286 results on '"John F.R. Robertson"'
Search Results
2. Data from Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
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Maggie C.U. Cheang, Mitch Dowsett, Ian E. Smith, John F.R. Robertson, Judith M. Bliss, Holly Tovey, Elena López-Knowles, Mariana F. Leal, Eugene F. Schuster, Joel Parker, Gabriele Morani, and Milana A. Bergamino
- Abstract
Purpose:Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor–positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs.Experimental Design:Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors.Results:The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study.Conclusions:Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.
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- 2023
3. Supplementary Figure 2 from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
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Supplementary Figure 2. Consort diagram of patients analysed from EFECT
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- 2023
4. Supplementary Figure 6 from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
- Abstract
Supplementary Figure 6. Progression free survival in monoclonal and polyclonal ESR1 mutations
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- 2023
5. Data from Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)
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Julia M.W. Gee, Andrew Foxley, Pauline Finlay, Rahul Deb, Gaia Schiavon, Paul Rugman, Martin Pass, Justin P.O. Lindemann, Loumpiana Koulai, Elza C. de Bruin, Marie Cullberg, S.Y. Amy Cheung, Roberta Littleford, Petra Rauchhaus, Kieran Horgan, Ali Jahan, Samreen Ahmed, Daniel Rea, Anthony Skene, Chris Holcombe, Abigail Evans, Kwok-Leung Cheung, Robert E. Coleman, and John F.R. Robertson
- Abstract
Purpose:The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation.Patients and Methods:STAKT was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring.Results:After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3β (H-score absolute change: −55.3, P = 0.006) and pPRAS40 (−83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: −9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (−42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident.Conclusions:Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.
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- 2023
6. Supplementary Data from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
- Abstract
Supplementary Data
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- 2023
7. Data from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
- Abstract
Purpose:ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane.Experimental Design:The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies.Results:ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P = 0.69).Conclusions:Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.
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- 2023
8. Supplementary Figure 1 from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
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Supplementary Figure 1. Impact of DNA input amount on ESR1 mutation detection in EFECT
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- 2023
9. Supplementary Data from Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)
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Julia M.W. Gee, Andrew Foxley, Pauline Finlay, Rahul Deb, Gaia Schiavon, Paul Rugman, Martin Pass, Justin P.O. Lindemann, Loumpiana Koulai, Elza C. de Bruin, Marie Cullberg, S.Y. Amy Cheung, Roberta Littleford, Petra Rauchhaus, Kieran Horgan, Ali Jahan, Samreen Ahmed, Daniel Rea, Anthony Skene, Chris Holcombe, Abigail Evans, Kwok-Leung Cheung, Robert E. Coleman, and John F.R. Robertson
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Supplementary Data from Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)
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- 2023
10. Supplementary Data from Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
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Maggie C.U. Cheang, Mitch Dowsett, Ian E. Smith, John F.R. Robertson, Judith M. Bliss, Holly Tovey, Elena López-Knowles, Mariana F. Leal, Eugene F. Schuster, Joel Parker, Gabriele Morani, and Milana A. Bergamino
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Supplementary Data from Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
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- 2023
11. Supplementary Figure 5 from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
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Supplementary Figure 5. Progression free survival by ESR1 mutation detected in ctDNA
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- 2023
12. Supplementary Figure 3 from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Stephen K. Chia, Stephen R.D. Johnston, Mitch Dowsett, Judith M. Bliss, Gaia Schiavon, Martine Piccart, William Gradishar, John F.R. Robertson, Aman U. Budzar, Isaac Garcia-Murillas, Matthew Beaney, Charlotte Fribbens, Lucy Kilburn, Claire Swift, and Nicholas C. Turner
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Supplementary Figure 3. Time To Progression in EFECT by detection of ESR1 mutations in baseline serum
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- 2023
13. Supplementary Figure from Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
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Maggie C.U. Cheang, Mitch Dowsett, Ian E. Smith, John F.R. Robertson, Judith M. Bliss, Holly Tovey, Elena López-Knowles, Mariana F. Leal, Eugene F. Schuster, Joel Parker, Gabriele Morani, and Milana A. Bergamino
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Supplementary Figure from Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
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- 2023
14. Regional lymphadenopathy following COVID-19 vaccination: Literature review and considerations for patient management in breast cancer care
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Shama Puri, Antonious Z. Hazim, Joanne York, Emanuele Garreffa, Anne Turnbull, John F.R. Robertson, Matthew P. Goetz, Ahmed Hamad, and Ciara C. O’Sullivan
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Cancer Research ,Pediatrics ,medicine.medical_specialty ,COVID-19 Vaccines ,Time Factors ,Coronavirus disease 2019 (COVID-19) ,Breast Neoplasms ,Review ,Supraclavicular lymphadenopathy ,Risk Assessment ,Diagnosis, Differential ,breast cancer ,Breast cancer ,Predictive Value of Tests ,Risk Factors ,Positron Emission Tomography Computed Tomography ,vaccine ,lymphadenopathy ,cancer diagnosis ,medicine ,Humans ,media_common.cataloged_instance ,Diagnostic Errors ,European union ,media_common ,business.industry ,Incidence ,Incidence (epidemiology) ,Vaccination ,COVID-19 ,Prognosis ,medicine.disease ,Patient management ,Oncology ,Female ,cancer follow-up ,business ,Mammography ,Regional lymphadenopathy - Abstract
Purpose Over 1 billion doses of COVID-19 vaccines have been already administered across the United States, the United Kingdom and the European Union at the time of writing. Furthermore, 1.82 million booster doses have been administered in the US since 13th August, and similar booster programmes are currently planned or under consideration in the UK and the EU beginning in the autumn of 2021. Early reports showed an association between vaccine administration and the development of ipsilateral axillary and supraclavicular lymphadenopathy, which could interfere with the diagnosis, treatment and follow-up of breast cancer patients. In this paper, we review the available evidence on vaccine-related lymphadenopathy, and we discuss the clinical implications of the same on breast cancer diagnosis and management. Methods A literature search was performed - PubMed, Ovid Medline, Scopus, CINHAL, Springer Nature, ScienceDirect, Academic Search Premier and the Directory of Open Access Journals were searched for articles reporting on regional palpable or image-detected lymphadenopathy following COVID-19 vaccination. Separately, we compiled a series of case studies from the University Hospitals of Derby and Burton, United Kingdom and the Mayo Clinic in Minnesota, United States of America, to illustrate the impact that regional lymphadenopathy post-COVID-19 vaccination can have on the diagnosis and management of patients being seen in diagnostic and therapeutic breast clinics. Results From the literature search, 15 studies met the inclusion criteria (n = 2057 patients, 737 with lymphadenopathy). The incidence of lymphadenopathy ranged between 14.5% and 53% and persisted for >6 weeks in 29% of patients. Conclusions Clinicians managing breast cancer patients should be aware that the COVID-19 vaccination may result in regional lymphadenopathy in a significant number of patients, which can result in unnecessary investigations, treatment and increased patient anxiety. An accurate COVID-19 vaccination history should be collected from all patients where regional lymphadenopathy is a clinical and/or an imaging finding and then combined with clinical judgement when managing individual cases.
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- 2021
15. Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies
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Robert Paridaens, Angelo Di Leo, Stephen Chia, Stephen R. D. Johnston, Judith M Bliss, John F.R. Robertson, Ian Bradbury, Christine M. Pierce Campbell, and Jasmine Lichfield
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cancer therapy ,Disease ,Article ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Medicine ,Endocrine system ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging ,RC254-282 ,Fulvestrant ,business.industry ,Hazard ratio ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Confidence interval ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Tamoxifen ,medicine.drug - Abstract
Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45−0.70) and 0.55 (95% CI 0.42−0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.
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- 2021
16. ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
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Charlotte Fribbens, Lucy Kilburn, Stephen R. D. Johnston, William J. Gradishar, Mitch Dowsett, Judith M Bliss, Aman U. Budzar, John F.R. Robertson, Claire Swift, Nicholas C. Turner, Stephen Chia, Gaia Schiavon, Isaac Garcia-Murillas, Matthew Beaney, and Martine Piccart
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Exemestane ,Internal medicine ,medicine ,Aromatase ,Survival analysis ,Aromatase inhibitor ,biology ,Fulvestrant ,business.industry ,Hazard ratio ,medicine.disease ,Metastatic breast cancer ,body regions ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,business ,medicine.drug - Abstract
Purpose: ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane. Experimental Design: The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies. Results: ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P = 0.69). Conclusions: Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.
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- 2020
17. Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients
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Maggie C.U. Cheang, John F.R. Robertson, Ian E. Smith, Kally Sidhu, James P Morden, Elizabeth Mallon, Elena Lopez-Knowles, Qiong Gao, Vera Martins, Anthony Skene, Ricardo Ribas, Chris Holcombe, Mitch Dowsett, Judith M Bliss, David Evans, Abigail Evans, Andrew Dodson, and Lesley-Ann Martin
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Oncology ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Oestrogen receptor ,medicine.drug_class ,Receptor, ErbB-2 ,Resistance ,Breast Neoplasms ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Surgical oncology ,Internal medicine ,Gene expression ,Biomarkers, Tumor ,Medicine ,Humans ,Perioperative Period ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Aromatase inhibitor ,business.industry ,Aromatase Inhibitors ,Gene Expression Profiling ,Signatures ,Cell Cycle Checkpoints ,Aromatase inhibition ,Cell cycle ,Gene signature ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,HDAC4 ,Gene Expression Regulation, Neoplastic ,Postmenopause ,Ki-67 Antigen ,Receptors, Estrogen ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Residual proliferation ,Female ,business ,Estrogen receptor alpha ,Research Article ,Signal Transduction - Abstract
BackgroundEndocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance.MethodsGlobal gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (controln = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67.ResultsHigh baselineESR1expression associated with better AI response in HER2+ tumours but not HER2− tumours. In HER2− tumours, baseline expression of 48 genes associated with poor antiproliferative response (p PERPandYWHAQ, the two most significant, and the transcription co-regulators (SAP130,HDAC4, andNCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, andIGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2− and HER2+ patients.ConclusionsThere is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors.Trial registrationISRCTN,ISRCTN63882543, registered on 18 December 2007.
