BRAF V600E mutation in metastatic colorectal cancer: Methods of detection and correlation with clinical and pathologic features

2016 ◽  
Vol 17 (8) ◽  
pp. 840-848 ◽  
Author(s):  
Cristin Roma ◽  
Anna Maria Rachiglio ◽  
Raffaella Pasquale ◽  
Francesca Fenizia ◽  
Alessia Iannaccone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Pathologic Features

ERCC1, KRAS mutation, redox status, and oxaliplatin sensitivity in colorectal cancer: “Radical” change in an old model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14156-e14156
Author(s):  
Armando Orlandi ◽  
Mariantonietta Di Salvatore ◽  
Michele Basso ◽  
Cinzia Bagalà ◽  
Antonia Strippoli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cell Lines ◽  
Pearson Correlation ◽  
Redox Status ◽  
Mutational Status ◽  
Retrospective Clinical Study ◽  
Significant Difference ◽  
The Impact

e14156 Background: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxa in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1 and cellular Redox status. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8, HT-29) and two K-RAS mt (SW620, SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test and the ERCC1 levels before and after 24h exposure to Oxa by RT-PCR. We silenced K-RAS in a K-RAS mt cell lines to evaluate the impact on Oxa sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxa resistance factor. Cellular oxidative stress was determined by DCFDA. Results: The K-RAS mt cell lines were more sensitive to Oxa (p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24h exposure to Oxa, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (p<0.005). The silencing of K-RAS in K-RAS mt cell lines (SW620s) demonstrated to reduce sensitivity to Oxa associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxa. The levels of reactive oxygen species were higher in K-RAS mt cell lines. The Pearson correlation test showed a statistically significant relationship between basal levels of ROS and sensitivity to Oxa ("r" -0,988, p<0.01). The baseline levels of ROS were higher SW620 than the line SW620s. The administration of Oxa in these cell lines resulted in a statistically higher fluorescence index in SW620 versus SW620s (p<0.003). Conclusions: The K-RAS mutated cell lines were more sensitive to Oxa. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxa and to the synergism between K-RAS mutation and Oxa in increasing oxidative stress. K-RAS can thus be a predictor of response to Oxa in colorectal cancer.

scholarly journals MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ho Wai Derrick Siu ◽  
Niall Tebbutt ◽  
Lorraine Chantrill ◽  
Chris Karapetis ◽  
Christopher Steer ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Tumour Response ◽  
Trial Registration ◽  
First Line ◽  
The Impact

Abstract Background Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a “lighter” treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. Methods/design MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. Discussion MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12618000233224, prospectively registered 14 February 2018.

scholarly journals The impact of the Glasgow Prognostic Score on survival in second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation

2019 ◽  
Vol 11 ◽  
pp. 175883591882029 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hiroya Taniguchi ◽  
Keiji Sugiyama ◽  
Toshiki Masuishi ◽  
Kazunori Honda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Prognostic Score ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Second Line ◽  
Second Line Chemotherapy ◽  
Colorectal Cancer Patients ◽  
Line Chemotherapy

Background: BRAF (v-raf murine sarcoma viral oncogene homolog B1) V600E mutant colorectal cancer is associated with short survival. Recently, clinical trials have been conducted to improve outcomes of second or later lines of chemotherapy. However, there is a paucity of reference data pertaining to outcomes of second-line chemotherapy and prognostic factors that are relevant only to BRAF mutant patients. Patients and methods: We retrospectively reviewed metastatic colorectal cancer patients with BRAF V600E mutation who underwent second-line chemotherapy between January 2007 and March 2017. We evaluated treatment outcomes and performed prognostic analyses. Results: A total of 52 patients were included. The median progression-free survival and overall survival (OS) were 2.5 [95% confidence interval (CI) = 1.91–4.11] and 6.5 (95% CI = 4.30–9.63) months, respectively. Overall response and disease control rates were 7% and 48%, respectively. All the regimens which elicited a partial response included BRAF inhibitors in combination with anti-epidermal growth factor receptor (EGFR) antibodies. Therefore, the overall response was 0% after exclusion of patients treated with study drugs. Multivariate analysis for OS revealed that the Glasgow Prognostic Score (GPS), elevated lactate dehydrogenase, and poor performance status were independent prognostic factors. In particular, survival curves according to the GPS stratified the patients into distinct risk groups. The median OSs in patients with GPS of 0, 1, and 2 were 9.9, 5.0, and 1.9 months, respectively. Conclusions: Outcomes of second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation were extremely poor. GPS may be useful in future clinical trials.

The impact of KRAS mutation on radioembolization in the treatment of unresectable liver predominant metastatic colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 664-664
Author(s):  
Michael Schacht ◽  
Douglas M. Coldwell ◽  
Vivek Sharma
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Median Time ◽  
Metastatic Disease ◽  
Disease Burden ◽  
Hepatic Metastases ◽  
Time To Progression ◽  
Kras Status ◽  
Significant Difference ◽  
The Impact

