scholarly journals Predictive Biomarkers in Metastatic Colorectal Cancer: A Systematic Review

2019 ◽  
pp. 1-17
Author(s):  
Juan Ruiz-Bañobre ◽  
Raju Kandimalla ◽  
Ajay Goel
Keyword(s):  
Colorectal Cancer ◽  
Systematic Review ◽  
Metastatic Colorectal Cancer ◽  
Retrospective Studies ◽  
Predictive Biomarkers ◽  
Treatment Decision ◽  
Final Analysis ◽  
Predictive Biomarker ◽  
Relevant Information ◽  
Mutational Status

PURPOSE The development and use of predictive biomarkers to guide treatment decisions are paramount not only for improving survival in patients with metastatic colorectal cancer (mCRC), but also for sparing them from unnecessary toxicity and reducing the economic burden of expensive treatments. We conducted a systematic review of published studies and evaluated the predictive biomarker landscape in the mCRC setting from a molecular and clinical viewpoint. METHODS Studies analyzing predictive biomarkers for approved therapies in patients with mCRC were identified systematically using electronic databases. Preclinical studies and those providing no relevant information were excluded. RESULTS A total of 173 studies comprising 148 biomarkers were selected for final analysis. Of all the biomarkers analyzed, 1.4% (two of 148) were explored in a prospective manner, whereas 98.6% (146 of 148) were evaluated in retrospective studies. Of the latter group, 78.8% (115 of 146) were not tested in subsequent phases, 9.6% (14 of 146) were tested in other retrospective cohorts, 8.9% (13 of 146) were retrospectively tested in at least one or more randomized cohorts, and only 2.7% (four of 146) were prospectively tested in a clinical trial. Finally, only 1.4% (two of 148) were validated sufficiently and are recognized as biomarkers for guiding treatment decision making in patients with mCRC. These markers were RAS mutational status for anti-EGFR antibodies and microsatellite instability status for anti–programmed cell death-1 drugs. CONCLUSION Despite notable efforts to identify predictive biomarkers for various therapies used in the mCRC setting, because of a lack of data beyond retrospective studies and successful biomarker-driven approaches, only two molecular biomarkers have thus far found their translation into the clinic, highlighting the imperative need for implementing novel strategies and additional research in this clinically important field.

scholarly journals Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000375 ◽  
Author(s):  
Jean-David Fumet ◽  
Nicolas Isambert ◽  
Alice Hervieu ◽  
Sylvie Zanetta ◽  
Jean-Florian Guion ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Performance Status ◽  
Human Monoclonal Antibody ◽  
Eastern Cooperative Oncology Group ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mutational Status

Background5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.MethodsThis phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

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.

Predictive biomarkers candidates for patients with metastatic colorectal cancer treated with bevacizumab-containing regimen

2016 ◽  
Vol 31 (2) ◽  
Author(s):  
Nicolás González-Vacarezza ◽  
Isabel Alonso ◽  
Gustavo Arroyo ◽  
Jorge Martínez ◽  
Fernando De Andrés ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Antiangiogenic Therapy ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Future Research ◽  
Free Survival ◽  
Interesting Candidate ◽  
Clinically Significant

AbstractBevacizumab was the first molecular-targeted antiangiogenic therapy approved for the treatment of metastatic colorectal cancer. Until now, there are no predictive biomarkers available to decide the prescription of bevacizumab in patients with colorectal cancer. The purposes of this review were to provide a critical appraisal of the evidence and to identify possible predictive genetic biomarkers. A literature search was performed to identify studies that determine different levels of treatment response between patients stratified according to defined biomarkers. Interesting findings were reported between patients stratified according to rs3025039 and rs833061 polymorphisms of the gene VEGFA, with statistically and clinically significant differences for progression-free survival and overall survival. However, another study conducted in a larger sample does not confirm these previous findings, suggesting that well-designed prospective studies are still needed to achieve conclusive results. FLT1 (or VEGFR1) rs9513070 seems to be an interesting candidate as a predictive biomarker, with differences of more than 10 months in OS between different patients groups. In our opinion, possible interesting biomarker candidates for future research could be the polymorphisms rs833061 and rs3025039 of VEGF-A, rs9513070 or haplotype analysis of FLT1, rs2661280 of RGS5, rs444903 and rs6220 of EGF and Ang-2 or LDH plasma levels.

scholarly journals Analysis of the role of RAS Family Mutations in Metastatic Colorectal Cancer (mCRC): Current Treatment Practice

