Publications by authors named "Nicholas Turner"

365 Publications

Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3.

Oncologist 2021 May 5. Epub 2021 May 5.

Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (ie, end of Week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.

Materials And Methods: ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n=584) and PALOMA-3 (n=442). SNP, race, and Cycle 1 Day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n=122) and non-Asian (n=530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed.

Results: ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR]=6.033, 95% CI=2.615-13.922, P<0.0001; Non-Asians: OR=6.884, 95% CI=4.138-11.451, P<0.0001). ABCB1_rs1128503 (C/C vs T/T: OR=0.57, 95% CI=0.311-1.047, P=0.070) and ERCC1_rs11615 (A/A vs G/G: OR=1.75, 95% CI=0.901-3.397, P=0.098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype.

Conclusion: This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135).

Implications For Practice: Palbociclib plus endocrine therapy improves HR+/HER2- advanced breast cancer (ABC) outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (P<0.0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (P<0.10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13811DOI Listing
May 2021

Asymptomatic or mild symptomatic SARS-CoV-2 infection elicits durable neutralizing antibody responses in children and adolescents.

medRxiv 2021 Apr 20. Epub 2021 Apr 20.

As SARS-CoV-2 continues to spread globally, questions have emerged regarding the strength and durability of immune responses in specific populations. In this study, we evaluated humoral immune responses in 69 children and adolescents with asymptomatic or mild symptomatic SARS-CoV-2 infection. We detected robust IgM, IgG, and IgA antibody responses to a broad array of SARS-CoV-2 antigens at the time of acute infection and 2 and 4 months after acute infection in all participants. Notably, these antibody responses were associated with virus neutralizing activity that was still detectable 4 months after acute infection in 94% of children. Moreover, antibody responses and neutralizing activity in sera from children and adolescents were comparable or superior to those observed in sera from 24 adults with mild symptomatic infection. Taken together, these findings indicate children and adolescents with mild or asymptomatic SARS-CoV-2 infection generate robust and durable humoral immune responses that are likely to protect from reinfection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.04.17.21255663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077583PMC
April 2021

Genomic profile of advanced breast cancer in circulating tumour DNA.

Nat Commun 2021 04 23;12(1):2423. Epub 2021 Apr 23.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22605-2DOI Listing
April 2021

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Nat Commun 2021 04 15;12(1):2349. Epub 2021 Apr 15.

Infectious and Tropical Diseases Department, Angers University Hospital, Angers, France.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22446-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050319PMC
April 2021

Sustained reduction in catheter-associated urinary tract infections using multi-faceted strategies led by champions: A quality improvement initiative.

Infect Control Hosp Epidemiol 2021 Apr 16:1-5. Epub 2021 Apr 16.

Duke University, Department of Medicine, Division of Infectious Diseases, Durham, North Carolina.

We reviewed the sustainability of a multifaceted intervention on catheter-associated urinary tract infection (CAUTI) in 3 intensive care units. During the 4-year postintervention period, we observed reductions in urine culture rates (from 80.9 to 47.5 per 1,000 patient days; P < .01), catheter utilization (from 0.68 to 0.58; P < .01), and CAUTI incidence rates (from 1.7 to 0.8 per 1,000 patient days; P = .16).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/ice.2021.135DOI Listing
April 2021

Development of continuous flow systems to access secondary amines through previously incompatible biocatalytic cascades.

Angew Chem Int Ed Engl 2021 Apr 15. Epub 2021 Apr 15.

The University of Manchester, chemistry, UNITED KINGDOM.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine. The flow biocatalysis platform shown here significantly increases the scope of novel biocatalytic cascades, removing previous limitations due to reaction and reagent batch incompatibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202103805DOI Listing
April 2021

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

Lancet Oncol 2021 04;22(4):489-498

British Columbia Cancer Agency, Vancouver, BC, Canada.

Background: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.

Methods: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.

Findings: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported.