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- 2019
18. Correction: Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)
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John F.R. Robertson, Robert E. Coleman, Kwok-Leung Cheung, Abigail Evans, Chris Holcombe, Anthony Skene, Daniel Rea, Samreen Ahmed, Ali Jahan, Kieran Horgan, Petra Rauchhaus, Roberta Littleford, S.Y. Amy Cheung, Marie Cullberg, Elza C. de Bruin, Loumpiana Koulai, Justin P.O. Lindemann, Martin Pass, Paul Rugman, Gaia Schiavon, Rahul Deb, Pauline Finlay, Andrew Foxley, and Julia M.W. Gee
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Cancer Research ,Oncology - Published
- 2022
19. Targeted screening for lung cancer with autoantibodies
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Shaun Treweek, Colin McCowan, John F.R. Robertson, Michael Sproule, Kavita Vedhara, Thomas H. Taylor, Chris Robertson, William Anderson, Nicola McMeekin, Denise Kendrick, Jose Antonio Robles-Zurita, Joseph Sarvesvaran, Roberta Littleford, Petra Rauchhaus, Cindy Chew, Manish G. Patel, John Haughney, Pauline Armory, Fiona Hogarth, Stuart Schembri, Frank Sullivan, Andrew Briggs, Alistair Dorward, Frances S. Mair, Lewis D Ritchie, Alex McConnachie, and Herbert F. Sewell
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Oncology ,medicine.medical_specialty ,business.industry ,Hazard ratio ,Autoantibody ,Cancer ,Disease ,medicine.disease ,Internal medicine ,medicine ,Targeted screening ,False positive rate ,Stage (cooking) ,business ,Lung cancer - Abstract
Earlier detection of lung cancer is possible, but difficult and costly to achieve. Screening with Low Dose Computed Tomography (LDCT)scanning has been shown to reduce mortality by 20-25% over the past decade but uptake amongst those most likely to suffer the disease has been slow. Resource constraints and a high false positive rate have also limited adoption of LDCT in many health systems. Targeted screening of people most likely to benefit using a range of biomarkers may be one way to improve the yield and reduce the resource requirements of LDCT. Autoantibodies, which amplify the signal produced by cancer derived proteins, are present in the blood of people mounting an immune response to cancer are a potential way to select those at highest risk. We have followed up 12 208 people enrolled in the ECLS trial for three years and shown that the specificity for early stage (I &II) disease is 90.3% throughout that period. More cancers were detected in the control than the intervention arm of the trial (101V 83). Sensitivity was 77.8% after 6 months and dropped to 46.4% after 3 years. At the end of three years the hazard ratios (95%CI) for All Cause, Cancer Specific and Lung Cancer Mortality was 0.82(0.67-1.01), 0.72(0.54-0.97) and 0.70(0.46-1.08) respectively for those randomised to Early CDT testing. As a range of treatment modalities become increasingly more effective it is even more important to target LDCT on those most likely to have early stage disease. Autoantibody testing may be one method of targeting early detection on those most likely to benefit.
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- 2021
20. Delayed second dose of the BNT162b2 vaccine: innovation or misguided conjecture?
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Marcia Stewart, John F.R. Robertson, and Herb F. Sewell
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2019-20 coronavirus outbreak ,Conjecture ,COVID-19 Vaccines ,Time Factors ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Vaccination ,MEDLINE ,COVID-19 ,General Medicine ,Virology ,United Kingdom ,Correspondence ,Medicine ,Humans ,business ,BNT162 Vaccine ,Randomized Controlled Trials as Topic - Published
- 2021
21. Reaffirming health and safety precautionary principles for COVID-19 in the UK
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Herb F. Sewell, Denise Kendrick, Marcia Stewart, John F.R. Robertson, and Raymond Agius
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medicine.medical_specialty ,2019-20 coronavirus outbreak ,Health Knowledge, Attitudes, Practice ,Safety Management ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,COVID-19 ,Health knowledge ,General Medicine ,Occupational safety and health ,United Kingdom ,Family medicine ,Correspondence ,medicine ,Humans ,Business - Published
- 2021
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22. 517MO Phase I study of the porcupine (PORCN) inhibitor RXC004 in patients with advanced solid tumours
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A. Ortego Franco, L. Goodwin, Ruth Plummer, Natalie Cook, Juanita Lopez, Alastair Greystoke, Rille Pihlak, A. Naderi, G. Nintos, Debashis Sarker, C. Tilston, F. Kazmi, S. Blagden, C. Phillips, S. Woodcock, R. Shinde, A. Saunders, John F.R. Robertson, and N. Harris
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Oncology ,biology ,business.industry ,biology.animal ,Cancer research ,Medicine ,In patient ,Hematology ,business ,Porcupine ,Phase i study ,PORCN - Published
- 2021
23. Markers of steroid receptor, kinase signalling pathways and Ki-67 expression in relation to tamoxifen sensitivity and resistance
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John F.R. Robertson, Christine M. Pierce Campbell, Andrew R. Green, Ian Bradbury, Signe Borgquist, Julia Margaret Wendy Gee, John Mathew, Ian O. Ellis, Karin Elebro, and Pauline Finlay
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biology ,business.industry ,AKT1 ,medicine.disease ,Breast cancer ,Ki-67 ,Cancer research ,biology.protein ,Biomarker (medicine) ,Medicine ,PTEN ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Tamoxifen ,medicine.drug - Abstract
Background: It remains clinically important to identify ER positive breast cancers likely to respond to tamoxifen (TAM) and so we aimed to select a group of biomarkers able to predict response. We also assessed whether data from different sample types [tumor microarrays (TMAs) and core biopsies] or tumor sites could be combined for biomarker studies. Methods: A total of 123 endocrine treatment naïve patients with known ER and HER2 status treated with TAM had paraffin-embedded tumor tissue available either as TMAs (n=102) or core biopsies (n=21). TMA cores were collected from three different tumor sites, two central and one peripheral. Ten biomarkers were evaluated by immunohistochemistry, for % positivity and/or H-Score, comprising: ER, HER2, Ki67, phosphorylated forms of ER (Ser118), IGF1R, PRAS40, Akt & MAPK (ERK1/2), and PTEN & androgen receptor expression (AR). Each tumor was analysed for Akt1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses [time to progression (TTP) and time to death (TTD)]. Results: There was no significant difference in % positivity or H-Score between central & peripheral tumor sites for all biomarkers examined. After False Discovery Rate (FDR) correction differences (P
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- 2020
24. Covid-19 in the workplace
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Herb F. Sewell, Marcia Stewart, John F.R. Robertson, Denise Kendrick, Martin McKee, and Raymond Agius
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Viral transmission ,Betacoronavirus ,Political science ,Occupational Exposure ,medicine ,Humans ,Workplace ,Pandemics ,Occupational Health ,Medicine(all) ,biology ,Viral Epidemiology ,SARS-CoV-2 ,COVID-19 ,General Medicine ,biology.organism_classification ,medicine.disease ,Virology ,United Kingdom ,Occupational Diseases ,Pneumonia ,Coronavirus Infections - Published
- 2020
25. Meta-analyses of phase 3 randomised controlled trials of third generation aromatase inhibitors versus tamoxifen as first-line endocrine therapy in postmenopausal women with hormone receptor-positive advanced breast cancer
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Ian Bradbury, Jasmine Lichfield, John F.R. Robertson, Christine Campbell, and Robert Paridaens
- Subjects
0301 basic medicine ,Oncology ,Selective Estrogen Receptor Modulators ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Anastrozole ,Breast Neoplasms ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Exemestane ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Aged ,Randomized Controlled Trials as Topic ,business.industry ,Aromatase Inhibitors ,Letrozole ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Postmenopause ,Tamoxifen ,030104 developmental biology ,chemistry ,Clinical Trials, Phase III as Topic ,Receptors, Estrogen ,Selective estrogen receptor modulator ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Background Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8%–55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. MethodsAnonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FindingsThe OR for clinical benefit rate was 1·56, in favour of AIs (p[less than] 0·001). The duration of clinical benefit was not significantly increased by AIs (hazard ratio [HzR] 0·88; p=0·08). For PFS the HzR (0·82) was in favour of AIs (p=0·007). However, for OS the HzR (1·05) was not significantly different between AIs and tamoxifen (p=0·42).InterpretationAlthough third generation AIs put significantly more patients into ‘clinical benefit’, their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.
