FOLFIRI plus panitumumab as second-line treatment in mutated RAS metastatic colorectal cancer patients who converted to wild type RAS after receiving first-line FOLFOX/CAPOX plus bevacizumab-based treatment: Phase II CONVERTIX trial

Montes, Ana; Lago, Nieves Martínez; Gómez, Jesús García; Rúa, Marta Covela; Castiñeiras, A. Cousillas; Villarroel, Paula González; Méndez, J. Méndez

doi:10.1093/annonc/mdz155.088

Cited by 13 publications

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“…Furthermore, enrolling phase II and III clinical studies CONVERTIX and KAIROS trials will provide clues about the clinical significance of liquid biopsy-based conversion of RAS mutant mCRC into RAS wild-type ( 28 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer

et al. 2020

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Treatment options for patients with metastatic colorectal cancer (mCRC) are limited. This particularly affects the largest group of patients with RAS mutations, who are considered ineligible for therapy with antiEGFR antibodies. In this liquid biopsy-based study, we performed the first in-depth analysis of the RAS mutational status in initially RAS-mutated patients during first-line therapy. RAS status of twelve patients with initially RAS-mutated mCRC was monitored longitudinally in 69 liquid biopsy samples. We focused on patients with stable disease (SD) or partial remission (PR) during first-line therapy (11 patients). Detection of fragmented RAS-mutated circulating cell-free tumor DNA (ctDNA) in plasma was performed by digital-droplet PCR (ddPCR) and BEAMing. Patients' total tumor masses were determined by measuring the tumor volumes using CT scan data. All patients with PR or SD at first follow-up showed a significant decrease of RAS mutational load. In ten patients (91%), the ctDNA-based RAS mutational status converted to wild-type in ddPCR and BEAMing. Remarkably, conversions were observed early after the first cycle of chemotherapy. Plasma concentration of ctDNA was controlled by determination of methylated WIF1-promotor ctDNA burden as a second tumor marker for mCRC. Persistent presence of methylated WIF1-promotor fragments confirmed the ongoing release of ctDNA during treatment. In patients with initially RAS-mutated mCRC, RAS mutations rapidly disappeared during first-line therapy in liquid biopsy, independent of type and intensity of chemotherapy and irrespective of anti-VEGF treatments. Following our results demonstrating conversion of RAS-mutational status, potential effectiveness of anti-EGFR antibodies in selected patients becomes an attractive hypothesis for future studies.

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Section: Discussionmentioning

confidence: 99%

Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer

et al. 2020

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“…Despite the initial skepticism, the clearance of RAS mutation in plasma from RAS mutant mCRC patients has now become a hot topic. To date, different groups are investigating the impact of EGFR inhibitors in patients with RAS mutant tumors at diagnosis who convert to RAS wt disease in blood during therapy [11][12][13][14]. Remarkably, the lack of RAS mutation detection in plasma might also be ascribed to the insufficient amount of ctDNA in the sample.…”

Section: Discussionmentioning

confidence: 99%

“…Recent literature shows that some RAS mutant mCRC switch to wt RAS disease in plasma, and three clinical trials aimed to investigate whether these patients might benefit from EGFR inhibitors are currently ongoing [7,12,16]. In order to avoid false negative results due to the low analytic sensitivity of some liquid biopsy assays, confirming the presence of ctDNA in all wt RAS plasma samples is mandatory [19,20].…”

Section: Discussionmentioning

confidence: 99%

Circulating Methylated DNA to Monitor the Dynamics of RAS Mutation Clearance in Plasma from Metastatic Colorectal Cancer Patients

Nicolazzo

Barault

Caponnetto

et al. 2020

Cancers

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The clearance of RAS mutations in plasma circulating tumor DNA (ctDNA) from originally RAS-mutant metastatic colorectal cancer (mCRC) has been recently demonstrated. Clinical trials investigating whether RAS mutant mCRC who “convert” to wild-type in plasma might benefit from EGFR blockade are ongoing. Detection of tumor-specific DNA methylation alterations in ctDNA has been suggested as a specific tool to confirm the tumoral origin of cell-free DNA. We monitored RAS clearance in plasma from patients with RAS-mutant mCRC at baseline (pre-treatment) (T0); after 4 months of first-line therapy (T1); at the time of first (T2) and second (T3) progression. A five-gene methylation panel was used to confirm the presence of ctDNA in samples in which RAS mutation clearance was detected. At T1, ctDNA analysis revealed wild-type RAS status in 83% of samples, all not methylated, suggesting at this time point the lack of ctDNA shedding. At T2, ctDNA analysis revealed wild-type RAS status in 83% of samples, of which 62.5% were found methylated. At T3, 50% of wild-type RAS samples were found methylated. Non-methylated samples were found in patients with lung or brain metastases. This five-gene methylation test might be useful to confirm the presence of ctDNA in RAS wild-type plasma samples.

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“…rechallenge, and this change occurs at a highly variable rate ranging from 2% to 45%. [33][34][35][36][37] However, RAS reversion in mCRC before disease progression has rarely been investigated.…”

Section: Gi Cancermentioning

confidence: 99%

Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment

Wang

Huang

et al. 2021

Gut

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ObjectiveCirculating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown.DesignWe conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up.ResultsThe RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type.ConclusionThis prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

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FOLFIRI plus panitumumab as second-line treatment in mutated RAS metastatic colorectal cancer patients who converted to wild type RAS after receiving first-line FOLFOX/CAPOX plus bevacizumab-based treatment: Phase II CONVERTIX trial

Cited by 13 publications

References 0 publications

Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer

Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer

Circulating Methylated DNA to Monitor the Dynamics of RAS Mutation Clearance in Plasma from Metastatic Colorectal Cancer Patients

Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment

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