Interpretation: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

Funding: Novartis Pharmaceuticals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(21)00034-6DOI Listing
April 2021

Age-related changes in the upper respiratory microbiome are associated with SARS-CoV-2 susceptibility and illness severity.

medRxiv 2021 Mar 23. Epub 2021 Mar 23.

Children are less susceptible to SARS-CoV-2 and typically have milder illness courses than adults. We studied the nasopharyngeal microbiomes of 274 children, adolescents, and young adults with SARS-CoV-2 exposure using 16S rRNA gene sequencing. We find that higher abundances of species are associated with SARS-CoV-2 infection and SARS-CoV-2-associated respiratory symptoms, while higher abundances of are present in SARS-CoV-2-infected individuals respiratory symptoms. We also demonstrate that the abundances of these bacteria are strongly, and independently, associated with age, suggesting that the nasopharyngeal microbiome may be a potentially modifiable mechanism by which age influences SARS-CoV-2 susceptibility and severity.

Summary: Evaluation of nasopharyngeal microbiome profiles in children, adolescents, and young adults with a SARS-CoV-2-infected close contact identified specific bacterial species that vary in abundance with age and are associated with SARS-CoV-2 susceptibility and the presence of SARS-CoV-2-associated respiratory symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.03.20.21252680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010748PMC
March 2021

Hybrid Aptamer-Molecularly Imprinted Polymer (aptaMIP) Nanoparticles from Protein Recognition-A Trypsin Model.

Macromol Biosci 2021 Mar 24:e2100002. Epub 2021 Mar 24.

Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.

Aptamers offer excellent potential for replacing antibodies for molecular recognition purposes however their performance can compromise with biological/environmental degradation being a particular problem. Molecularly imprinted Polymers (MIPs) offer an alternative to biological materials and while these offer the robustness and ability to work in extreme environmental conditions, they often lack the same recognition performance. By slightly adapting the chemical structure of a DNA aptamer it is incorporated for use as the recognition part of a MIP, thus creating an aptamer-MIP hybrid or aptaMIP. Here these are developed for the detection of the target protein trypsin. The aptaMIP nanoparticles offer superior binding affinity over conventional MIP nanoparticles (nanoMIPs), with K values of 6.8 × 10 (±0.2 × 10 ) m and 12.3 × 10 (±0.4 × 10 ) m for the aptaMIP and nanoMIP, respectively. The aptaMIP also outperforms the aptamer only (10.3 × 10 m). Good selectivity against other protein targets is observed. Using surface plasmon resonance, the limit of detection for aptaMIP nanoparticles is twofold lower (2 nm) compared to the nanoMIP (4 nm). Introduction of the aptamer as a "macro-monomer" into the MIP scaffold has beneficial effects and offers potential to improve this class of polymers significantly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mabi.202100002DOI Listing
March 2021

Biotechnological synthesis of Pd/Ag and Pd/Au nanoparticles for enhanced Suzuki-Miyaura cross-coupling activity.

Microb Biotechnol 2021 Mar 15. Epub 2021 Mar 15.

Department of Earth and Environmental Sciences and Williamson Research Centre for Molecular Environmental Science, University of Manchester, Manchester, UK.

Bimetallic nanoparticle catalysts have attracted considerable attention due to their unique chemical and physical properties. The ability of metal-reducing bacteria to produce highly catalytically active monometallic nanoparticles is well known; however, the properties and catalytic activity of bimetallic nanoparticles synthesized with these organisms is not well understood. Here, we report the one-pot biosynthesis of Pd/Ag (bio-Pd/Ag) and Pd/Au (bio-Pd/Au) nanoparticles using the metal-reducing bacterium, Shewanella oneidensis, under mild conditions. Energy dispersive X-ray analyses performed using scanning transmission electron microscopy (STEM) revealed the presence of both metals (Pd/Ag or Pd/Au) in the biosynthesized nanoparticles. X-ray absorption near-edge spectroscopy (XANES) suggested a significant contribution from Pd(0) and Pd(II) in both bio-Pd/Ag and bio-Pd/Au, with Ag and Au existing predominately as their metallic forms. Extended X-ray absorption fine-structure spectroscopy (EXAFS) supported the presence of multiple Pd species in bio-Pd/Ag and bio-Pd/Au, as inferred from Pd-Pd, Pd-O and Pd-S shells. Both bio-Pd/Ag and bio-Pd/Au demonstrated greatly enhanced catalytic activity towards Suzuki-Miyaura cross-coupling compared to a monometallic Pd catalyst, with bio-Pd/Ag significantly outperforming the others. The catalysts were very versatile, tolerating a wide range of substituents. This work demonstrates a green synthesis method for novel bimetallic nanoparticles that display significantly enhanced catalytic activity compared to their monometallic counterparts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1751-7915.13762DOI Listing
March 2021

