Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3577-3577
Author(s):  
Stefano Mariani ◽  
Marco Puzzoni ◽  
Nicole Liscia ◽  
Valentino Impera ◽  
Andrea Pretta ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Selection Criteria ◽  
Wild Type ◽  
Braf Mutations ◽  
Previous Response ◽  
Clinical Variables ◽  
Ct Dna

3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.

scholarly journals Clinical Practice Use of Liquid Biopsy to Identify RAS/BRAF Mutations in Patients with Metastatic Colorectal Cancer (mCRC): A Single Institution Experience

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1504 ◽  
Author(s):  
Vitiello ◽  
De Falco ◽  
Giunta ◽  
Ciardiello ◽  
Cardone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Treatment Naïve

Tumor heterogeneity represents a possible cause of error in detecting predictive genetic alterations on tumor tissue and can be overcome by testing alterations in circulating tumor DNA (ctDNA) using liquid biopsy. We assessed 72 consecutive patients with a diagnosis of metastatic colorectal cancer (mCRC) using Idylla™ Biocartis, a fully automated platform that evaluates the most frequent mutations of KRAS, NRAS and BRAF genes. We correlated the results of liquid biopsy and standard tissue-based next generation sequencing (NGS) analyses to patient clinical features. The overall agreement was 81.94%. Concordance was 85.71% and 96.15% in treatment-naïve patients and in the patient subgroup with liver metastases, respectively. In liver metastases positive, treatment-naïve patients, sensitivity, specificity and positive predictive value (PPV) were 92.31%, 100% and 100%, respectively. Circulating mutational fraction (CMF) was significantly higher in patients with liver metastases and high carcinoembryonic antigen (CEA) levels. In a subgroup of patients pre-treated with anti-Epidermal Growth Factor Receptor (EGFR) agents, emerging KRAS mutations were evidenced in 33% of cases. Testing RAS/BRAF mutations on plasma using the Idylla™ Biocartis platform is feasible and reliable in mCRC patients in clinical practice.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3542-3542 ◽  
Author(s):  
Alexandre Harle ◽  
Celine Gavoille ◽  
Olivier Bouche ◽  
Meher Ben Abdelghani ◽  
Jérôme Edouard Plaza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Accurate Determination ◽  
Braf V600e ◽  
Molecular Testing ◽  
Braf Mutations ◽  
Blood Samples

3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.

scholarly journals Mutational status of plasma exosomal KRAS predicts outcome in patients with metastatic colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donatella Lucchetti ◽  
Ina Valeria Zurlo ◽  
Filomena Colella ◽  
Claudio Ricciardi-Tenore ◽  
Mariantonietta Di Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Clinical Information ◽  
Wild Type ◽  
Blood Samples ◽  
Mutational Status ◽  
Fractional Abundance ◽  
Radiological Response ◽  
Metastatic Sites

AbstractLiquid biopsy has become a useful alternative in metastatic colorectal cancer (mCRC) patients when tissue biopsy of metastatic sites is not feasible. In this study we aimed to investigate the clinical utility of circulating exosomes DNA in the management of mCRC patients. Exosomes level and KRAS mutational status in exosomal DNA was assesed in 70 mCRC patients and 29 CRC primary tumor and were analysed at different disease steps evaluating serial blood samples (240 blood samples). There was a significant correlation between the extension of disease and exosomes level and the resection of primary localized tumor was correlated with a decrease of KRAS G12V/ D copies and fractional abundance in metastatic disease. CEA expression and liver metastasis correlated with a higher number of KRAS G12V/D copies/ml and a higher fractional abundance; in the subgroup of mCRC patients eligible for surgery, the size of tumor and the radiological response were related to exosomes level but only the size was related to the number of KRAS WT copies; both KRAS wild-type and mutated levels were identified as a prognostic factor related to OS. Finally, we found that 91% of mutated mCRC patients became wild type after the first line chemotherapy but this status reverted in mutated one at progression in 80% of cases. In a prospective cohort of mCRC patients, we show how longitudinal monitoring using exosome-based liquid biopsy provides clinical information relevant to therapeutic stratification.