- Published
- 2020
26. A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer
- Author
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Michele Moschetta, Abigail Evans, S. Henschen, Rachel Wuerstlein, Kwok-Leung Cheung, Teresa Klinowska, Ashutosh Kothari, A Jahan, Cliona C. Kirwan, Justin P.O. Lindemann, Myria Nikolaou, Diansong Zhou, Martine P. Roudier, John F.R. Robertson, Omar Mohamed, J Michael Dixon, Alexander MacDonald, Danielle Carroll, Nadia Harbeck, Peter Schmid, Rhiannon Maudsley, Richard Mather, Li Zhou, Peter A. Fasching, Tinnu Sarvotham, Gaia Schiavon, and Laura M. Kenny
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cancer Research ,Newly diagnosed ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Window of opportunity ,Fulvestrant ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Open label ,business ,Primary breast cancer ,medicine.drug - Abstract
Purpose:Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods:Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results:Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions:This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
- Published
- 2020
27. Evidence-based guidelines for managing patients with primary ER+ HER2− breast cancer deferred from surgery due to the COVID-19 pandemic
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Ian E. Smith, Sherko Kuemmel, Arran K Turnbull, J Michael Dixon, Matthias Christgen, John F.R. Robertson, Cynthia X. Ma, Samuel A. Jacobs, Ulrike Nitz, Nadia Harbeck, Vera J. Suman, Peter A. Barry, Oleg Gluz, Ronald E. Kates, Hans Kreipe, Mitch Dowsett, Matthew J. Ellis, Stephen R. D. Johnston, and Judith M Bliss
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Evidence-based practice ,Coronavirus disease 2019 (COVID-19) ,medicine.medical_treatment ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Pandemic ,medicine ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging ,skin and connective tissue diseases ,Chemotherapy ,business.industry ,Endocrine therapy ,Cancer ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Surgery ,030104 developmental biology ,Oncology ,Radiology Nuclear Medicine and imaging ,030220 oncology & carcinogenesis ,Primary breast cancer ,business - Abstract
Many patients with ER+ HER2− primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER 10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2− breast cancer during and in the aftermath of the COVID-19 crisis.
- Published
- 2020
28. Proliferation and AKT activity biomarker analyses after capivasertib (AZD5363) treatment of patients with ER+ invasive breast cancer (STAKT)
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A Jahan, S.Y. Amy Cheung, Andrew Foxley, John F.R. Robertson, Petra Rauchhaus, Gaia Schiavon, Julia Margaret Wendy Gee, Elza C. de Bruin, Samreen Ahmed, Kieran Horgan, Loumpiana Koulai, Kwok-Leung Cheung, Robert E. Coleman, Chris Holcombe, Roberta Littleford, Marie Cullberg, Anthony Skene, R. Deb, Justin P.O. Lindemann, Paul Rugman, Pauline Finlay, Abigail Evans, Daniel Rea, and Martin Pass
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,Pharmacology ,medicine.disease ,Placebo ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Tolerability ,Oncology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Biomarker (medicine) ,Medicine ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Blood sampling - Abstract
Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3β (H-score absolute change: −55.3, P = 0.006) and pPRAS40 (−83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: −9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (−42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.
- Published
- 2020
29. The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ
- Author
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John F.R. Robertson, Islam M. Miligy, Qing Ting Tan, Michael S. Toss, Emad A. Rakha, Binafsha Manzoor Syed, Hazem Khout, Georgette Oni, Andrew R. Green, Sho Shiino, and R. Douglas Macmillan
- Subjects
Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,medicine.medical_treatment ,Breast Neoplasms ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Predictive Value of Tests ,Internal medicine ,Carcinoma ,Biomarkers, Tumor ,Medicine ,Humans ,Clinical significance ,skin and connective tissue diseases ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chemotherapy ,business.industry ,Carcinoma, Ductal, Breast ,Correction ,Retrospective cohort study ,Ductal carcinoma ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Treatment Outcome ,Receptors, Estrogen ,Chemotherapy, Adjuvant ,Tissue Array Analysis ,030220 oncology & carcinogenesis ,Predictive value of tests ,Female ,business ,Carcinoma in Situ - Abstract
Background Oestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision. Methods In total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate. Results ER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence). Conclusion The strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.
- Published
- 2020
30. Improving primary care identification of familial breast cancer risk using proactive invitation and decision support
- Author
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Brittany Dutton, Denise Kendrick, Wendy Chorley, John F.R. Robertson, Stephen Weng, Christina Sheehan, Joe Kai, and Nadeem Qureshi
- Subjects
Adult ,Cancer Research ,medicine.medical_specialty ,Referral ,Population ,Family history ,Ethnic group ,Breast Neoplasms ,Risk Assessment ,White People ,Decision Support Techniques ,Breast cancer ,Risk Factors ,Epidemiology ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Risk factor ,education ,Referral and Consultation ,Genetics (clinical) ,Family Health ,education.field_of_study ,Primary Health Care ,business.industry ,Medical genetics ,Age Factors ,Middle Aged ,medicine.disease ,Health Surveys ,Decision support ,Oncology ,Family medicine ,Educational Status ,Female ,Original Article ,Risk assessment ,business - Abstract
Family history of breast cancer is a key risk factor, accounting for up to 10% of cancers. We evaluated the proactive assessment of familial breast cancer (FBC) risk in primary care. Eligible women (30 to 60 years) were recruited from eight English general practices. Practices were trained on FBC risk assessment. In four randomly-assigned practices, women were invited to complete a validated, postal family history questionnaire, which practice staff inputted into decision support software to determine cancer risk. Those with increased risk were offered specialist referral. Usual care was observed in the other four practices. In intervention practices, 1127/7012 women (16.1%) returned family history questionnaires, comprising 1105 (98%) self-reported white ethnicity and 446 (39.6%) educated to University undergraduate or equivalent qualification, with 119 (10.6%) identified at increased breast cancer risk and offered referral. Sixty-seven (56%) women recommended referral were less than 50 years old. From 66 women attending specialists, 26 (39.4%) were confirmed to have high risk and recommended annual surveillance (40–60 years) and surgical prevention; while 30 (45.5%) were confirmed at moderate risk, with 19 offered annual surveillance (40–50 years). The remaining 10 (15.2%) managed in primary care. None were recommended chemoprevention. In usual care practices, only ten women consulted with concerns about breast cancer family history. This study demonstrated proactive risk assessment in primary care enables accurate identification of women, including many younger women, at increased risk of breast cancer. To improve generalisability across the population, more active methods of engagement need to be explored. Trial registration: CRUK Clinical Trials Database 11779. Electronic supplementary material The online version of this article (10.1007/s10689-020-00188-z) contains supplementary material, which is available to authorized users.
- Published
- 2020
31. Progression-free survival results in postmenopausal Asian women: subgroup analysis from a phase III randomized trial of fulvestrant 500 mg vs anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON)
- Author
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Mehdi Fazal, Zhimin Shao, Matthew J. Ellis, John F.R. Robertson, Jackie Thirlwell, and Shinzaburo Noguchi
- Subjects
Adult ,0301 basic medicine ,Oncology ,China ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Receptor, ErbB-2 ,Population ,Taiwan ,Anastrozole ,Breast Neoplasms ,Subgroup analysis ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Internal medicine ,Nitriles ,Humans ,Medicine ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging ,Breast ,Progression-free survival ,education ,Fulvestrant ,Response Evaluation Criteria in Solid Tumors ,Aged ,Aged, 80 and over ,education.field_of_study ,Estradiol ,Performance status ,business.industry ,Hazard ratio ,General Medicine ,Middle Aged ,Triazoles ,Postmenopause ,030104 developmental biology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Female ,Receptors, Progesterone ,business ,medicine.drug - Abstract
The international, phase III FALCON study (NCT01602380) in postmenopausal patients with hormone receptor-positive, locally advanced/metastatic breast cancer (LA/MBC) who had not received prior endocrine therapy, demonstrated statistically significant improvement in progression-free survival (PFS) for patients who received fulvestrant 500 mg vs anastrozole 1 mg. This subgroup analysis evaluated PFS in Asian (randomized in China, Japan, or Taiwan) and non-Asian patients from the FALCON study. Eligible patients (estrogen receptor- and/or progesterone receptor-positive LA/MBC; World Health Organization performance status 0–2; ≥ 1 measurable/non-measurable lesion[s]) were randomized. PFS was assessed via Response Evaluation Criteria in Solid Tumours version 1.1, surgery/radiotherapy for disease worsening, or death (any cause). Secondary endpoints included: objective response rate, clinical benefit rate, duration of response, and duration of clinical benefit. Consistency of effect across subgroups was assessed via hazard ratios and 95% confidence intervals (CIs) using a log-rank test. Adverse events (AEs) were evaluated. Of the 462 randomized patients, the Asian and non-Asian subgroups comprised 67 and 395 patients, respectively. In the Asian subgroup, median PFS was 16.6 and 15.9 months with fulvestrant and anastrozole, respectively (hazard ratio 0.81; 95% CI 0.44–1.50). In the non-Asian subgroup, median PFS was 16.5 and 13.8 months, respectively (hazard ratio 0.79; 95% CI 0.62–1.01). Secondary outcomes were numerically improved with fulvestrant vs anastrozole in both subgroups. AE profiles were generally consistent between Asian and non-Asian subgroups. Results of this subgroup analysis suggest that treatment effects in the Asian patient subgroup are broadly consistent with the non-Asian population.