Understanding divergent trial results of adjuvant CDK4/6 inhibitors for early stage breast cancer.

Cancer Cell 2021 Mar;39(3):307-309

Breast Unit, The Royal Marsden Hospital, London, UK; Ralph Lauren Centre for Breast Cancer Research, The Royal Marsden Hospital, London, UK; Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK. Electronic address:

CDK4/6 inhibitors have transformed the treatment of metastatic estrogen-receptor-positive HER2-negative breast cancer, with efficacy found consistently for three different inhibitors. Recent adjuvant trials of CDK4/6 inhibitors in early stage breast cancer have produced discordant results, shedding light on their clinical utility and future trial design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.02.011DOI Listing
March 2021

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 04 4;22(4):499-511. Epub 2021 Mar 4.

International Breast Cancer Center, Quiron Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.

Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.

Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).

Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.

Funding: Merck Sharp & Dohme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30754-3DOI Listing
April 2021

RetroBioCat as a computer-aided synthesis planning tool for biocatalytic reactions and cascades.

Nat Catal 2021 Feb 4;4(2):98-104. Epub 2021 Jan 4.

Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, UK.

As the enzyme toolbox for biocatalysis has expanded, so has the potential for the construction of powerful enzymatic cascades for efficient and selective synthesis of target molecules. Additionally, recent advances in computer-aided synthesis planning are revolutionising synthesis design in both synthetic biology and organic chemistry. However, the potential for biocatalysis is not well captured by tools currently available in either field. Here we present RetroBioCat, an intuitive and accessible tool for computer-aided design of biocatalytic cascades, freely available at retrobiocat.com. Our approach uses a set of expertly encoded reaction rules encompassing the enzyme toolbox for biocatalysis, and a system for identifying literature precedent for enzymes with the correct substrate specificity where this is available. Applying these rules for automated biocatalytic retrosynthesis, we show our tool to be capable of identifying promising biocatalytic pathways to target molecules, validated using a test-set of recent cascades described in the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41929-020-00556-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116764PMC
February 2021

Racial, Ethnic, and Geographic Disparities in Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Test Positivity in North Carolina.

Open Forum Infect Dis 2021 Jan 8;8(1):ofaa413. Epub 2020 Sep 8.

Duke University School of Medicine, Durham, North Carolina, USA.

Background: Emerging evidence suggests that black and Hispanic communities in the United States are disproportionately affected by coronavirus disease 2019 (COVID-19). A complex interplay of socioeconomic and healthcare disparities likely contribute to disproportionate COVID-19 risk.

Methods: We conducted a geospatial analysis to determine whether individual- and neighborhood-level attributes predict local odds of testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed 29 138 SARS-CoV-2 tests within the 6-county catchment area for Duke University Health System from March to June 2020. We used generalized additive models to analyze the spatial distribution of SARS-CoV-2 positivity. Adjusted models included individual-level age, gender, and race, as well as neighborhood-level Area Deprivation Index, population density, demographic composition, and household size.

