5 research outputs found
Genomic profile of advanced breast cancer in circulating tumour DNA.
The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities
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Genomic profile of advanced breast cancer in circulating tumour DNA.
The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities
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Abstract PS5-02: Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial
Abstract
Background: Early changes in circulating tumour DNA (ctDNA) levels may identify which patients respond to therapy earlier than imaging, with ctDNA levels falling rapidly in patients who respond to therapy. The plasmaMATCH trial assessed the utility of ctDNA testing with an error-corrected 73-gene targeted panel (Guardant360, Guardant Health) to allocate patients to four mutation matched therapy cohorts. ESR1-extended fulvestrant (A), HER2-neratinib +/- fulvestrant (B), AKT1-capivasertib + fulvestrant (C), AKT basket-capivasertib (D). Here, we report paired baseline and early on treatment ctDNA analysis from plasmaMATCH, to establish the optimal criteria for predicting progression free survival (PFS). Methods: In plasmaMATCH treatment cohorts, plasma samples were collected for ctDNA analysis pre-treatment at cycle 1-day 1 (C1D1) and cycle 2-day 1 (C2D1) timepoints, and sequenced with the Guardant 360 assay. Patients were included if they had a minimum of 14 days of treatment in the first cycle. Multiple different methods were investigated to integrate variant allele fractions (VAF) of mutations identified at each timepoint to estimate the level of ctDNA, including maximum VAF, mean VAF and weighted mean VAF, and weighted mean VAF of clonal mutations at C1D1. Variants with a VAF <0.3%, set as the limit of detection, in C1D1 were excluded. Genes frequently mutated in CHIP were excluded (GNAS, JAK2, IDH1, IDH2 and ATM) from the weighted mean VAF of clonal mutations method. The circulating DNA ratio (CDR) was calculated as the ratio of C2D1 level relative to C1D1 level. The optimal cut-point for predicting PFS was assessed by fitting a range of cutpoints for each VAF integration method, identifying the cut-point with the highest Harrell’s C-index. Results: A total of 142 patients were enrolled into plasmaMATCH cohorts A-D, 79 patients had samples sent for paired C1D1-C2D1 plasma ctDNA sequencing, 1 failed sequencing and 1 insufficient treatment, and 77 (54%) patients had assessable C1D1-C2D1 plasma ctDNA sequencing results (45 cohort A, 12 cohort B, 12 cohort C, 8 cohort D). A weighted mean of clonal mutations in C1D1 ctDNA sequencing was the optimal method for integrating VAF, with peak C-Index 0.67. At the optimal C-index cutoff of 0.132, median PFS with high ctDNA CDR was 2.4 months (95% CI 2.0-3.7) and with suppressed ctDNA CDR was 9.9 months (95% CI 7.0-13.7) (HR 4.3, 95% CI 2.4-7.6, p<0.0001). Early changes in ctDNA level were also predictive in cohorts A extended dose fulvestrant alone (HR 5.8, 95% CI 2.2-16, p=0.0001) and cohorts B-D of targeted therapy (HR 3.8, 95% CI 1.7-8.6, p=0.00063). In analysis that was not pre-planned, patients with undetectable ctDNA at C2D1 had a particularly good outcome (p<0.0001, table 1). Conclusions: We identify an optimal methodology for assessing early dynamic changes in ctDNA that predicts treatment efficacy in patients with metastatic breast cancer. This methodology will require validation in independent data-sets, and if validated would allow trials of adapting therapy on the basis of early ctDNA dynamics.
Table 1ctDNA dynamics categoryMedian PFS months (95%CI)6-month PFSORRUndetectable (N=11) CDR=018.2 (10.2-NA)91%9/11 (82%)Suppressed (N=14) CDR <0.132 and >05.4 (4.6-NA)48%6/14 (43%)High (N=52) CDR >=0.1322.4 (2.0-3.7)8%4/52 (8%)
Citation Format: Javier Pascual, Rosalind J Cutts, Belinda Kingston, Sarah Hrebien, Lucy S Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M Wardley, Iain R Macpherson, Richard D Baird, Rebecca Roylance, Michael Hubank, Giselle Walsh, Iris Faull, Kimberly C Banks, Richard B Lanman, Isaac Garcia-Murillas, Judith M Bliss, Alistair Ring, Nicholas C Turner. Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-02.</jats:p