- Published
- 2018
32. Was enough, and is enough, being done to protect the primary care workforce from COVID-19?
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John F.R. Robertson, Raymond Agius, Herb F. Sewell, Denise Kendrick, and Marcia Stewart
- Subjects
medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,health care facilities, manpower, and services ,education ,Specialty ,Primary care ,Lower risk ,03 medical and health sciences ,0302 clinical medicine ,Intensive care ,Interim ,Health care ,Pandemic ,Humans ,Infection control ,Medicine ,030212 general & internal medicine ,Pandemics ,Personal protective equipment ,Geriatrics ,Primary Health Care ,SARS-CoV-2 ,business.industry ,030503 health policy & services ,Public health ,Editorials ,COVID-19 ,virus diseases ,medicine.disease ,Family medicine ,Workforce ,Medical emergency ,Risk assessment ,0305 other medical science ,Family Practice ,business - Abstract
There is clear evidence that healthcare workers (HCWs) are at increased risk of contracting COVID-19. Compared to nonessential workers, HCWs have a seven-fold increase in risk of severe COVID-19 (testing positive in hospital or death).1 Frontline, or patient-facing, HCWs have a three-fold increase in risk of testing positive for COVID-19 compared to the general population.2 Compared to non-patient facing HCWs they have a three-fold risk, and their household members have a two-fold risk of hospital admission with COVID-19.3 COVID-19 risk is also specialty dependent: ‘front-door’ speciality HCWs (A&E, medical specialties including general, acute, and geriatric medicine, and infectious diseases) are at increased risk compared to intensive care HCWs,3 who in some studies had a lower risk than other HCWs.4 The only publicly available data on COVID-19-related deaths of doctors in the UK comes from tributes in the medical press, …
- Published
- 2021
33. Assessing risk for healthcare workers during the pandemic: don’t forget workplace safety committees or airborne transmission
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Lewis T Hughes, Marcia Stewart, John F.R. Robertson, Raymond Agius, and Denise Kendrick
- Subjects
Coronavirus disease 2019 (COVID-19) ,business.industry ,General Medicine ,030204 cardiovascular system & hematology ,Workplace safety ,Occupational safety and health ,03 medical and health sciences ,0302 clinical medicine ,Nursing ,Health care ,Workforce ,Pandemic ,Social care ,030212 general & internal medicine ,Business ,Risk assessment - Abstract
Khunti and colleagues advocate integrating “the workplace, the workforce, and the individual” in “assessing risk for healthcare workers during the covid-19 pandemic.”1 The same approach is relevant to other workers, notably in social care. It also warrants highlighting that health and safety law requires a “suitable and sufficient” risk assessment and the involvement of workers and their representatives.2 The pandemic ought to encourage active and effective safety committees and …
- Published
- 2021
34. Factors influencing local control in patients undergoing breast conservation surgery for ductal carcinoma in situ
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A. Bello, R. Karia, Ian O. Ellis, Andrew H S Lee, D.A.L. Morgan, J. Mathew, and John F.R. Robertson
- Subjects
Adult ,medicine.medical_specialty ,Multivariate analysis ,Breast Neoplasms ,Mastectomy, Segmental ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Humans ,Medicine ,In patient ,030212 general & internal medicine ,Pathological ,Aged ,Retrospective Studies ,Aged, 80 and over ,Breast conservation ,business.industry ,Proportional hazards model ,Age Factors ,Margins of Excision ,Retrospective cohort study ,General Medicine ,Guideline ,Middle Aged ,Ductal carcinoma ,Surgery ,Carcinoma, Intraductal, Noninfiltrating ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business - Abstract
The aim of our study was to assess various predictors for local recurrence (LR) in patients undergoing breast conservation surgery (BCS) for ductal carcinoma in situ (DCIS).An audit was performed of 582 consecutive patients with DCIS between Jan 1975 to June 2008. In patients undergoing BCS, local guidelines reported a margin of ≥10 mm during the above period. Guideline with regard to margin of excision changes soon after this period. We retrospectively analysed clinical and pathological risk factors for local recurrence in patients undergoing BCS. Statistical analysis was carried out using SPSS version 19, and a cox regression model for multivariate analysis of local recurrence was used.Overall 239 women had BCS for DCIS during the above period. The actuarial 5-year recurrence rate was 9.6%. The overall LR rate was 17% (40/239. LR was more common in patients ≤50 years: (10/31 patients, 32%) compared to patients 50 years (30/208, 14%, P = 0.02). Forty three per cent of patients (6/14) with5 mm margin developed LR which was significantly higher compared to patients with 5-9 mm margin (12%, 3/25) and with ≥10 mm margin (14%, 27/188, P = 0.01). On multivariate analysis age ≤50 years,5 mm pathological margin were independent prognostic factors for local recurrence.Our study shows that younger age (≤50 years) and a margin5 mm are poor prognostic factors for LR in patients undergoing breast conservation surgery for DCIS.
- Published
- 2017
35. Breast conservation in ductal carcinomain situ(DCIS): what defines optimal margins?
- Author
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Jeremy Thomas, Sarah E Pinder, Michael S. Toss, Emad A. Rakha, Andrew R. Green, Ian O. Ellis, David L Morgan, and John F.R. Robertson
- Subjects
Oncology ,medicine.medical_specialty ,Histology ,medicine.medical_treatment ,Breast Neoplasms ,Routine practice ,Mastectomy, Segmental ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Ductal carcinoma in situ (DCIS) ,medicine ,Breast-conserving surgery ,Humans ,030212 general & internal medicine ,skin and connective tissue diseases ,Breast conservation ,business.industry ,Margins of Excision ,Cosmesis ,General Medicine ,Ductal carcinoma ,medicine.disease ,Radiation therapy ,Carcinoma, Intraductal, Noninfiltrating ,030220 oncology & carcinogenesis ,Female ,business - Abstract
The introduction of mammographic screening has resulted in a rise in the detection rate of ductal carcinoma in situ (DCIS), currently accounting for one-fifth of screen-detected breast cancers. Although 60-70% of DCIS are treated with breast-conserving surgery (BCS) with or without radiotherapy, the frequency of subsequent surgery to re-excise positive margins in order to reduce the probability of recurrences remains high. DCIS recurrence is associated not only with financial, health and psychological implications; approximately half these recurrences are invasive disease. An appropriate margin width for patients undergoing BCS for invasive breast cancer has been largely agreed. Although there is a perception that such recommendations may be applicable to DCIS, major differences exist which may affect this application. Importantly, DCIS patients often do not receive systemic adjuvant (endocrine) therapy and not all receive radiotherapy in routine practice. There is evidence that wide margins (i.e. >10 mm) confer better protection against recurrence than positive (i.e. 0 mm) margins; however, there remains a debate concerning the optimum margin width between 0 and 10 mm. Previous studies have demonstrated that radiation therapy may not compensate for lack of re-excision in those patients with positive or close margins, while wide margins will inevitably compromise cosmesis and patients' body image perception. This review aims to address the clinical question of the minimal margin width in DCIS treated with BCS that is associated with the lowest recurrence rate and when, therefore, further surgical intervention for re-excision can be safely avoided. A range of clinical circumstances that might affect this are considered.
- Published
- 2016
36. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial
- Author
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Matthew J. Ellis, Mary Stuart, Alexey Manikhas, John F.R. Robertson, Mehdi Fazal, Kwok-Leung Cheung, Ekaterina Trishkina, Manuel Ruiz-Borrego, Lynda Grinsted, Lawrence Panasci, Igor Bondarenko, Servando Cardona-Huerta, Manuel Jesus Philco-Salas, M. Dvorkin, Zhimin Shao, Yaroslav Shparyk, Jacqui Rowbottom, Shinzaburo Noguchi, [Robertson, John F. R.] Univ Nottingham, Royal Derby Hosp, Sch Med, Div Med Sci & Grad Entry Med, Derby, England, [Cheung, Kwok-Leung] Univ Nottingham, Royal Derby Hosp, Sch Med, Div Med Sci & Grad Entry Med, Derby, England, [Bondarenko, Igor M.] Dnipropetrovsk State Med Acad, Dept Oncol, Dnepropetrovsk, Ukraine, [Trishkina, Ekaterina] Leningrad Reg Oncol Dispensary, St Petersburg, Russia, [Dvorkin, Mikhail] Clin Oncol Dispensary, Omsk, Russia, [Panasci, Lawrence] Jewish Gen Hosp, Dept Oncol, Montreal, PQ, Canada, [Manikhas, Alexey] City Clin Oncol Dispensary, St Petersburg, Russia, [Shparyk, Yaroslav] Lviv State Oncol Reg Treatment & Diagnost Ctr, Lvov, Ukraine, [Cardona-Huerta, Servando] Tecnol Monterrey, Breast Canc Ctr, Monterrey, Mexico, [Philco-Salas, Manuel Jesus] Inst Oncol Lima, Unidad Invest, Lima, Peru, [Ruiz-Borrego, Manuel] Hosp Univ Virgen Rocio, Seville, Spain, [Shao, Zhimin] Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China, [Noguchi, Shinzaburo] Osaka Univ, Grad Sch Med, Dept Breast & Endocrine Surg, Osaka, Japan, [Rowbottom, Jacqui] AstraZeneca, Alderley Pk, Macclesfield, Cheshire, England, [Stuart, Mary] AstraZeneca, Alderley Pk, Macclesfield, Cheshire, England, [Grinsted, Lynda M.] AstraZeneca, Cambridge, England, [Fazal, Mehdi] AstraZeneca, Gaithersburg, MD USABaylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX USA, and AstraZeneca
- Subjects
0301 basic medicine ,Oncology ,Survival ,0302 clinical medicine ,Clinical endpoint ,Breast ,Fulvestrant ,education.field_of_study ,Estradiol ,Aromatase Inhibitors ,General Medicine ,Middle Aged ,Postmenopausal women ,Metastatic breast cancer ,Postmenopause ,Receptors, Estrogen ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Letrozole ,Female ,medicine.drug ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Efficacy ,medicine.drug_class ,Population ,Anastrozole ,Breast Neoplasms ,Disease-Free Survival ,03 medical and health sciences ,Double-Blind Method ,Superior ,Internal medicine ,Nitriles ,medicine ,Humans ,education ,Aromatase inhibitor ,Performance status ,business.industry ,Triazoles ,medicine.disease ,Surgery ,Tamoxifen ,030104 developmental biology ,First-line therapy ,Endocrine-therapy ,business ,1st-line therapy - Abstract
Summary Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. Funding AstraZeneca.