Results: Our dataset included 27 099 negative and 2039 positive unique SARS-CoV-2 tests. The odds of a positive SARS-CoV-2 test were higher for males (odds ratio [OR], 1.43; 95% credible interval [CI], 1.30-1.58), blacks (OR, 1.47; 95% CI, 1.27-1.70), and Hispanics (OR, 4.25; 955 CI, 3.55-5.12). Among neighborhood-level predictors, percentage of black population (OR, 1.14; 95% CI, 1.05-1.25), and percentage Hispanic population (OR, 1.23; 95% CI, 1.07-1.41) also influenced the odds of a positive SARS-CoV-2 test. Population density, average household size, and Area Deprivation Index were not associated with SARS-CoV-2 test results after adjusting for race.

Conclusions: The odds of testing positive for SARS-CoV-2 were higher for both black and Hispanic individuals, as well as within neighborhoods with a higher proportion of black or Hispanic residents-confirming that black and Hispanic communities are disproportionately affected by SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499753PMC
January 2021

Asymmetric Synthesis of N-Substituted α-Amino Esters from α-Ketoesters via Imine Reductase-Catalyzed Reductive Amination.

Angew Chem Int Ed Engl 2021 04 9;60(16):8717-8721. Epub 2021 Mar 9.

Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN, UK.

N-Substituted α-amino esters are widely used as chiral intermediates in a range of pharmaceuticals. Here we report the enantioselective biocatalyic synthesis of N-substituted α-amino esters through the direct reductive coupling of α-ketoesters and amines employing sequence diverse metagenomic imine reductases (IREDs). Both enantiomers of N-substituted α-amino esters were obtained with high conversion and excellent enantioselectivity under mild reaction conditions. In addition >20 different preparative scale transformations were performed highlighting the scalability of this system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202016589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048798PMC
April 2021

Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up.

Oncologist 2021 May 10;26(5):e749-e755. Epub 2021 Mar 10.

Centre Eugène Marquis, Rennes, France.

Background: Previous studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure.

Patients And Methods: Data were pooled from three randomized studies of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA-1/-2) and pre- and postmenopausal women who had progressed on prior ET (PALOMA-3).

Results: Updated cutoff dates were December 21, 2017 (PALOMA-1), May 31, 2017 (PALOMA-2), and April 13, 2018 (PALOMA-3). Total person-years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any-grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p < .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all-grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET.

Conclusion: This 5-year, long-term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2- ABC.

Implications For Practice: Several treatments for patients with breast cancer are associated with long-term or latent adverse events. This long-term, 5-year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100571PMC
May 2021

Enzymatic Late-Stage Modifications: Better Late Than Never.

Angew Chem Int Ed Engl 2021 Jan 16. Epub 2021 Jan 16.

School of Chemistry, The University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN, United Kingdom.

Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202014931DOI Listing
January 2021

Uncovering the Harms of Treating Clostridioides difficile Colonization.

mSphere 2021 01 13;6(1). Epub 2021 Jan 13.

Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.

Patients with toxin-negative -positive diarrhea are often treated with oral vancomycin with the assumption that treatment is more beneficial than harmful. However, this hypothesis has never been formally tested, and recent studies suggest that most such patients recover quickly without treatment and can be colonized rather than infected. Fishbein et al. conducted a prospective, placebo-controlled randomized trial to systematically evaluate the effects, risks, and benefits of oral vancomycin in these patients (S. R. S. Fishbein, T. Hink, K. A. Reske, C. Cass, et al., mSphere 6:e00936-20, 2020, https://doi.org/10.1128/mSphere.00936-20). Although small, the results are intriguing and suggest the adverse antibiotic-induced effects of vancomycin outweigh the clinical benefit when colonization is more likely than disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.01296-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845611PMC
January 2021

Species sensitivity assessment of five Atlantic scleractinian coral species to 1-methylnaphthalene.

Sci Rep 2021 Jan 12;11(1):529. Epub 2021 Jan 12.

Nova Southeastern University, Halmos College of Natural Sciences and Oceanography, Dania, FL, USA.

