Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial

Santos, Cristina; Azuara, Daniel; Jm, Vieitez; Páez, David; Falcó, Esther; Élez, Elena; López-López, Carlos; Valladares, Manuel; Robles-Díaz, Luis; García‐Alfonso, Pilar; Bugés, Cristina; Durán, Gema; Salud, Antonieta; Navarro, A.; Capellà, Gabriel; Aranda, Enrique; Salazar, Ramón

doi:10.1093/annonc/mdz082

Cited by 22 publications

(14 citation statements)

References 25 publications

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“…were not associated with worse outcomes, further corroborating the current clinical use of validated assays with 5% limit of detection for RAS testing in tumor tissue. 23 On the other side, mutations detected thanks to ctDNA genotyping may mirror the presence of clinically important tumor subclones and could be associated with the rapid emergence of acquired resistance rather than primary resistance to anti-EGFRs. In attempt to further characterize this phenomenon, we showed that patients with RAS and/or PIK3CA VAF >5% in cfDNA have the worst PFS and OS, while patients with RAS VAF >5% also showed worse dynamics of response including ETS and DoR.…”

Section: Discussionmentioning

confidence: 99%

The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

Manca

Corallo

Busico

et al. 2021

Clinical Cancer Research

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Background:The routine use of liquid biopsy is not recommended for the choice of initial treatment of patients with metastatic colorectal cancer (mCRC). Experimental design:We included patients with left-sided, RAS/BRAF wild-type, HER2-negative and microsatellite stable mCRC, treated with upfront FOLFOX-panitumumab in the Valentino study. We performed amplicon-based genomic profiling of 14 genes in baseline plasma samples and compared these data with tumor tissue ultra-deep sequencing results. Specific gene mutations in ctDNA and their clonality were associated with PFS, OS and radiological dynamics.Results: Ten and 15 out of 120 patients had a mutation of RAS and PIK3CA in ctDNA, with a positive concordance with tissue deep-sequencing of only 31.3% and 47.1%, respectively. Presence of RAS or PIK3CA mutations in baseline ctDNA was associated with worse median PFS (8.0 vs.

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Section: Discussionmentioning

confidence: 99%

The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

Manca

Corallo

Busico

et al. 2021

Clinical Cancer Research

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“…A major point of discussion is whether the optimal threshold of the RAS mutant allele fraction to identify patients likely to benefit from anti-EGFR drugs should be 1% or 5%. We used a threshold of 5% as it has been reported that reducing the threshold to 1% does not improve outcomes [ 36 , 37 ]. We found one sensitive patient (P28) who harbored the A146V KRAS mutation at 5%.…”

Section: Discussionmentioning

confidence: 99%

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

Riera

Rodríguez-Santiago

Lasa

et al. 2020

Cancers

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Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

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“…Of note, focusing on the issue of analytical sensitivity in evaluating predictive biomarkers to anti-EGFR treatments, the phase II ULTRA trial investigated a high-sensitivity tumor tissue genotyping technique of KRAS, NRAS, BRAF and PIK3CA to ultra-select irinotecan-resistant mCRC patients for panitumumab plus FOLFIRI treatment. Results from this study identify the optimal RAS/BRAF mutational threshold for outcome prediction to be 5%, suggesting that the biological and clinical implications of mutation frequencies below this cut-off still warrant further investigations 79…”

Section: Novel Mechanisms Of Resistance and Future Perspectivesmentioning

confidence: 91%

<p>The impact of panitumumab treatment on survival and quality of life in patients with <em>RAS</em> wild-type metastatic colorectal cancer</p>

Battaglin¹,

Puccini²,

Ahcene-Djaballah³

et al. 2019

CMAR

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Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is currently approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC) in combination with chemotherapy in first- and second-line and as monotherapy in chemorefractory patients. This review will provide an overview of main efficacy data on panitumumab from its early development up to latest evidences, including novel perspectives on predictive biomarkers of anti-EGFRs efficacy and mechanisms of secondary resistance. Quality of life (QoL) related issues and panitumumab safety profile will be addressed as well.

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Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial

Cited by 22 publications

References 25 publications

The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

<p>The impact of panitumumab treatment on survival and quality of life in patients with <em>RAS</em> wild-type metastatic colorectal cancer</p>

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