Dataset Information

Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.

ABSTRACT:

Background

RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice.

Patients and methods

RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients.

Results

Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment.

Conclusion

The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.

SUBMITTER: Vidal J

PROVIDER: S-EPMC5834035 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.

Vidal J J Muinelo L L Dalmases A A Jones F F Edelstein D D Iglesias M M Orrillo M M Abalo A A Rodríguez C C Brozos E E Vidal Y Y Candamio S S Vázquez F F Ruiz J J Guix M M Visa L L Sikri V V Albanell J J Bellosillo B B López R R Montagut C C

Annals of oncology : official journal of the European Society for Medical Oncology 20170601 6

<h4>Background</h4>RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practi ...[more]

PMID: 28419195

Similar Datasets

Project description:ImportanceThe available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies.ObjectiveTo evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC.Design, setting, and participantsThis nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months).InterventionPatients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy.Main outcomes and measuresOverall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported.ResultsOverall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects.Conclusions and relevanceThese findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival.Trial registrationClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.

Project description:Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with RAS wild-type (RAS-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with RAS mutation (RAS-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was RAS-wt. The occurrence of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (BRAF), and PI3KCA mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed RAS-mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with RAS-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with RAS-mt ctDNA were treated with the oncologist's choice of therapy. Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified RAS-mt in seven patients (44%) and RAS-wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with RAS-wt ctDNA and 17.9% for those with RAS-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively. Patients with RAS-mt mCRC whose plasma biopsies contained RAS-wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.

Project description:BackgroundIn the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy.MethodsA total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed.DiscussionLiquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC.Trial registrationThe date of trial registration ( NCT03401957 ) in this study was January 17, 2018.

Dataset Information

Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.

Background

Patients and methods

Results

Conclusion

Publications

Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.

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