78, 31123121 (2018). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. p values from pairwise two-sided KruskalWallis test with correction for multiple testing (number of mutations: HR+HER2- vs TNBC q=0.008; 0 vs 5 lines of treatment q=0.0005, 12 vs 5 lines of treatment q=0.0005; 0 vs 3 lines of chemotherapy q=0.003. mVAF: 0 vs 5 lines of treatment q=0.03, 12 vs 5 lines of treatment q=0.006; 0 vs 12 lines of chemotherapy q=0.003, 0 vs 3 lines of chemotherapy q=0.0003; soft tissue/nodal vs visceral disease q=0.002). Right, variant classification of the alterations within each gene. Desmedt, C. et al. Each mutation site was counted once, however, if a mutation was differentially classified as clonal and subclonal in different patients, the mutation was counted in both sets. Genomic and Expression Profiling of Chromosome 17 in Breast Cancer Correspondence to Within individual genes, ESR1 and PIK3CA hotspot mutations showed significant variation in clonal dominance (both p<0.0001, Fig. J. Med. 7 Citations 4 Altmetric Metrics Summary The herald of genomic testing opened novel diagnostic and therapeutic possibilities for many tumor entities. Google Scholar. More comprehensive approaches to genotyping ctDNA such as whole exome sequencing could extend our observations. B.K., H.B., M.B., G.W.-C., S.H., C.S., S.K., L.M., K.W., M.H., I.F., K.C.B. Mutation profiling of key cancer genes in primary breast cancers and their distant metastases. 1,2,3,4,5 A multifocal breast cancer . 15). Jamal-Hanjani, M. et al. Mutated genes showed tendency for patterns of co-enrichment and mutual exclusivity. Biotechnol. Arielle J. Medford, Taronish D. Dubash, Aditya Bardia, Daniel Fernandez-Garcia, Georgios Nteliopoulos, Jacqueline A. Shaw, Mizunori Yaegashi, Takeshi Iwaya, Satoshi S. Nishizuka, Christian Rolfo, Alexander Drilon, David R. Gandara, Axel Muendlein, Kathrin Geiger, Thomas Decker, Jingying Nong, Yuhua Gong, Jinghui Wang, Shelly Sorrells, Kelly E. McKinnon, Christopher Sumey, Neelima Vidula, Andrew Lipman, Aditya Bardia, Stephanie N. Shishido, Rahul Masson, Peter Kuhn, Nature Communications In single site biopsies, these routes to endocrine therapy resistance are mutually exclusive11. 13a). Giacona, M. B. et al. Genomic characterization of primary invasive lobular breast cancer. Nat. B.K., R.J.C., I.G.M., J.M.B., A.R. Plasma samples were sequenced by duplex error corrected sequencing with a clinical diagnostic panel targeting 74 cancer genes (Supplementary Fig. Molecular profiling in breast cancerready for clinical routine? b Analysis of patients with H1047R (left, N=39) and E726K (right, N=26) dual pathogenic PIK3CA mutations, with linkage of cancer fraction of indicated PIK3CA mutation with the other PIK3CA mutation present in the same patient. ESR1 mutations D538G and Y537S were more dominant than other ESR1 mutations. 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G. et al. Deep whole genome sequencing identifies recurrent genomic alterations Genomic profiling of breast cancers - PubMed Cancer Res. 3040ml of blood was collected in 34 10ml cell-free DNA BCT Streck tubes. Samples underwent 40 cycles of PCR on a thermal cycler before analysis on a QX200 Digital Reader (Bio-Rad, Pleasanton). 34, 29612968 (2016). Trial documentation including the protocol are available on request by contacting plasmamatch-icrctsu@icr.ac.uk. Get what matters in cancer research, free to your inbox weekly. In metastatic tissue sequencing datasets, alterations within the MAPK pathway and ESR1 mutations are mutually exclusive in HR+HER2- disease11. Overman, M. J. et al. 6a). A. Le, D. T. et al. Genet. and R.B.L. Tumor profiling, also called tumor genomic profiling, is a way to personalize your cancer treatment. Cancer Discov. Jahr, S. et al. If a patient had two samples, the most recent biopsy result was analysed. The trial is registered NCT03182634 and ISRCTN:16945804. plasmaMATCH is supported by the National Institute for Health research (NIHR) Manchester Clinical Research Facility at The Christie Hospital, Manchester UK, and by the Cancer Research UK Cambridge Centre, the Cambridge NIHR Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre, Cambridge UK, and the NIHR Biomedical Research Centre at University College London Hospital (UCLH), London UK. We identify a number of new therapeutic approaches for advanced breast cancer. The data can be obtained by submitting a formal data access request in accordance with the Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU) data and sample access policy. The Guardant360 targeted sequencing panel identifies single nucleotide variants (SNVs), indels, copy number alterations and fusions within protein-coding regions of 73 (version 2.10) or 74 genes (version 2.11) (Supplementary Fig. Nat. Am. Baseline pre-treatment ctDNA targeted sequencing results were available for 800 patients28 (available in Supplementary Data1). It looks at a sample of your cancer cells for unique gene changes that help the. a Mutational profile of advanced breast cancer determined by ctDNA targeted sequencing of 800 patients in the plasmaMATCH trial. Mutation calls were filtered to only include loci present in both sequencing panels for comparison and mutations judged to be pathogenic (described earlier). Relative to the broad sequencing approaches of whole-exome and whole-genome sequencing, targeted panels sequence selected areas of interest and as such cover less of the genome, which may limit mutational signature analysis on this data. In this ad-hoc analysis we investigate how the profile of somatic genetic alterations in ctDNA differs from that obtained by tumour tissue sequencing. The same predisposition did not occur in PIK3CA mutant TNBC disease, where dominant and subclonal alterations were equally likely to occur at APOBEC sites (Fig. Nature Communications (2022) and N.C.T. Soc. For patients enroled prior to prospective targeted sequencing, a banked plasma sample was sent for retrospective testing, where available. Soc. In HR+ breast cancer oestrogen receptor mutations (ESR1)23, MAP kinase (MAPK) pathway mutations11,24, and transcription factor alterations11 such as ARID1A mutations11,25,26, are acquired as mechanism of resistance to prior endocrine therapy. Learn how gene mutations can affect breast cancer risk, as well as about how genetic testing works. 8, 14944 (2017). c Example of polyclonal genomic resistance in a patient with multiple MAPK pathway and ESR1 mutations in ctDNA. In HR+HER2- PIK3CA mutant disease, 23% (47/202) of patients had multiple PIK3CA mutations (Supplementary Fig. High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. p-values from Chi-squared test (PIK3CA: histological subtype p<0.0001, lines of treatment p=0.006; ESR1:histological subtype p<0.0001, lines of treatment p<0.0001, disease site p=0.003; HER2:histological subtype p=0.004, primary breast cancer subtype p<0.0001). 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. PubMedGoogle Scholar. Genome Biol. 6) compared to primary. J. Poisson probability was used to calculate allele frequency (AF). FS, frameshift; IF, in-frame. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Bootstrap sampling to define confidence intervals of assignments was applied sampling 90% of the data in 200 iterations for each subtype. Comparison of likely pathogenic mutations with false discovery corrected two-sided pairwise Kruskal-Wallis test, HR+HER2- vs HER2+ q=0.03, HR+HER2- vs TNBC q<0.0001. d Frequency of copy number increases in ctDNA split by breast cancer subtype in patients with known phenotype (HR+HER2- N=515, HER2+ N=72, TNBC N=138). N.C.T. N. Engl. 2021 American Association for Cancer Research. and R.C. Sci. We also identified novel subtype associations, with HER2 (also known as ERBB2) mutations enriched in HER2+disease compared to HR+HER2- (q=0.05) and TNBC (q=0.005, Fig. Nat. All other data are available within the Article, Supplementary Information or available from the authors upon request. Soc. Google Scholar. Fribbens, C. et al. For HR+HER2- and TNBC respectively, somatic alterations were aggregated into clonal (cancer fraction 0.5) versus subclonal alterations. Pancreas 17, 8997 (1998). & Park, P. J. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Detection of HER2 amplification in plasma in other tumour types has identified responders to HER2 directed therapy39,40. We report the sub-clonal structure of advanced breast cancer, and whilst many classic cancer driver genes are shown to be dominant in the cancer (present in all or most tumour cells), multiple other cancer genes are frequently subclonal. Why Genomic Profiling is Critical for Cancer Treatment Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. Other Breast Cancer Genes Family history is one of . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. Ann. https://doi.org/10.1038/s41467-021-22605-2, DOI: https://doi.org/10.1038/s41467-021-22605-2. 1b). 47, D941D947 (2018). The genomic and immune landscapes of lethal metastatic breast cancer. a Association analysis for most frequent mutated genes with overall Fishers exact test two-sided p-values. PIK3CA mutations vary in clonal dominance (Fig.
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