Coral reefs are keystone coastal ecosystems that are at risk of exposure to petroleum from a range of sources, and are one of the highest valued natural resources for protection in Net Environmental Benefit Analysis (NEBA) in oil spill response. Previous research evaluating dissolved hydrocarbon impacts to corals reflected no clear characterization of sensitivity, representing an important knowledge gap in oil spill preparedness related to the potential impact of oil spills to the coral animal and its photosymbiont zooxanthellae. This research addresses this gap, using a standardized toxicity protocol to evaluate effects of a dissolved reference hydrocarbon on scleractinian corals. The relative sensitivity of five Atlantic scleractinian coral species to hydrocarbon exposure was assessed with 48-h assays using the reference polycyclic aromatic hydrocarbon 1-methylnaphthalene, based on physical coral condition, mortality, and photosynthetic efficiency. The threatened staghorn coral Acropora cervicornis was found to be the most sensitive to 1-methylnaphthalene exposure. Overall, the acute and subacute endpoints indicated that the tested coral species were comparatively more resilient to hydrocarbon exposure than other marine species. These results provide a framework for the prediction of oil spill impacts and impact thresholds on the coral animal and related habitats, essential for informing oil spill response in coastal tropical environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80055-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804185PMC
January 2021

Risk Factors for Mortality and Progression to Severe COVID-19 Disease in the Southeast United States (US): A Report from the SEUS Study Group.

Infect Control Hosp Epidemiol 2021 Jan 11:1-33. Epub 2021 Jan 11.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.

Objective: Identify risk factors that could increase progression to severe disease and mortality in hospitalized SARS-CoV-2 patients in the Southeast US.

Design, Setting, And Participants: Multicenter, retrospective cohort including 502 adults hospitalized with laboratory-confirmed COVID-19 between March 1, 2020 and May 8, 2020 within one of 15 participating hospitals in 5 health systems across 5 states in the Southeast US.

Methods: The study objectives were to identify risk factors that could increase progression to hospital mortality and severe disease (defined as a composite of intensive care unit admission or requirement of mechanical ventilation) in hospitalized SARS-CoV-2 patients in the Southeast US.

Results: A total of 502 patients were included, and the majority (476/502, 95%) had clinically evaluable outcomes. Hospital mortality was 16% (76/476), while 35% (177/502) required ICU admission, and 18% (91/502) required mechanical ventilation. By both univariate and adjusted multivariate analysis, hospital mortality was independently associated with age (adjusted odds ratio [aOR] 2.03 for each decade increase, 95% CI 1.56-2.69), male sex (aOR 2.44, 95% CI: 1.34-4.59), and cardiovascular disease (aOR 2.16, 95% CI: 1.15-4.09). As with mortality, risk of severe disease was independently associated with age (aOR 1.17 for each decade increase, 95% CI: 1.00-1.37), male sex (aOR 2.34, 95% CI 1.54-3.60), and cardiovascular disease (aOR 1.77, 95% CI 1.09-2.85).

Conclusions: In an adjusted multivariate analysis, advanced age, male sex, and cardiovascular disease increased risk of severe disease and mortality in patients with COVID-19 in the Southeast US. In-hospital mortality risk doubled with each subsequent decade of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/ice.2020.1435DOI Listing
January 2021

Test-guided dietary management of eczema in children: A randomized controlled feasibility trial (TEST).

Clin Exp Allergy 2021 Mar 15;51(3):452-462. Epub 2021 Jan 15.

Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK.

Background: Parents commonly ask about food allergy tests, to find a cause for their child's eczema, yet the value of routine testing is uncertain.

Objective: To determine whether a clinical trial comparing test-guided dietary advice versus usual care, for the management of eczema, is feasible.

Methods: Children (>3 months and <5 years) with mild-to-severe eczema, recruited via primary care, were individually randomized (1:1) to intervention or usual care. Intervention participants underwent structured allergy history and skin prick tests (SPT) with dietary advice for cow's milk, hen's egg, wheat, peanut, cashew and codfish. All participants were followed up for 24 weeks. A sample of doctors and parents was interviewed. Registration ISRCTN15397185.