664 Background: Radioembolization with either Yttrium-90 labeled resin or glass microspheres is an FDA approved treatment for hepatic metastases from primary colorectal cancer. Y-90 therapy is used almost exclusively in unresectable liver metastases. However, radioembolization is only an optional part of the treatment process along with first-line, second-line, and salvage chemotherapy. KRAS is a known proto-onco gene that has typically been studied as a negative prognostic factor in the chemotherapeutic treatment of metastatic colorectal cancer (mCRC). KRAS is a known marker for resistance to anti-EGFR antibodies and generally have a poorer prognosis. The aim of this study is to begin to shed light on the impact of KRAS status on the outcome of patients undergoing radioembolization for the treatment of unresectable liver predominant metastatic CRC, regardless of their chemotherapy regimens. Methods: This is a retrospective analysis of 18 subjects treated with radioembolization for liver predominant metastatic CRC. KRAS status and treatment outcomes were followed for each patient up to the study close date of 9/15/13. Statistical analysis was performed using the Mann-Whitney U test. Results: Of the 18 subjects included in the study, 5 were found to have KRAS mutant oncogene. The remaining 13 were found to have the KRAS wildtype. Overall, those subjects with KRAS mutant were found to have a statistically significant difference in median time to progression of intrahepatic metastatic disease burden when compared to KRAS wildtype even when liver-directed therapy was utilized (2.0 vs. 6.4 months). Differences in median time to progression of extrahepatic metastatic disease burden and overall survival were not found to be statistically significant at this time. Conclusions: KRAS mutant patients are exceedingly difficult to treat due to both intrahepatic and extrahepatic disease recurrence/progression.

Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 611-611 ◽  
Author(s):  
Rona D. Yaeger ◽  
Andrea Cercek ◽  
Eileen Mary O'Reilly ◽  
Diane Lauren Reidy ◽  
Nancy E. Kemeny ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Stable Disease ◽  
Tumor Regression ◽  
Performance Status ◽  
Pilot Trial ◽  
Braf V600e ◽  
Egfr Inhibition ◽  
Correlative Studies ◽  
Braf Mutant

611 Background: BRAF mutant metastatic colorectal cancer (mCRC) is an aggressive subset of colorectal cancer that exhibits minimal response to selective RAF inhibitors. Preclinical data suggest that epidermal growth factor receptor (EGFR) reactivation with RAF inhibition attenuates the efficacy of RAF inhibitors in mCRC and that combined EGFR and RAF inhibition may be a promising therapeutic strategy. Methods: We undertook a pilot trial to assess the response rate and safety of the combination of the selective RAF inhibitior vemurafenib and anti-EGFR antibody panitumumab in patients with BRAF mutant mCRC. Patients received panitumumab 6 mg/kg IV every 14 days starting on day 1 and vemurafenib 960 mg orally twice daily continuously starting on day 8, with treatment staggered for planned correlative studies. Results: Fifteen patients received treatment. Median age was 62 years (range 22-83 years), seven patients (47%) were male, and 11 patients (73%) had a right-sided primary tumor. Performance status was ECOG 0 in four patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and eight patients (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Acneiform rash (all grade 1 or 2) (53%), fatigue (53%), and arthralgias (40%) were the most frequently observed treatment-related adverse events. Treatment response was assessed in 12 patients because two patients died from disease progression before the first scan and one patient withdrew consent soon after starting treatment. Two patients (13%) had confirmed partial responses (100% and 64% regression) lasting 40 and 24 weeks, respectively. Eight patients (53%) had stable disease (SD) with tumor regression of >15% by RECIST measurement in six of these patients, including two of whom achieved stable disease lasting over six months. Conclusions: Combined RAF and EGFR inhibition is well tolerated and leads to tumor regression in a subset of patients with BRAF mutant mCRC. Planned correlative studies will evaluate degree of pathway inhibition and reactivation of other upsteam pathways with vemurafenib and panitumumab treatment. Clinical trial information: NCT01791309.

Meat consumption and BRAF mutation status in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15135-e15135
Author(s):  
Rosa L. Frias ◽  
Michael Lam ◽  
Michael J. Overman ◽  
Van K. Morris ◽  
David R. Fogelman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Logistic Regression ◽  
Meat Consumption ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
P Value ◽  
Mutation Status ◽  
Molecular Features ◽  
Total Meat

e15135 Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value < .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.

Survival among colorectal cancer patients with a history of previous cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16146-e16146
Author(s):  
Sandi Pruitt ◽  
David E. Gerber ◽  
Hong Zhu ◽  
Daniel Heitjan ◽  
Bhumika Maddineni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cox Regression ◽  
Population Based ◽  
Competing Risk ◽  
Cancer Specific Survival ◽  
Risk Of Death ◽  
Number Of Patients ◽  
Significant Difference ◽  
The Impact

e16146 Background: A growing number of patients with colorectal cancer (CRC) have survived a previous cancer. Although little is known about their prognosis, this population is frequently excluded from clinical trials. We examined the impact of previous cancer on overall and cancer-specific survival in a population-based cohort of patients diagnosed with incident CRC. Methods: We identified patients aged ≥66 years and diagnosed with CRC between 2005-2015 in linked SEER-Medicare data. For patients with and without previous cancer, we estimated overall survival using Cox regression and cause-specific survival using competing risk regression, separately by CRC stage, while adjusting for numerous covariates and competing risk of death from previous cancer, other causes, or the incident CRC. Results: Of 112,769 CRC patients diagnosed with incident CRC, 15,935 (14.1%) had a previous cancer – most commonly prostate (32.9%) or breast (19.4%) cancer, with many 7505 (47.1%) diagnosed ≤5 years of CRC. For all CRC stages except IV in which there was no significant difference in survival, patients with previous cancer had modestly worse overall survival (hazard ratios from fully adjusted models range from 1.11-1.28 across stages; see Table). This survival disadvantage was driven by deaths due to previous cancer and other causes. Notably, most patients with previous cancer had improved CRC-specific survival. Conclusions: CRC patients who have survived a previous cancer have generally worse overall survival but superior CRC-specific survival. This evidence should be considered concurrently with concerns about trial generalizability, low accrual, and heterogeneity of participants when determining exclusion criteria. [Table: see text]

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