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- 2016
37. Lung cancer screening: does pulmonary nodule detection affect a range of smoking behaviours?
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Kavita Vedhara, Roberta Littleford, Ben Young, Denise Kendrick, Frances S. Mair, John F.R. Robertson, Roshan das Nair, Stuart Schembri, Marcia E. Clark, Laura Elizabeth Bedford, Francis Sullivan, University of St Andrews. Population and Behavioural Science Division, and University of St Andrews. School of Medicine
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Male ,Smoking behaviour ,medicine.medical_specialty ,Teachable moment ,Lung Neoplasms ,medicine.medical_treatment ,NDAS ,Logistic regression ,RC0254 ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Surveys and Questionnaires ,Internal medicine ,Lung cancer screening ,medicine ,Humans ,030212 general & internal medicine ,Lung cancer ,Early Detection of Cancer ,Aged ,Autoantibodies ,business.industry ,RC0254 Neoplasms. Tumors. Oncology (including Cancer) ,030503 health policy & services ,Smoking ,Public Health, Environmental and Occupational Health ,Solitary Pulmonary Nodule ,Cancer ,Nodule (medicine) ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,United Kingdom ,Smoking cessation ,Female ,medicine.symptom ,0305 other medical science ,business ,Pulmonary nodules - Abstract
Background Lung cancer screening can reduce lung cancer mortality by 20%. Screen-detected abnormalities may provide teachable moments for smoking cessation. This study assesses impact of pulmonary nodule detection on smoking behaviours within the first UK trial of a novel auto-antibody test, followed by chest x-ray and serial CT scanning for early detection of lung cancer (Early Cancer Detection Test–Lung Cancer Scotland Study). Methods Test-positive participants completed questionnaires on smoking behaviours at baseline, 1, 3 and 6 months. Logistic regression compared outcomes between nodule (n = 95) and normal CT groups (n = 174) at 3 and 6 months follow-up. Results No significant differences were found between the nodule and normal CT groups for any smoking behaviours and odds ratios comparing the nodule and normal CT groups did not vary significantly between 3 and 6 months. There was some evidence the nodule group were more likely to report significant others wanted them to stop smoking than the normal CT group (OR across 3- and 6-month time points: 3.04, 95% CI: 0.95, 9.73; P = 0.06). Conclusion Pulmonary nodule detection during lung cancer screening has little impact on smoking behaviours. Further work should explore whether lung cancer screening can impact on perceived social pressure and promote smoking cessation.
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- 2019
38. A Hybrid Evolutionary Strategy to Optimise Early-Stage Cancer Screening
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Patrick J. Tighe, John F.R. Robertson, Keith Evans, Ola H. Negm, Peng Shi, Herbert F. Sewell, Jonathan M. Garibaldi, Grazziela P. Figueredo, and Andrew J. Parkes
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Computer science ,business.industry ,Cancer ,Machine learning ,computer.software_genre ,medicine.disease ,Early-stage cancer ,Antigen ,Cancer screening ,medicine ,Harmony search ,Artificial intelligence ,Evolution strategy ,business ,computer - Abstract
Current methods to identify cut-off values for tumour-associated molecules (antigens) discrimination are based on statistics and brute force. These methods applied to cancer screening problems are very inefficient, especially with large data sets with many antigens being investigated. There is a long wait to produce outcomes for clinicians, high performance computing is required, the best solution is not likely to be achieved and scalability is an issue. Cancer research is therefore limited in the number of antigens the methods can efficiently handle, and good solutions are potentially missed. We present an alternative evolutionary method based on Genetic Algorithms and Harmony Search to accelerate clinical research and to enable the consideration of a larger number of candidate antigens during the designing of the screening. We show that compared to the traditional methodology employed by clinicians, our approach is able to produce better results in a timely manner.
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- 2019
39. Lung cancer CT screening : psychological responses in the presence and absence of pulmonary nodules
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Kavita Vedhara, Stuart Schembri, Roshan das Nair, Ben Young, Francis Sullivan, Frances S. Mair, Denise Kendrick, Laura Elizabeth Bedford, John F.R. Robertson, Marcia E. Clark, Roberta Littleford, Petra Rauchhaus, University of St Andrews. School of Medicine, and University of St Andrews. Population and Behavioural Science Division
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Male ,Cancer Research ,Lung Neoplasms ,law.invention ,Thinking ,0302 clinical medicine ,Randomized controlled trial ,law ,Surveys and Questionnaires ,Psychological impact ,Early Detection of Cancer ,media_common ,education.field_of_study ,Hematologic Tests ,medicine.diagnostic_test ,Middle Aged ,Oncology ,030220 oncology & carcinogenesis ,Multiple Pulmonary Nodules ,Anxiety ,Female ,medicine.symptom ,Worry ,Pulmonary nodules ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,media_common.quotation_subject ,Population ,NDAS ,RC0254 ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,Lung cancer screening ,Avoidance Learning ,medicine ,Humans ,Blood test ,education ,Lung cancer ,Aged ,business.industry ,RC0254 Neoplasms. Tumors. Oncology (including Cancer) ,Nodule (medicine) ,medicine.disease ,United Kingdom ,030228 respiratory system ,Case-Control Studies ,Perception ,Tomography, X-Ray Computed ,business ,Follow-Up Studies - Abstract
This study was carried out as part of a National Institute for Health Research (NIHR) School for Primary Care Research (SPCR) funded academic clinical fellowship. The ECLS study was funded by the Scottish Executive and Oncimmune Ltd. The follow-up data collection was funded by University of Nottingham PhD studentships and by Oncimmune Ltd. Objectives: To determine the psychological response (thoughts, perceptions and affect) to a diagnosis of pulmonary nodules following a novel antibody blood test and computed tomography (CT) scans within a UK population. Materials and methods: This study was nested within a randomised controlled trial of a blood test (Early CDT®-Lung test), followed by a chest x-ray and serial CT-scanning of those with a positive blood test for early detection of lung cancer (ECLS Study). Trial participants with a positive Early CDT®-Lung test were invited to participate (n = 338) and those agreeing completed questionnaires assessing psychological outcomes at 1, 3 and 6 months following trial recruitment. Responses of individuals with pulmonary nodules on their first CT scan were compared to those without (classified as normal CT) at 3 and 6 months follow-up using random effects regression models to account for multiple observations per participant, with loge transformation of data where modelling assumptions were not met. Results: There were no statistically significant differences between the nodule and normal CT groups in affect, lung cancer worry, health anxiety, illness perceptions, lung cancer risk perception or intrusive thoughts at 3 or 6 months post-recruitment. The nodule group had statistically significantly fewer avoidance symptoms compared to the normal CT group at 3 months (impact of events scale avoidance (IES-A) difference between means -1.99, 95%CI -4.18, 0.21) than at 6 months (IES-A difference between means 0.88, 95%CI -1.32, 3.08; p-value for change over time = 0.003) with similar findings using loge transformed data. Conclusion: A diagnosis of pulmonary nodules following an Early CDT®-Lung test and CT scan did not appear to result in adverse psychological responses compared to those with a normal CT scan. Postprint
- Published
- 2018
40. Abstract OT-09-05: A randomized, pre-surgical study to investigate the biological effects of AZD9833 doses in women with ER-positive HER2-negative primary breast cancer (SERENA-3)
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Andy Sykes, Richard Mather, Teresa Klinowska, Christopher J. Morrow, John F.R. Robertson, Joanna Harding, Alastair Mathewson, Li Zhang, Rhiannon Maudsley, Giorgi Dzagnidze, Andrew Saunders, Juan Enrique Bargallo Rocha, Iain K. Moppett, and Justin P.O. Lindemann
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Oncology ,Cancer Research ,medicine.medical_specialty ,Fulvestrant ,business.industry ,Estrogen receptor ,Cancer ,Palbociclib ,medicine.disease ,Breast cancer ,Tolerability ,Internal medicine ,Pharmacodynamics ,medicine ,Clinical endpoint ,business ,medicine.drug - Abstract
Background AZD9833 is an orally bioavailable selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown anti-tumor efficacy in a range of preclinical breast cancer models. SERENA-1, an ongoing first-in-human study assessing AZD9833 as a monotherapy and in combination with palbociclib, established dose-dependent tolerability in pre- and post-menopausal women at doses of 25-450 mg once daily (QD), with clinical benefit and target engagement at all dose levels. Two randomized, open-label Phase 2 trials are also ongoing in women with ER+ HER2- breast cancer. SERENA-2 compares the efficacy of AZD9833 with fulvestrant in post-menopausal women with advanced breast cancer following treatment with ≤1 endocrine therapy. SERENA-3 will examine the biological effects of different doses of AZD9833 in treatment-naïve women with primary breast cancer. Methods SERENA-3 is a randomized, open-label, parallel-group, pre-surgical study to investigate the biological effects of different doses of AZD9833 in ER+, HER2- primary breast cancer. Eligible patients will be post-menopausal (and potentially pre-menopausal) women awaiting curative-intent surgery for newly diagnosed, ER+ HER2- primary breast cancer. The study is designed in two stages. In Stage 1, 24 post-menopausal women will be randomized 1:1 to receive either 75 mg or 150 mg oral AZD9833 QD for 5-7 days, followed by a minimum 5-day pre-surgery washout period; Stage 2 gives provision for additional groups depending on emerging data from Stage 1. The primary objective of this study is to explore the effect of AZD9833 on ER expression in pre- and on-treatment tumor samples from women with primary breast cancer, as assessed by immunohistochemistry and H-score. Safety and tolerability will be assessed as secondary endpoints, along with the pharmacokinetic and pharmacodynamic effects of AZD9833 on other biomarkers. Blood will be collected at screening, on the day of biopsy and the day of surgery to assess circulating tumor DNA and exploratory biomarkers. Primary endpoint analysis will be performed on the pharmacodynamic analysis set. The study will be conducted in 20 centers across 3 countries. For more information please contact Professor John Robertson at: john.robertson@nottingham.ac.uk. Citation Format: John FR Robertson, Iain Moppett, Juan Enrique Bargalló Rocha, Giorgi Dzagnidze, Joanna Harding, Teresa Klinowska, Richard Mather, Alastair Mathewson, Rhiannon Maudsley, Christopher J Morrow, Andrew Saunders, Andy Sykes, Li Zhang, Justin PO Lindemann. A randomized, pre-surgical study to investigate the biological effects of AZD9833 doses in women with ER-positive HER2-negative primary breast cancer (SERENA-3) [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 OT-09-05.