Phase II multicenter study of second-line FOLFIRI plus cetuximab (FLIER) in patients with KRAS wild-type metastatic colorectal cancer: Final analysis of survival and additional analysis of BRAF, PI3CA mutations.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 481-481 ◽  
Author(s):  
Yasuhiro Miyake ◽  
Shigeyoshi Iwamoto ◽  
Shoichi Hazama ◽  
Fuminori Goda ◽  
Chu Matsuda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Predictive Biomarker ◽  
Second Line ◽  
Wild Type ◽  
Braf Mutations

481 Background: Survival advantage of second line FOLFIRI plus cetuximab in patients with KRAS wild-type metastatic colorectal cancer has not been well reported. Since mutations in codons 12 and 13 of the KRAS gene predict lack of response to Cetuximab, mutations of V600E BRAF and PI3CA have been controversial. Methods: The aim of this study was to assess the efficacy of second-line FOLFIRI plus cetuximab in KRAS wt mCRC. Primary endpoint was response rate, other secondary endpoints were PFS, OS and safety. KRAS, BRAF, PI3CA tests by direct sequence were performed in Yamaguchi University. The starting dose of irinotecan was 150mg/ m2 (approved dose in Japan), but decreased to 100mg/m2 with UGT1A1 *28,*6 homozygous or both heterozygous. Results: From December 2008 to November 2009, 112 pts were preregistered. 67 (59.8%) pts were KRAS codon 12, 13 wt, and 60 pts were enrolled: 39 males (65%), 21 females (35%); median age was 62 years (range 37-82). The incidence of UGT1A1*28, *6 homozygous was 2.8%, 4.7% respectively. Grade 3/4 adverse events were leucopenia 26.7%, neutropenia 43.3%, paronychia 10.0%, skin toxity (fissure) 10.0% and acne 5.0%. The confirmed response rate (RECIST) was 31.7% (19/60). The median progression free survival and overall survival were 7.5 (C.I. 5.2-10.1) and 19.5 (C.I. 11.7-22.2) months respectively. Three pts had BRAF mutations and tumor shirinkage were +50.9%, +12%, +85.6% respectively. Two pts had PI3CA mutations and tumor shirinkage were +4%, +44%, respectively. Conclusions: FLIER was the first multicenter phase II trial with prospective analysis of KRAS as a predictive biomarker for cetuximab in second-line mCRC in Japan. Second-line FOLFIRI+cetuximab is well-tolerated and active. Mutations in BRAF and PI3CA gene seemed to be lack of response to cetuximab.

Clinical practice use of panitumumab combined with chemotherapy in patients with wild-type RAS metastatic colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 852-852
Author(s):  
Holger Frithjof Hebart ◽  
Jiri Tomasek ◽  
Tibor Csõszi ◽  
Reija Koukakis ◽  
George Kafatos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
Metastatic Colorectal Cancer ◽  
Overall Response Rate ◽  
Skin Toxicity ◽  
Wild Type ◽  
Response Data ◽  
Randomized Controlled ◽  
Study Results ◽  
Anticancer Treatment

