scholarly journals The interplay of KRAS mutational status with tumor laterality in non‐metastatic colorectal cancer: An international, multi‐institutional study in patients with known KRAS, BRAF, and MSI status

2020 ◽  
Author(s):  
Carsten Kamphues ◽  
Shigenori Kadowaki ◽  
Neda Amini ◽  
Inge Berg ◽  
Jaeyun Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mutational Status ◽  
Tumor Laterality

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 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.

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.

Impact of primary tumor sidedness on erlotinib efficacy in patients with metastatic colorectal cancer treated with bevacizumab maintenance: Results from the DREAM phase III trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 737-737 ◽  
Author(s):  
Benoist Chibaudel ◽  
Thierry Andre ◽  
Benoit Samson ◽  
Marie-Line Garcia-Larnicol ◽  
Jérôme Dauba ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Maintenance Therapy ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Primary Tumor ◽  
Phase Iii ◽  
Primary Tumors ◽  
Phase Iii Trial ◽  
Mutational Status

737 Background: Primary tumor sidedness (PTS) could be a predictive maker for treatment efficacy of EGFR inhibitors monoclonal antibodies in patients with wild-type (WT) RAS metastatic colorectal cancer (MCRC), cetuximab having limited efficacy in patients with WT-RAS right-sided tumors. DREAM study demonstrated that adding erlotinib, an oral EGFR tyrosine kinase inhibitor (TKI) to bevacizumab during maintenance therapy improved clinical outcomes (RR, PFS, OS) in patients with MCRC, whatever KRAS status. The aim of this post-hoc analysis is to evaluate the clinical outcomes according to KRAS mutational status and PTS when adding erlotinib to bevacizumab maintenance therapy. Methods: PTS was retrospectively collected in patients from the DREAM phase III trial treated with bevacizumab with or without erlotinib as maintenance therapy for MCRC who have been controlled by induction therapy. The limit for the definition of PTS was splenic flexure, and rectal tumors were considered as left-sided tumors. The primary endpoint was overall survival (OS). Results: Among 452 patients who received maintenance therapy, PTS ascertainment was 84.7% (n = 383) with 265 (71.0%) patients having left-sided primary tumor and 108 (28.9%) having right-sided primary tumors (3 patients had both and tumor location was unknown in 7 patients). Median OS and treatment effect are presented in table 1. Conclusions: The greatest OS benefit of adding erlotinib to bevacizumab maintenance therapy was observed in patients with WT-KRAS and right-sided MCRC, suggesting a clinical impact of the different mechanism of action between EGFR TKI and monoclonal antibodies. Clinical trial information: NCT00265824. [Table: see text]

scholarly journals Concordance of Acquired Mutations between Metastatic Lesions and Liquid Biopsy in Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

2021 ◽  
Author(s):  
Fumitaka Taniguchi ◽  
Akihiro Nyuya ◽  
Toshiaki Toshima ◽  
Kazuya Yasui ◽  
Yoshiko Mori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Acquired Resistance ◽  
Metastatic Tumor ◽  
Primary Tumors ◽  
Blood Samples ◽  
Activating Mutations ◽  
Metastatic Lesions ◽  
Mutational Status

Abstract Background: Acquired mutations are detected in plasma. However, still few reports examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Herein we evaluated whether a polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Methods: Firstly, we examined the presence of acquired mutations in 7 chemoresistant metastatic lesions and blood samples obtained from a metastatic colorectal cancer (mCRC) patient without RAS activating mutations treated with anti-EGFR treatment. The patient (patient 1) displayed initial early tumor shrinkage and finally progressed to disease (PD). Blood samples were collected before the development of PD and after acquiring resistance. Next, we evaluated RAS and BRAF mutational status among blood samples, primary tumors, and metastatic lesions obtained from three additional mCRC patients without RAS activating mutations. Acquired mutations were examined using Sanger sequencing and the PCR-rSSO approach.Results: Of patient 1, metastatic tumor specimens harbored diverse acquired mutations in the KRAS gene in all of the 7 (100%) metastases, and the three acquired mutations were detected in blood specimens collected after acquiring resistance. Next, we analyzed primary tumors, metastatic lesions after chemotherapy, and blood samples from three additional mCRC patients but noted that none of the patients exhibited mutations in liquid biopsy except for one case with BRAF V600E mutation, which was confirmed in both primary tumor and peritoneal dissemination. Of the four cases, acquired mutations of RAS, as well as BRAF V600E mutation, was detected in the blood obtained only after confirmation of acquiring resistance by radiological examinations.Conclusions: Our results suggest liquid biopsy based on the PCR-rSSO is a successful procedure for capturing acquired mutations with precise information of mutational spectrum that may lend us to reach selective target agents for RAS mutations.

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