- Published
- 2021
41. Abstract P6-04-01: A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer
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Omar Mohamed, Li Zhou, Myria Nikolaou, Rhiannon Maudsley, A Jahan, Rachel Wuerstlein, Tinnu Sarvotham, Kwok-Leung Cheung, Martine P. Roudier, S. Henschen, Michele Moschetta, Teresa Klinowska, Nadia Harbeck, Peter A. Fasching, Richard Mather, Danielle Carroll, J Michael Dixon, Alexander MacDonald, Cliona C. Kirwan, Ashutosh Kothari, Justin P.O. Lindemann, Diansong Zhou, Laura M. Kenny, Gaia Schiavon, John F.R. Robertson, Peter Schmid, and Abigail Evans
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Oncology ,Cancer Research ,medicine.medical_specialty ,Fulvestrant ,business.industry ,Cmax ,Estrogen receptor ,Cancer ,medicine.disease ,Breast cancer ,Pharmacokinetics ,Internal medicine ,Pharmacodynamics ,medicine ,business ,Tamoxifen ,medicine.drug - Abstract
Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve and resistant to tamoxifen and aromatase inhibitors. FULV has low oral bioavailability, and its dose-dependent pharmacodynamic (PD) activity and clinical efficacy is limited by the currently approved maximal feasible dose (MFD) of 500 mg, which is administered monthly as two intramuscular injections. AZD9496 is an orally bioavailable, nonsteroidal, selective and potent degrader and antagonist of ER in preclinical models. This pre-surgical, window of opportunity study (NCT03236974) compared PD changes and the PD/pharmacokinetic (PK) relationships of AZD9496 with FULV in patients with newly diagnosed ER+ HER2- breast cancer awaiting curative intent surgery.Methods: In this open-label, multicenter study, patients were randomized 1:1 to receive oral AZD9496 250 mg BID from Day 1 for 5-14 days or FULV 500 mg administered intramuscularly on Day 1 only. On-treatment image-guided core tumor biopsies were taken between Days 5 and 14. The primary objective was to compare the effects of AZD9496 and FULV on ER expression in tumor tissue using pre-dose biopsies as baseline. Secondary objectives were changes in progesterone receptor (PR) and Ki-67 biomarkers, AZD9496 and FULV plasma concentrations during treatment, and safety. Immunohistochemistry was used to determine ER and PR H-scores, and Ki-67 index, and treatment effects were compared using an analysis of covariance model. Blood samples for PK analysis were taken at on-treatment biopsy and 1-2 hours afterwards. Adverse events (AEs) were monitored from screening through to a follow-up visit 28 days after the last study dose.Results: Of the 49 women enrolled, 46 received treatment (AZD9496 n=22; FULV n=24) and of these, 35 paired biopsies were evaluable (AZD9496 n=15; FULV n=20). The least square mean estimate for the reduction in ER H-score after AZD9496 treatment was 24% (80% CI: 34.4, 14.3), and after FULV treatment was 36% (44.9, 27.7), with a least square mean difference between AZD9496 and FULV of 12% (p=0.86). AZD9496 was not superior to FULV in terms of ER modulation at the tested dose. AZD9496 also reduced PR H-scores and Ki-67 levels from baseline (by 33.3% and 39.9%, respectively). These effects were not statistically superior to FULV at the tested dose (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98).Plasma exposure of AZD9496 (AUC -40%, Cmax -25%) was lower than predicted based on PK data from the previous phase 1 study, whereas FULV exposure was consistent with historical data. No clear exposure-response relationship for plasma concentration at biopsy and PD markers for AZD9496 or FULV were observed.The median treatment duration of AZD9496 was 9.5 days (range: 6-15), and the relative dose intensity was 100% (range: 90-125); no patients discontinued AZD9496. AZD9496 and FULV were both well tolerated, and no new safety findings were identified. No grade ≥3 toxicities or serious AEs occurred. Conclusion: AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development. Citation Format: John FR Robertson, Abigail Evans, Stephan Henschen, Cliona Kirwan, Ali Jahan, Laura Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin PO Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck. A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-01.
- Published
- 2020
42. Correction to: Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells
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Julia Margaret Wendy Gee, Janice Mary Knowlden, Iain Robert Hutcheson, Robert Ian Nicholson, Denise Barrow, S. Hiscox, John F.R. Robertson, and Ian O. Ellis
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Antineoplastic Agents, Hormonal ,Receptor, ErbB-3 ,Receptor, ErbB-2 ,Neuregulin-1 ,Blotting, Western ,Breast Neoplasms ,Biology ,Antibodies, Monoclonal, Humanized ,lcsh:RC254-282 ,Tamoxifen resistant ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Breast cancer ,Gefitinib ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,Neoplasm Invasiveness ,Protein Kinase Inhibitors ,Cell Proliferation ,Correction ,Antibodies, Monoclonal ,Trastuzumab ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Blot ,ErbB Receptors ,Tamoxifen ,MCF-7 ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Quinazolines ,Neuregulin ,Female ,Breast cancer cells ,Mitogen-Activated Protein Kinases ,Dimerization ,Proto-Oncogene Proteins c-akt ,medicine.drug ,Signal Transduction - Abstract
Resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies is an emerging clinical problem. The efficacy of anti-EGFR therapies can be influenced by the presence of heregulins (HRGs), which can bind erbB3/4 receptors and can activate alternative signalling pathways. In the present study we have examined whether HRG signalling can circumvent EGFR blockade in an EGFR-positive tamoxifen-resistant MCF-7 (Tam-R) breast cancer cell line.Tam-R cells, incubated with the selective EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839), were exposed to HRGbeta1 and the effects on erbB receptor dimerization profiles and on activation of associated downstream signalling components were assessed by immunoprecipitation, western blotting and immunocytochemistry. The effects of HRGbeta1 on gefitinib-treated Tam-R cell growth and invasion were also examined, and HRGbeta1 expression levels were assessed in breast cancer tissue by immunohistochemistry to address the potential clinical relevance of such a resistance mechanism.In Tam-R cells, HRGbeta1 promoted erbB3/erbB2 and erbB3/EGFR heterodimerization, promoted ERK1/2 and AKT pathway activation and increased cell proliferation and invasion. Gefitinib prevented HRGbeta1-driven erbB3/EGFR heterodimerization, ERK1/2 activation and Tam-R cell proliferation, but HRGbeta1-driven erbB3/erbB2 heterodimerization, AKT activation and Tam-R cell invasion were maintained. A combination of gefitinib and the phosphatidylinositol 3-kinase inhibitor LY294002 effectively blocked HRGbeta1-mediated intracellular signalling activity, growth and invasion in Tam-R cells. Similarly, targeting erbB2 with trastuzumab in combination with gefitinib in Tam-R cells reduced HRGbeta1-induced erbB2 and ERK1/2 activity; however, HRGbeta1-driven AKT activity and cell growth were maintained while cell invasion was significantly enhanced with this combination. In clinical tissue all samples demonstrated cytoplasmic tumour epithelial HRGbeta1 protein staining, with expression correlating with EGFR positivity and activation of both AKT and ERK1/2.HRGbeta1 can overcome the inhibitory effects of gefitinib on cell growth and invasion in Tam-R cells through promotion of erbB3/erbB2 heterodimerization and activation of the phosphatidylinositol 3-kinase/AKT signalling pathway. This may have implications for the effectiveness of anti-EGFR therapies in breast cancer as HRGbeta1 is enriched in many EGFR-positive breast tumours.
- Published
- 2018
43. Major Impact of Sampling Methodology on Gene Expression in Estrogen Receptor–Positive Breast Cancer
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Chris Holcombe, Andrew Dodson, James P Morden, Abigail Evans, Trialists, Ian E. Smith, Judith M Bliss, Kally Sidhu, Mitch Dowsett, John F.R. Robertson, Lesley-Ann Martin, Anthony Skene, Qiong Gao, Elena Lopez-Knowles, Ricardo Ribas, Maggie C.U. Cheang, Vera Martins, Elizabeth Mallon, and David Evans
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Aromatase inhibitor ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,Estrogen receptor ,Brief Communication ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Estrogen ,030220 oncology & carcinogenesis ,Internal medicine ,Gene expression ,Biopsy ,Medicine ,business ,Gene ,FOSB - Abstract
To investigate the impact of sampling methodology on gene expression data from primary estrogen receptor–positive (ER+) breast cancer biopsies, global gene expression was measured in core-cut biopsies at baseline and surgery from patients randomly assigned to receive either two weeks of presurgical aromatase inhibitor (AI; n = 157) or no presurgical treatment (n = 56). Those genes most markedly altered in the AI group (eg, FOS, DUSP1, RGS1, FOSB) were similarly altered in the no treatment group; some widely investigated genes that were apparently unaffected in the AI group (eg, MYC) were counter-altered in the control group, masking actual AI-dependent changes. In the absence of a control group, these artefactual changes would likely lead to the most affected genes being the erroneous focus of research. The findings are likely relevant to all archival collections of ER+ breast cancer.