2014 ◽  
Vol 5 (2) ◽  
pp. 12-15
Author(s):  
Zenia Saridaki ◽  
John Souglakos ◽  
Vassilis Georgoulias ◽  
Jean-Yves Douillard
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Specific Treatment ◽  
Growth Factor Receptor ◽  
Treatment Decision ◽  
Current Treatment ◽  
Exon 2 ◽  
Treatment Practice ◽  
Mutational Status ◽  
Ras Family

Abstract A major challenge in metastatic colorectal cancer (mCRC) is the identification of specific biomarkers that are likely to predict which patients will benefit from a specific treatment. To this date, a number of studies have shown that a tumour's mutational profile influences treatment outcome in patients with mCRC and should, therefore, be used to guide treatment decision. For more than 5 years now, we know that patients with tumours harbouring mutations in exon 2, codons 12 and 13 of the KRAS oncogene gain no benefit from the administration of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (moAbs), Cetuximab and Panitumumab. It has just recently being elucidated that KRAS mutations outside codons 12 and 13 and mutations in the NRAS gene confer resistance to Cetuximab and Panitumumab, as well. Thus, since June 2013, the analysis of exons 2, 3 and 4 of KRAS and NRAS has been incorporated in daily clinical practice to improve patients’ selection for anti-EGFR moAbs treatment. Nevertheless, even if patients’ outcome under anti-EGFR moAbs therapy is improved with better selection based on Ras mutational status, more research is needed in this field; the matter is far from being resolved, since there are still a minority of wt RAS patients who do not respond upfront to such a treatment.

New biomarkers to predict response to oxaliplatin-based chemotherapy in metastatic colorectal cancer: KRAS and ERCC1.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Antonia Strippoli ◽  
Michele Basso ◽  
Armando Orlandi ◽  
Giovanni Schinzari ◽  
Alessandra Calegari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Excision Repair ◽  
Predictive Biomarker ◽  
Entire Group ◽  
Second Line ◽  
Front Line ◽  
First Line ◽  
Line Therapy ◽  
Mutational Status

500 Background: In the present study we have evaluated the possibility that KRAS mutational status might be predictive of the efficacy of oxaliplatin-based chemotherapy. In addition, we explored the possible role of excision repair cross complementing group-1 (ERCC-1) that is envolved in repair of oxaliplatin (OXA) produced DNA-adducts. Methods: We performed a retrospective analysis of 90 patients with metastatic colorectal cancer, who received FOLFOX-6 schedule and FOLFIRI schedule ± Bevacizumab, in first or second line therapy. In sixty out of 90 patients the expression of ERCC-1 was also determined by fluorescence-based real-time detection method. Results: Among 90 patients, 42 (47%) wild-type (wt) and 48 (53%) mutated (mt) KRAS tumors were found. Twenty-two out of 42 wt KRAS patients received FOLFOX-6 as first-line therapy and the other 20 patients as second-line treatment; in the mt KRAS population, 27 and 21 patients received FOLFOX-6 as front-line or second-line, respectively. One complete response (CR) and 10 partial responses (PR) were observed in the wt KRAS group (RR 26%), whereas 2 CR and 25 PR were obtained in the mt KRAS group (56%); the difference is statistically significant in the total sample (p=0.003) and when only patients receiving FOLFOX-6 in first-line are considered (p=0006). PFS was longer in mt than in wt KRAS patients in the entire group of patients (10 vs 8 months, respectively; p=0.001) and in those treated in front-line (10 vs 8 months, respectively; p=0.003). ERCC-1 was over-expressed in 30 out of 60 patients, but the efficacy of FOLFOX-6 was not different in patient showing high ERCC-1 levels in comparison to those with low level of the gene. In ERCC-1 over-expressing patients, however, RR and PFS were higher in mt than in wt patients (40% vs 13% and 10 vs 8 months, respectively); a similar, not significant, trend was also observed in patients not over-expressing ERCC-1. Conclusions: Our data, if confirmed in larger series and in a prospective setting, suggest that activating mutation of KRAS oncogene could be a predictive biomarker of response to oxaliplatin. Basal tumor expression of ERCC-1 doesn’t explain the high efficacy of FOLFOX-6 in mt KRAS patients.

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.

scholarly journals Baseline and Kinetic Circulating Tumor Cell Counts Are Prognostic Factors in a Prospective Study of Metastatic Colorectal Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 502
Author(s):  
Virgílio Souza e Silva ◽  
Emne Ali Abdallah ◽  
Angelo Borsarelli Carvalho de Brito ◽  
Alexcia Camila Braun ◽  
Milena Shizue Tariki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Prospective Study ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Predictive Biomarkers ◽  
Multi Drug Resistance ◽  
Cell Counts ◽  
Potential Clinical Benefit ◽  
A Prospective Study

The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2−CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.

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