Identification of an RNF43 mutated gastric cancer patient population with potential sensitivity to porcupine inhibitor RXC004 and development of a complimentary ctDNA liquid biopsy assay for patient screening

Bingham, Matilda; Bhamra, Inder; Armer, Richard; Thompson, B.; Woodcock, Simon; Thomason, Andrew G.; Phillips, Caroline; McKeever, Helen; Bradford, James R.; Chaffey, Ben T.; Little, Latasha; Clack, Glen

doi:10.1093/annonc/mdx369.076

Cited by 2 publications

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“…In contrast, NGS allows a considerable number of genomic regions to be interrogated concurrently and can detect both known and unknown mutations but has traditionally displayed a lower level of sensitivity than ddPCR and is more expensive. A third methodology, MALDI-TOF mass spectrometry, can identify moderate numbers of specific mutations with similar sensitivity and cost to NGS [29][30][31]. Using these methodologies, it has been reported that the concentration of released ctDNA positively correlates with tumour size [32].…”

Section: Introductionmentioning

confidence: 99%

Dynamic ctDNA mutational complexity in melanoma patients receiving immunotherapy

Fitzgerald

Blenkiron

Stephens

et al. 2022

Preprint

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Circulating tumour DNA (ctDNA) analysis promises to improve the care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 New Zealand (NZ) unresectable advanced-stage cutaneous melanoma patients through multiple cycles of immunotherapy, to identify the breadth and complexity of tumour genomic information that ctDNA analysis can reliably report. During the course of treatment, a high level of dynamic mutational complexity was identified in blood plasma of these patients, including: multiple BRAF mutations in the same patient, clinically-relevant BRAF mutations emerging through therapy, and co-occurring sub-clonal BRAF and NRAS mutations. The technical validity of this ctDNA analysis was supported by high sample analysis-reanalysis concordance as well as by concordance between three ctDNA measurement technologies: droplet digital polymerase chain reaction (ddPCR), a custom melanoma-specific amplicon next-generation sequencing (NGS) panel and mass spectrometry. In addition, we observed >90% concordance in the detection of ctDNA when using cell-stabilising collection tubes followed by 7-day delayed processing, compared to standard EDTA blood collection protocols with rapid processing. We also found that undetectability of ctDNA at a proportion of treatment cycles was associated with both clinical benefit (best RECIST response) and prognosis (disease-specific survival). In summary, we found that multiple ctDNA processing and analysis methods consistently identified complex longitudinal patterns of clinically-relevant mutations, adding support for expanded implementation of this technology to guide in-treatment tailored cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Dynamic ctDNA mutational complexity in melanoma patients receiving immunotherapy

Fitzgerald

Blenkiron

Stephens

et al. 2022

Preprint

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Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy

et al. 2023

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Background Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles of immunotherapy. Method A melanoma-specific ctDNA next-generation sequencing (NGS) panel, droplet digital polymerase chain reaction (ddPCR) and mass spectrometry analysis were used to identify ctDNA mutations in longitudinal blood plasma samples from Aotearoa New Zealand (NZ) patients receiving immunotherapy for melanoma. These technologies were used in conjunction to identify the breadth and complexity of tumour genomic information that ctDNA analysis can reliably report. Results During the course of immunotherapy treatment, a high level of dynamic mutational complexity was identified in blood plasma, including multiple BRAF mutations in the same patient, clinically relevant BRAF mutations emerging through therapy and co-occurring sub-clonal BRAF and NRAS mutations. The technical validity of this ctDNA analysis was supported by high sample analysis–reanalysis concordance, as well as concordance between different ctDNA measurement technologies. In addition, we observed > 90% concordance in the detection of ctDNA when using cell-stabilising collection tubes followed by 7-day delayed processing, compared with standard EDTA blood collection protocols with rapid processing. We also found that the undetectability of ctDNA at a proportion of treatment cycles was associated with durable clinical benefit (DCB). Conclusion We found that multiple ctDNA processing and analysis methods consistently identified complex longitudinal patterns of clinically relevant mutations, adding support for expanded clinical trials of this technology in a variety of oncology settings. Supplementary Information The online version contains supplementary material available at 10.1007/s40291-023-00651-4.

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Identification of an RNF43 mutated gastric cancer patient population with potential sensitivity to porcupine inhibitor RXC004 and development of a complimentary ctDNA liquid biopsy assay for patient screening

Cited by 2 publications

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Dynamic ctDNA mutational complexity in melanoma patients receiving immunotherapy

Dynamic ctDNA mutational complexity in melanoma patients receiving immunotherapy

Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy

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