- Published
- 2018
44. Health-related quality of life from the FALCON phase III randomised trial of fulvestrant 500 mg versus anastrozole for hormone receptor-positive advanced breast cancer
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Matthew J. Ellis, Kwok-Leung Cheung, Mehdi Fazal, Zhimin Shao, Jasmine Lichfield, Shinzaburo Noguchi, Arnold Degboe, Jackie Thirlwell, and John F.R. Robertson
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0301 basic medicine ,Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Anastrozole ,Breast Neoplasms ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Double-Blind Method ,Internal medicine ,Surveys and Questionnaires ,medicine ,Humans ,Fulvestrant ,Aged ,Health related quality of life ,Aged, 80 and over ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Discontinuation ,030104 developmental biology ,Hormone receptor ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,business ,medicine.drug - Abstract
Background The phase III randomised FALCON trial (NCT01602380) demonstrated improved progression-free survival with fulvestrant 500 mg versus anastrozole 1 mg in endocrine therapy-naive postmenopausal women with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). Furthermore, overall health-related quality of life (HRQoL) was maintained and comparable for fulvestrant and anastrozole. Here, we present additional analyses of patient-reported HRQoL outcomes from FALCON. Methods Women with endocrine therapy-naive HR+ LA/MBC were randomised 1:1 to fulvestrant (days 0, 14, 28, then every 28 d) or anastrozole (daily) until disease progression or discontinuation. HRQoL was assessed by FACT-B questionnaire (TOI and FACT-B total score) at randomisation and every 12 weeks during treatment. HRQoL data post-treatment (with or without progression) were also collected. Results In total, 462 patients were randomised (fulvestrant, n = 230; anastrozole, n = 232). Compliance to FACT-B overall ranged from 60.0 to 97.4%. Mean change from baseline in TOI and FACT-B total score remained broadly stable (approximately ± 3 points to week 132) and was similar between arms during treatment. HRQoL was also maintained in FACT-B subscales. Approximately one-third of patients had improved TOI (≥+6 points) and FACT-B (≥+8 points) total scores from baseline up to week 120 and 132, respectively, of treatment with fulvestrant (ranges 26.4–45.0% and 22.4–35.8%, respectively) and anastrozole (ranges 18.6–32.9%, and 22.7–37.9%, respectively). Conclusions Mean change from baseline in TOI and FACT-B total score was maintained for fulvestrant and anastrozole; similar proportions of patients in both arms had improved TOI and FACT-B total scores.
- Published
- 2017
45. Abstract S1-04: Exome sequencing of post-menopausal ER+ breast cancer (BC) treated pre-surgically with aromatase inhibitors (AIs) in the POETIC trial (CRUK/07/015)
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Lesley-Ann Martin, Trialists, Ian E. Smith, Tiandao Li, Mitch Dowsett, Judith M Bliss, Pascal Gellert, Qiong Gao, Christopher Holcombe, Anthony Skene, John F.R. Robertson, Elaine R. Mardis, Christopher A. Miller, and Corrinne V. Segal
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Cancer ,MAP3K1 ,medicine.disease ,Bioinformatics ,Breast cancer ,Internal medicine ,Biopsy ,biology.protein ,medicine ,Missense mutation ,Aromatase ,business ,Exome ,Exome sequencing - Abstract
Aims 1. To determine the variability of mutational profiles and sub-clonality in core-cut biopsies from ER+ BC and the impact of 2-weeks’ AI therapy on these. 2. To identify mutations or patterns of mutations associated with poor anti-proliferative response to AI treatment. Background DNA alterations may lead to de novo and acquired resistance to medical therapies including AIs. Assessing this requires single time-point or sequential sampling usually with core-cuts but there is little information on their ability to represent mutational profiles or sub-clonal structure. We studied this in paired biopsies from ER+ BC primaries in 60 selected postmenopausal patients from the Peri-Operative Endocrine Therapy for Individualising Care (POETIC) trial (CRUK/07/015) before and after 2-weeks’ non-steroidal AI or no AI (randomised 2:1). Methods DNA was extracted from RNAlater-preserved diagnostic and surgical 14-gauge core-cut samples and peripheral blood from 20 no AI (Control) and 40 AI-treated patients (15 poor and 25 good Ki67-responders [PR and GR, respectively]). Patients with low ER+ BC or unsuppressed estradiol on treatment were not considered. Exome sequencing (Illumina HiSeq 2000) achieved >60% coverage across the exome at 15x depth. Variants were validated by re-sequencing (median >100x) together with 79 genes of interest curated from COSMIC and selected publications. Statistically significant genes (SMGs) were determined using MuSiC. Sub-clonality was analysed by SciClone. Results Good quality exomes were obtained on 102 samples including 44 pairs (control n=14; PR n=10; GR n=20). There were 5684 mutations (including 3616 missense and 1322 silent) affecting 3261 genes. SMGs in this series were PIK3CA (35.3%), TP53 (27.5%), CDH1 (13.8%), HEATR7B2 (8.8%), GATA3 (5.9%), CENPF (5.9%), MAP3K1 (5.9%), MAP2K4 (4.9%), HTR1A (2.9%) and C22orf23 (1%). PR had more mutations than GR (median 65 vs 36, p=0.04). More PR than GR were HER2+ (5/14 vs 1/24, p=0.019) and/or TP53-mutated (5/10 vs 3/20, p=0.08) but similar proportions were PIK3CA-mutated. The correlation of diagnostic vs surgical variant allele frequencies was strong for the control (r=0.75) and treated (r=0.89) groups (for treated GR r=0.83; for treated PR r=0.65). In the treated group there were fewer mutations at surgery vs diagnosis (p Conclusion This is the largest reported study of exome reproducibility in ER+ BC for mutation profiles based on core-cut biopsy. Multiple sub-clones are identifiable in ER+ primary BC. In c.20% tumours, a single core-cut does not allow inference of all sub-clonal populations, probably due to spatial heterogeneity. TP53 mutations but not PIK3CA mutations are associated with PR. Large numbers of BC will be needed to identify any associations of lower frequency mutations with resistance. A trend to fewer mutations after just 2 weeks AI needs confirmation. Citation Format: Pascal Gellert, Corrinne V Segal, Qiong Gao, Tiandao Li, Christopher A Miller, Elaine Mardis, Lesley-Ann Martin, Christopher Holcombe, Anthony Skene, Judith Bliss, John Robertson, Ian Smith, Mitch Dowsett, POETIC Trial Management Group and Trialists. Exome sequencing of post-menopausal ER+ breast cancer (BC) treated pre-surgically with aromatase inhibitors (AIs) in the POETIC trial (CRUK/07/015) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-04.
- Published
- 2015
46. Personalization of loco-regional care for primary breast cancer patients (part 1)
- Author
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Ian Kunkler, Alexey Larionov, Stephen R. Grobmyer, Dong Young Noh, V. Suzanne Klimberg, Masakazu Toi, John F. Forbes, John R. Benson, John F.R. Robertson, Alice Y. Ho, Jose Luiz Barbosa Bevilacqua, Eun Sook Lee, Tomoharu Sugie, Mark D. Pegram, Hideko Yamauchi, Akira Yamauchi, Eric P. Winer, Gunter von Minckwitz, Wonshik Han, Chiun-Sheng Huang, Takashi Inamoto, Chikako Yamauchi, Shinzaburo Noguchi, Michio Yoshimura, Ian E. Krop, Louis W.C. Chow, Hironobu Sasano, and Ismail Jatoi
- Subjects
Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,General surgery ,medicine.medical_treatment ,Axillary Lymph Node Dissection ,General Medicine ,medicine.disease ,Systemic therapy ,Personalization ,Radiation therapy ,Breast cancer ,Oncology ,medicine ,Genetic predisposition ,Hormonal therapy ,business ,Genetic testing - Abstract
ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.
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- 2015
47. Personalization of loco-regional care for primary breast cancer patients (part 2)
- Author
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John F.R. Robertson, Chikako Yamauchi, Akira Yamauchi, Louis W.C. Chow, Tomoharu Sugie, Ian Kunkler, Jose Lb Bevilacqua, V. Suzanne Klimberg, John R. Benson, Ian E. Krop, Alexey Larionov, Dong Young Noh, Alice Y. Ho, Stephen R. Grobmyer, Shinzaburo Noguchi, Michio Yoshimura, Gunter von Minckwitz, Eun Sook Lee, Takashi Inamoto, Hideko Yamauchi, Mark D. Pegram, Ismail Jatoi, Hironobu Sasano, Masakazu Toi, John F. Forbes, Eric P. Winer, Wonshik Han, and Chiun-Sheng Huang
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Breast Neoplasms ,Systemic therapy ,Contralateral Prophylactic Mastectomy ,Breast cancer ,Internal medicine ,medicine ,Genetic predisposition ,Humans ,Precision Medicine ,Stage (cooking) ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Disease Management ,General Medicine ,medicine.disease ,Surgery ,Radiation therapy ,Hormonal therapy ,Female ,business - Abstract
ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.