Results: From 1059 invitation letters sent to carers of potentially eligible children, 84 were randomized (42 per group) with mean age of 32.4 months (SD 13.9) and POEM of 8.7 (4.8). Of the 42, 6 (14%) intervention participants were advised to exclude one or more foods, most commonly egg, peanut or milk. By participant, 1/6 had an oral food challenge (negative); 3/6 were told to exclude until review in allergy clinic; and 6/6 advised a home dietary trial (exclusion and reintroduction of food over 4-6 weeks) - with 1/6 partially completing it. Participant retention (four withdrawals) and data completeness (74%-100%) were acceptable and contamination low (two usual care participants had allergy tests). There were three minor SPT-related adverse events. During follow-up, 12 intervention and 8 usual care participants had minor, unrelated adverse events plus one unrelated hospital admission.

Conclusions: It is possible to recruit, randomize and retain children with eczema from primary care into a trial of food allergy screening and to collect the outcomes of interest. Changes to recruitment and inclusion criteria are needed in a definitive trial, to ensure inclusion of younger children from more diverse backgrounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cea.13816DOI Listing
March 2021

Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination.

Nat Chem 2021 02 30;13(2):140-148. Epub 2020 Dec 30.

Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, Manchester, UK.

Finding faster and simpler ways to screen protein sequence space to enable the identification of new biocatalysts for asymmetric synthesis remains both a challenge and a rate-limiting step in enzyme discovery. Biocatalytic strategies for the synthesis of chiral amines are increasingly attractive and include enzymatic asymmetric reductive amination, which offers an efficient route to many of these high-value compounds. Here we report the discovery of over 300 new imine reductases and the production of a large (384 enzymes) and sequence-diverse panel of imine reductases available for screening. We also report the development of a facile high-throughput screen to interrogate their activity. Through this approach we identified imine reductase biocatalysts capable of accepting structurally demanding ketones and amines, which include the preparative synthesis of N-substituted β-amino ester derivatives via a dynamic kinetic resolution process, with excellent yields and stereochemical purities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41557-020-00606-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116802PMC
February 2021

Annular atrophic lichen planus induced by anti-HER2 antibodies.

Australas J Dermatol 2020 Nov 20. Epub 2020 Nov 20.

Royal Marsden NHS Foundation Trust, London, UK.

Pertuzumab and trastuzumab are monoclonal antibody inhibitors targeting human epidermal growth factor receptor 2 (HER-2) and are increasingly being utilised in the management of HER2-positive breast cancer, having been demonstrated to improve progression-free survival in conjunction with docetaxel. We present a rare presentation of a lichenoid drug eruption, in an annular atrophic variant, in a 35-year-old woman after initiation of HER2-inhibitor (pertuzumab and trastuzumab) therapy for metastatic breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajd.13501DOI Listing
November 2020

Engineering towards production of gatekeeper (2)-flavanones: naringenin, pinocembrin, eriodictyol and homoeriodictyol.

Synth Biol (Oxf) 2020 6;5(1):ysaa012. Epub 2020 Aug 6.

Manchester aaSynthetic Biology Research Centre for Fine and Speciality Chemicals (SYNBIOCHEM), Manchester Institute of Biotechnology and Department of Chemistry, The University of Manchester, Manchester M1 7DN, UK.

Natural plant-based flavonoids have drawn significant attention as dietary supplements due to their potential health benefits, including anti-cancer, anti-oxidant and anti-asthmatic activities. Naringenin, pinocembrin, eriodictyol and homoeriodictyol are classified as (2)-flavanones, an important sub-group of naturally occurring flavonoids, with wide-reaching applications in human health and nutrition. These four compounds occupy a central position as branch point intermediates towards a broad spectrum of naturally occurring flavonoids. Here, we report the development of production chassis for each of these key gatekeeper flavonoids. Selection of key enzymes, genetic construct design and the optimization of process conditions resulted in the highest reported titers for naringenin (484 mg/l), improved production of pinocembrin (198 mg/l) and eriodictyol (55 mg/l from caffeic acid), and provided the first example of production of homoeriodictyol directly from glycerol (17 mg/l). This work provides a springboard for future production of diverse downstream natural and non-natural flavonoid targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/synbio/ysaa012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644443PMC
August 2020

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

Clin Infect Dis 2020 Nov 3. Epub 2020 Nov 3.

