Ian E Smith

The Royal Marsden NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (149)1382.97 Total impact

  • Susana Banerjee · Ian E Smith ·
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    ABSTRACT: Trastuzumab has revolutionised the treatment of HER2-positive early-stage breast cancer and is now standard of care in combination with chemotherapy for patients with tumours larger than 1 cm. However, 5 years after publication of the landmark trials establishing the efficacy of the drug, the management of small (≤1 cm), HER2-positive tumours remains difficult. Most small breast cancers have a good prognosis and adjuvant chemotherapy is not routinely recommended. However, retrospective data suggest that some small HER2-positive cancers might have a worse clinical outcome than others. This notion raises the key clinical question of whether patients with small HER2-positive cancers should be offered adjuvant trastuzumab and chemotherapy. The pivotal adjuvant trastuzumab trials did not include patients with tumours smaller than 1 cm, but a subset analysis of one trial showed that patients with tumours 1-2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort. Clinicians face the dilemma of whether the potential reduction in risk of recurrence in this patient group warrants the toxic effects and risks of adjuvant chemotherapy and trastuzumab. In this review, we discuss the evidence for prognosis of small HER2-positive cancers, and for possible benefit from adjuvant trastuzumab. We suggest potential treatment strategies and clinical trial designs to address this important issue. On the basis of present evidence, we recommend that the benefits and risks of adjuvant trastuzumab should be discussed with patients with small, HER2-positive breast cancer.
    The Lancet Oncology 12/2010; 11(12):1193-9. DOI:10.1016/S1470-2045(10)70119-4 · 24.69 Impact Factor
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    William D Foulkes · Ian E Smith · Jorge S Reis-Filho ·
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    ABSTRACT: A PUBMED SEARCH OF THE MEDICAL LITERATURE SHOWS THAT THE FIRST mention of "triple-negative" breast cancer was in October 2006; since then, the term has appeared in more than 600 publications.1 This increase reflects the growing recognition of the importance of triple-negative breast cancer (see the Glossary for this and other key terms) by oncologists, pathologists, and geneticists, as well as by the approximately 12 to 17% of women with breast cancer who have triple-negative breast cancer. As a group, patients with triple-negative tumors have a relatively poor outcome and cannot be treated with endocrine therapy or therapies targeted to human epidermal growth factor receptor type 2 (HER2). A close cousin of triple-negative breast cancer is basal-like breast cancer (synonymous terms include "basal-type," "basal-epithelial phenotype," "basal breast cancer," and "basaloid breast cancer"). This molecular subtype of breast cancer is characterized by a gene-expression profile that is similar to that of the basal-myoepithelial layer of the normal breast. 2 Immunohistochemical markers have been used as a surrogate for this profile. The multiplicity of names reflects an underlying uncertainty as to the true nature of this entity.
    New England Journal of Medicine 11/2010; 363(20):1938-48. DOI:10.1056/NEJMra1001389 · 55.87 Impact Factor
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    ABSTRACT: Hypoxic challenge testing (HCT) is not readily available in all hospitals. It has recently been shown that resting oximetry does not reliably predict the results of HCT in patients with extrapulmonary restrictive lung disease. We assessed other clinical tests to see if they might be used as an alternative screen for HCT. People with primary thoracic scoliosis were recruited. Resting SpO(2), arterial blood gases (ABG's), lung function and shuttle walking test (SWT) were measured. All subjects underwent HCT breathing an inhaled oxygen fraction of 15% for 20 min, or until SpO(2) fell below 85%, when ABG's were taken. Fourteen people (5 male) with thoracic scoliosis, Cobb angle 93 (31) degrees , aged 65 (8.5) years, FEV(1) 0.86 (0.4) L, FVC 1.2 (0.4)L were studied. The resting SpO(2) was 96 (2) %, PaO(2) 9.2 (1) kPa and PaCO(2) 6.1 (0.4) kPa. HCT was positive in 11 subjects (PaO(2) <6.6 kPa). Eight of 11 HCT positive subjects had a resting SpO(2) > 95%. Positive correlation was found between SpO(2) at SWT termination and PaO(2) following HCT (r = 0.56, p = 0.02). Those with saturations of 92% or under at SWT termination had positive HCT. Despite normal resting SpO(2) subjects with thoracic scoliosis may have positive HCT. Current recommendations for air travel do not accurately identify these people. Desaturation following a SWT may provide a useful screening tool, however a low threshold for performing HCT on people with thoracic scoliosis prior to air travel is warranted.