- Published
- 2015
48. Abstract P1-13-02: Visceral metastases from hormone receptor positive breast cancer are as sensitive to endocrine therapy as non-visceral metastases
- Author
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Ian Bradbury, Yuri Rukazenkov, Robert Paridaens, John F.R. Robertson, Christine M. Pierce Campbell, and Jan Bogaerts
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Oncology ,Cancer Research ,medicine.medical_specialty ,Fulvestrant ,business.industry ,Hazard ratio ,Cancer ,Anastrozole ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,Endocrinology ,Exemestane ,chemistry ,Internal medicine ,medicine ,Progression-free survival ,business ,Tamoxifen ,medicine.drug - Abstract
Background: There remains a perception among many clinicians that visceral metastases (VMs) from hormone receptor positive (HR) breast cancer (BC) respond less well to endocrine therapy (ET) than non-VMs and so should receive chemotherapy as first line treatment. Patients & Methods: Four phase 3 randomised controlled trials (RCTs) of first line ET, all with tamoxifen (TAM) as their control arm) have been reviewed – Exemestane (Exe), fulvestrant 250mg (F250) and two with anastrozole (Ana); the latter, were study 27 in the Rest of the World (ROW) & study 30 in North America (NA). All reported objective response (OR), clinical benefit (CB), time to progression (TTP) / progression free survival (PFS): all have been published (1-5). Only HR positive tumors were included in this review. Data have been analysed both for Tam control arms alone and also for the four different endocrine agents combined. Results: CB & OR for TAM alone in each study individually and then combined are shown in the Table. The OR and CB rates were similar for non-VMs versus VMs in all studies except study 30 (NA) where CB rates were 59% for non-VM and 33% for VM (Test for heterogeneity of CB rates was p=0.047). For the four studies combined, the CB rates for non-VM versus VMs were 64% and 57% respectively (p=0.06) while the OR rates were 34% versus 30% respectively (p= 0.28). When all endocrine agents were combined the OR rate between non-VMs and VMs was significantly different (p = 0.038) as was the CB rate (p = 0.0015). Rates of CB and OR in study 30 (NA) again appear different between non-VMs and VMs (data not shown). The Median Duration of CB on Tam appear similar between non-VMs versus VMs, both for each study individually and when combined (see Table); when combined the Medians were 420 versus 418 days respectively with a Hazard Ratio (HR)=0.952 (0.748-1.211) (p=0.69). When all endocrine therapies for the combined four studies were assessed the HR for DoCB between non-VMs and VMs was 0.922 (0.779-1.093) (p=0.35). For the TTP the HR of non-VMs versus VMs on Tam alone was 0.851 (0.715-1.011) (p=0.07) and for all endocrine therapies the HR was 0.821 (0.727-0.926) (p=0.001). Conclusions: HR+VMs which achieve clinical benefit on ET remain controlled for as long as non-VMs as shown by the DoCB results for both Tam and all endocrine therapies combined. There was no significant difference in OR rates between VMs and non-VMs with Tamoxifen. There was when all endocrine agents were combined and the difference appears to be primarily due to one study (30 – NA). There is no confirmed explanation for these differences. TTP differences appear to be due primarily to the difference in initial CB rates in study 30 (see Table). HR+ VMs have hormone sensitivity similar to non-visceral mets – they respond as well and for as long as non-VMs. In the absence of visceral crisis (ie immediately life-threatening disease) ET would appear to be the treatment of choice for VMs in the same way as it is for non-VMs. Clinical Outcome by VM and Non VM (Tamoxifen only patients) N (%)StudiesExeAna (EUR)Ana (NA)F250Combined N = 168N = 144N = 162N = 209N=683Without VM (55%)N = 88N = 71N = 82N = 135N=376CB (%)66 (75)42 (59)47 (59)87 (64)242 (64)OR (%)41 (47)26 (37)15 (19)45 (33)127 (34)TTP (Median in days)287254305234277DoCB (Median in days)343360445451420With VM (45%)N = 80N = 73N = 80N = 74N=307CB (%)64 (80)38 (52)27 (33)46 (62)175 (57)OR (%)36 (45)21 (29)13 (16)21 (28)91 (30)TTP (Median in days)340230152281238DoCB (Median in days)376505411339418 Citation Format: John FR Robertson, Robert Paridaens, Jan Bogaerts, Yuri Rukazenkov, Christine Campbell, Ian Bradbury. Visceral metastases from hormone receptor positive breast cancer are as sensitive to endocrine therapy as non-visceral metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-02.
- Published
- 2015
49. Pilot randomised study of early intervention based on tumour markers in the follow-up of patients with primary breast cancer
- Author
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Kwok-Leung Cheung, E. Gutteridge, C. Marenah, John F.R. Robertson, P. Prinsloo, Amit Agrawal, and J. Mathew
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Adult ,Clinical team ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Bone Neoplasms ,Breast Neoplasms ,Pilot Projects ,Anastrozole ,Asymptomatic ,Internal medicine ,Intervention (counseling) ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,medicine ,Humans ,Single-Blind Method ,Oestrogen receptor ,Early Detection of Cancer ,Aged ,business.industry ,Liver Neoplasms ,Mucin-1 ,Significant difference ,General Medicine ,Middle Aged ,Triazoles ,Carcinoembryonic Antigen ,Surgery ,Tamoxifen ,Treatment Outcome ,Radiological weapon ,Goserelin ,Female ,medicine.symptom ,Primary breast cancer ,business ,Adjuvant ,Follow-Up Studies - Abstract
Background This pilot study aimed to test the possibility of therapeutic benefit imparted by early intervention based on sequential tumour marker (TM) measurements during follow-up of primary breast cancer (PBC) patients. Methods Patients with oestrogen receptor positive PBC with no clinical and/or radiological evidence of metastases were recruited and followed-up 3-monthly with clinical assessment and TM (CA15.3 and CEA) measurements. The clinical team was blinded to the TM results. Asymptomatic patients who developed raised TMs (based on pre-defined cut-offs) were randomised to either ‘treatment change’ (either start or change of adjuvant endocrine agent to another agent) or ‘no change’ (control). Patients who developed symptomatic metastases came off the study. The primary and secondary endpoints were intervals from randomisation to symptomatic metastases and to last follow-up/death respectively. Results Eighty-five patients (median age = 54 years (30–72)) were recruited with a median follow-up of 81 months (1–124). Sixteen patients were randomised as described. There was no significant difference (treatment change versus no change) with regards to interval from randomisation to symptomatic metastases – 23 (2–62) and 22 (1–63) months respectively (p = 0.9), as well as interval from randomisation to last follow-up/death – 36 (7–63) and 37 (10–63) months respectively (p = 0.9). Conclusions Despite long follow-up (up to 10+ years), this small study has thus far shown no significant difference in outcome. However, we have confirmed the feasibility of this study design but a larger study will be required to show if there is a benefit to this approach.
- Published
- 2014
50. OP36 Decisions about smoking in patients screened with the earlycdt-lung test for the early detection of lung cancer: a qualitative study
- Author
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John F.R. Robertson, Denise Kendrick, Kavita Vedhara, Ben Young, and R. Das Nair
- Subjects
Teachable moment ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,media_common.quotation_subject ,Cancer ,Context (language use) ,medicine.disease ,Surgery ,medicine ,Anxiety ,Smoking cessation ,medicine.symptom ,Worry ,Lung cancer ,business ,Lung cancer screening ,Clinical psychology ,media_common - Abstract
Background: Routine screening for lung cancer in high risk groups (characterised by age and smoking history) is recommended in the USA and may be implemented elsewhere. It is unclear whether being screened for lung cancer promotes smoking cessation or conversely provides false reassurance and a ‘license to smoke’. This study aimed to understand how experiences of lung cancer screening influence individual decision making about smoking. Methods: Thirty one people in Scotland, aged 51–74, took part in semi-structured interviews. They had been screened with the EarlyCDT-Lung Test (13 positive result; 18 negative) as part of the Early Cancer Detection Test–Lung Cancer Scotland (ECLS) Study and were long-term smokers when screened. Verbatim transcripts were analysed using thematic analysis. Results: Interpretations of test results was a key theme, but were often inaccurate, for example a negative result interpreted as an ‘all-clear’ from lung cancer and a positive result as meaning lung cancer will definitely develop. There was no clear pattern in decisions made about smoking in response to positive or negative test results. Emotional response to those interpretations was an overarching theme in decisions about smoking. Emotions included fear, shock, upset, worry, anxiety, guilt, relief, reassurance and indifference. Other themes included changes in perceived risk of smoking-related disease, a feeling that now is the time to stop smoking, interpersonal family influences and avoidance of thoughts about smoking. Of those who had stopped smoking, some cited screening experiences as the sole reason and some cited screening along with other coinciding factors. Cues to change were experienced at different stages of the screening process and not always immediately following a test result. Some participants indicated they underwent screening in order to try and stop smoking. Others expressed little or no desire to stop. In general, lung cancer screening was experienced as a unique opportunity, which sometimes prompted successful or unsuccessful attempts to stop smoking. Conclusion: Lung cancer screening can be a ‘teachable moment’ for smoking behaviour change. Emotional responses to test results, which can be misinterpreted, were an important theme but behavioural responses varied according to the individual. Findings should be considered within the context of a group of predominantly life-long smokers undergoing a novel blood screening test, who might already have increased motivation to stop smoking. Lung cancer screening presents an opportunity to engage high risk smokers in cessation support but our findings suggest such support may need to be available flexibly to be most effective. In collaboration with the ECLS study team.
- Published
- 2017
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