852 Background: This study aimed to understand panitumumab (pmab) use in clinical practice for patients with wild-type RAS metastatic colorectal cancer (mCRC), in first-line (1L) with FOLFOX or second-line (2L) with FOLFIRI following fluoropyrimidine-based chemotherapy (excl. irinotecan). Methods: This is a combined analysis of two observational, non-interventional prospective cohort studies conducted in Germany/France (2012-2016) and Bulgaria/Czech Republic/Hungary (2013-2016). Results: Results are presented in the order of 1L FOLFOX (n = 332) followed by 2L FOLFIRI (n = 94). Patients received a median of 10 and 11.5 pmab infusions. The median duration of pmab exposure was 5.7 and 6.9 months (note that 53 and 10 patients continued pmab use after study end). The unadjusted overall response rate (complete or partial response) was 42% and 29%, based on 45% and 44% of patients with available response data post-baseline. In the 1L setting, resectability was achieved in 9%, not achieved in 42%, and unknown in 48%. Hospitalizations were reported for 100% and 99%, mostly cancer-related visits such as scheduled anticancer treatment (e.g. chemotherapy/pmab administrations), tumor assessment visits, or interventions; 93% in both groups reported outpatient, 66% and 60% inpatient visits. Conclusions: Overall, the study results show that treatment patterns and clinical efficacy of pmab in routine clinical practice were comparable to randomized controlled trials (RCTs). The ADR/SADR skin toxicity events are lower than expected based on findings from RCTs, however, similar findings have been shown in a previous observational study. More investigation is required to understand the reason for this.[Table: see text]

Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes in patients with BRAF non-V600 mutated metastatic colorectal cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 659-659 ◽  
Author(s):  
Daisuke Kotani ◽  
Sebastián Mondaca ◽  
Aparna Parikh ◽  
Hideaki Bando ◽  
Emily Van Seventer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Therapy Response ◽  
Clinicopathological Features ◽  
Survival Outcomes ◽  
Wild Type ◽  
Braf Mutations ◽  
Type Mutant ◽  
Negative Predictive Factor

659 Background: BRAF non-V600 mutations occur in 2-3% of colorectal cancer. These mutants can be classified as RAS independent (class 2) or RAS dependent (class 3). We reported BRAF non-V600 mutations could be a negative predictive factor for anti-EGFR therapy in patients (pts) with pretreated metastatic colorectal cancer (mCRC), while mCRC pts with class 3 BRAF mutations could respond to anti-EGFR therapy because of its dependency on receptors and RAS. Methods: This study evaluates the efficacy to anti-EGFR therapy in a large cohort of pts with BRAF non-V600 mutated mCRC. Pts with mCRC referred to the participating centers from 2010 to 2017 were included. Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes were stratified by BRAF mutational class. Results: One hundred seventeen pts with BRAF non-V600 mutated mCRC were identified. Median age was 58 years (range, 27-83), 68 pts (58%) were male, and 38 pts (33%) had right-sided tumors. Mucinous histology was seen in 11 cases (9%); concurrent RAS mutations occurred in 31 cases (27%), and 3 cases (3%) were MSI-H. Also, TP53 mutations were detected in 74 pts among 90 analyzed cases (82%). Regarding BRAF mutation subtype, 25/63/29 pts were classified as class 2/3/not reported (NR), respectively. Median OS in RAS wild-type/mutant were 44.8/34.6 months, respectively (p=0.082). The median OS in RAS wild-type pts with BRAF non-V600 mutations for class 2, 3, and NR were 25.7, 44.2, and 79.1 months, respectively (class 2 vs. 3, p=0.219). Among 40 pts treated with anti-EGFR therapy, response rates were 14%, 44%, and 40% for class 2, 3, and NR, respectively. Median PFS was 4.4, 8.3, 4.0 months for class 2, 3, and NR, respectively. Moreover, in 25 pts receiving anti-EGFR therapy as third or later line, response rate was 0%, 27%, and 50% in class 2, 3, and NR, and median PFS was 2.8, 3.7, and 4.0 months (p=0.762), respectively. Conclusions: Pts with class 2 BRAF mutations tend to have a poor prognosis compared to those with class 3 mutations. While almost half of pts with class 3 BRAF mutations responded to anti-EGFR therapy, response was rare for pts with class 2 BRAF mutations, and none achieved objective response in the third or later line.

scholarly journals 469P Potential emergent role of liquid biopsy in clinical practice in metastatic colorectal cancer (mCRC) treatment

2021 ◽  
Vol 32 ◽  
pp. S566
Author(s):  
V. Zurlo ◽  
D. Lucchetti ◽  
F. Colella ◽  
C. Ricciardi Tenore ◽  
M. Di Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy
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