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      Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer

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          Abstract

          CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

          Abstract

          Circulating tumor DNA (ctDNA) may provide a prediction of treatment response, but could be impacted by tumor heterogeneity. Here, the authors investigate ctDNA in CDK4/6 inhibitor treatment in advanced breast cancer, finding ctDNA levels predict progression-free survival and anticipate clonal selection.

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          Most cited references 13

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          Detection and quantification of rare mutations with massively parallel sequencing.

          The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Although massively parallel sequencing instruments are in principle well suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. The keys to this approach, called the Safe-Sequencing System ("Safe-SeqS"), are (i) assignment of a unique identifier (UID) to each template molecule, (ii) amplification of each uniquely tagged template molecule to create UID families, and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are considered mutant ("supermutants") only if ≥95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized in vitro, and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells.
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            Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer.

             J Tie,  I Kinde,  Y. WANG (2015)
            Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy.
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              Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy.

              Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study.
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                Author and article information

                Contributors
                +442073528133 , nicholas.turner@icr.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                1 March 2018
                1 March 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Breast Cancer Now Research Centre, , The Institute of Cancer Research, ; Fulham Rd, London, SW3 6JB UK
                [2 ]ISNI 0000 0004 0417 0461, GRID grid.424926.f, Breast Unit, , Royal Marsden Hospital, ; London, SW3 6JJ UK
                [3 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, The Institute of Cancer Research Clinical Trials and Statistics Unit, ; London, SM2 5NG UK
                [4 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Pfizer, ; 235 E 42nd St, New York, NY 10017 USA
                [5 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Robert H Lurie Comprehensive Cancer Center, , Feinberg School of Medicine, ; 675 N St. Clair, Chicago, IL, 60611 USA
                Article
                3215
                10.1038/s41467-018-03215-x
                5832789
                29497091
                © The Author(s) 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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