Department of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC.

Background: Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children.

Methods: We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay.

Results: Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have asthma (p=0.005), and more likely to have an infected sibling contact (p=0.001) than uninfected children. Children ages 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs. 48%; p=0.01) or adolescents (29% vs. 60%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p<0.0001), gastrointestinal (27% vs. 9%; p=0.002), and sensory symptoms (42% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.01]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children.

Conclusions: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665428PMC
November 2020

A Cluster of Non-tuberculous Mycobacterial Tenosynovitis following Hurricane Relief Efforts.

Clin Infect Dis 2020 Nov 2. Epub 2020 Nov 2.

Division of Infectious Diseases, Duke University School of Medicine, Durham NC, USA.

Background: Non-tuberculous mycobacteria (NTM) are a rare cause of infectious tenosynovitis of the upper extremity. Using molecular methods, clinical microbiology laboratories are increasingly reporting identification down to the species level. Improved methods for speciation are revealing new insights into the clinical and epidemiologic features of rare NTM infections.

Methods: We encountered three cases of epidemiologically linked upper extremity NTM tenosynovitis associated with exposure to hurricane-damaged wood. We conducted whole genome sequencing to assess isolate relatedness followed by a literature review of NTM infections involving the upper extremity.

Results: Despite shared epidemiologic risk, the cases were caused by three distinct organisms. Two cases were rare infections caused by closely related but distinct species within the M. terrae complex that could not be differentiated by traditional methods. The third case was caused by M. intracellulare. An updated literature review focusing on articles using modern molecular speciation methods found that several species within M. terrae complex are increasingly reported as a cause of upper extremity tenosynovitis, often in association with environmental exposures.

Conclusions: These cases illustrate the importance of molecular methods for speciating phenotypically similar NTM, as well as the limitations of laboratory-based surveillance in detecting point-source outbreaks when the source is environmental and may involve multiple organisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1665DOI Listing
November 2020

PIK3CA mutation enrichment and quantitation from blood and tissue.

Sci Rep 2020 10 13;10(1):17082. Epub 2020 Oct 13.

Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK.

PIK3CA is one of the two most frequently mutated genes in breast cancers, occurring in 30-40% of cases. Four frequent 'hotspot' PIK3CA mutations (E542K, E545K, H1047R and H1047L) account for 80-90% of all PIK3CA mutations in human malignancies and represent predictive biomarkers. Here we describe a PIK3CA mutation specific nuclease-based enrichment assay, which combined with a low-cost real-time qPCR detection method, enhances assay detection sensitivity from 5% for E542K and 10% for E545K to 0.6%, and from 5% for H1047R to 0.3%. Moreover, we present a novel flexible prediction method to calculate initial mutant allele frequency in tissue biopsy and blood samples with low mutant fraction. These advancements demonstrated a quick, accurate and simple detection and quantitation of PIK3CA mutations in two breast cancer cohorts (first cohort n = 22, second cohort n = 25). Hence this simple, versatile and informative workflow could be applicable for routine diagnostic testing where quantitative results are essential, e.g. disease monitoring subject to validation in a substantial future study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74086-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555501PMC
October 2020

Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in -Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers.

Cancer Discov 2020 Sep 21. Epub 2020 Sep 21.

Breast Unit, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.

Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in -mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with -mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8-59.4]. Durable disease control was observed in -mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3-13.1; = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4-19.4; = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated -mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with -mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-0553DOI Listing
September 2020

Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer.

J Natl Cancer Inst 2021 Mar;113(3):309-317

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Background: There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i.

Methods: PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided.

Results: Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed.

Conclusions: Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936069PMC
March 2021