    Respiratory medicine 10/2010; 104(10):1566-70. DOI:10.1016/j.rmed.2010.05.007 · 3.09 Impact Factor
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    Psychopharmacology 10/2010; 212(3):449-51. DOI:10.1007/s00213-010-1958-9 · 3.88 Impact Factor
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    ABSTRACT: Very few studies have investigated whether the time elapsed between surgical resection and tissue fixation or the difference between core-cut and excision biopsies impact on immunohistochemically measured biomarkers including phosphorylated proteins in primary breast cancer. The aim of this study was to characterize the differences in immunoreactivity of common biomarkers that may occur (a) due to tissue handling at surgery and (b) between core-cuts and resected tumours. Core-cuts taken from surgical breast cancer specimens immediately after resection (sample A) and after routine X-ray of the excised tumour (sample B) were formalin-fixed and paraffin-embedded and compared to the routinely fixed resection specimen (sample C). The variation in immunohistochemical expression of Ki67, oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor 2 (HER2), p-Akt and p-Erk were investigated. Twenty-one tissue sets with adequate tumour were available. Median time between collection of core-cuts A and B was 30 minutes (range 20 to 80). None of the markers showed significant differences between samples A and B. Similarly, Ki67, ER, PgR and HER2 did not differ significantly between core-cuts and main resection specimen although there was a trend for lower resection values for ER (P=0.06). However, p-Akt and p-Erk1/2 were markedly lower in resections than core-cuts (median 27 vs 101 and 69 vs 193, respectively; both P<0.0001 [two-sided]). This difference was significantly greater in mastectomy than lumpectomy specimens for p-Erk1/2 (P=0.01). The delay in fixation in core-cuts taken after post-operative X-ray of resection specimens has no significant impact on expression of Ki67, ER, PgR, HER2, p-Akt or p-Erk1/2. However extreme loss of phospho-staining can occur during routine fixation of resection specimens. These differences are likely attributable to suboptimal fixation and may have major repercussions for clinical research involving these markers.
    Breast cancer research: BCR 09/2010; 12(5):R76. DOI:10.1186/bcr2719 · 5.49 Impact Factor
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    ABSTRACT: Patients with ventilatory failure at discharge from hospital following an exacerbation of COPD (ECOPD) have increased work of breathing and reduced inspiratory muscle strength compared with those with a normal arterial carbon dioxide tension (PaCO(2)). They also have a significantly worse prognosis. Long-term non-invasive positive pressure ventilation (NIPPV) may offer a treatment strategy but benefits have not been established. We examined the outcomes of 35 patients, with a PaCO(2) >7.5 kPa and normal pH, following hospital admission with an ECOPD. Patients were initiated on long-term NIPPV. Our aims were to establish if NIPPV was tolerated and to describe the effects on ventilatory parameters. Daytime arterial blood gases and nocturnal ventilatory parameters improved significantly on NIPPV. Diurnal PaO(2), self-ventilating, rose from (mean (SD)) 7.3 (1.8) to 8.1 (0.9) kPa (P = 0.005) and PaCO(2) fell from 8.8 (1.3) to 7.3 (0.8) kPa (P <or= 0.001). Mean overnight oxygen saturations increased from 82% (7%) to 89% (2%) (P <or= 0.001) and mean overnight transcutaneous carbon dioxide fell from 7.6 (1.3) to 5.6 (1.7) kPa (P <or= 0.001). Similar changes were seen in a group of stable COPD patients, who initiated NIPPV without a preceding exacerbation, suggesting improvements were not solely due to recovery from exacerbation. Acceptance (89%) and compliance (8.4 (3.5) h/day) with domiciliary treatment were good. Median survival was 28.6 months (95% CI: 10.9-46.8). NIPPV was well tolerated in this group and appears to improve ventilation. Our preliminary data support further investigation of NIPPV in patients who remain hypercapnic after hospital admission with ECOPD.
    Respirology 07/2010; 15(5):818-22. DOI:10.1111/j.1440-1843.2010.01787.x · 3.35 Impact Factor
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    ABSTRACT: Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered. Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS. The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation. Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook.
    Cancer 06/2010; 116(11 Suppl):2815-20. DOI:10.1002/cncr.25178 · 4.89 Impact Factor
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    ABSTRACT: PURPOSE To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)-positive breast cancers in postmenopausal women. Materials and METHODS Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = -0.179; P = .05; and r = -0.389; P = .0005, respectively). CONCLUSION Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.
    Journal of Clinical Oncology 03/2010; 28(7):1161-7. DOI:10.1200/JCO.2009.23.9616 · 18.43 Impact Factor
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    ABSTRACT: The concentration of estradiol (E(2)) in breast tumors is significantly higher than that in plasma, particularly in postmenopausal women. The contribution of local E(2) synthesis versus uptake of E(2) from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E(2) levels in breast cancer patients. The expression of genes involved in estrogen synthesis, metabolism, and signaling was measured in 34 matched samples of breast tumor and normal breast tissue, and their correlation with estrogen concentrations assessed. ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER(+) tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E(2) levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER(+) patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r = 0.59, P < 0.001) whereas HSD17B2 (r = -0.46, P = 0.0057) and HSD17B12 (r = -0.45, P = 0.0076) showed significant negative correlations with intratumoral E(2) in all patients. Intratumoral E(2) revealed no correlation to CYP19, STS, and HSD17B1 expression. Multivariate models comprising ESR1 and plasma E(2) predicted between 50% and 70% of intratumoral E(2) variability. Uptake due to binding to the ER, rather than intratumoral estrogen synthesis by aromatase or sulfatase, is the single most important correlate and a probable determinant of intratumoral E(2). An increased expression of HSD17B7 may explain the increased ratio of E(2) to estrone (E(1)) in breast tumors compared with normal tissue.
    Clinical Cancer Research 03/2010; 16(6):1790-801. DOI:10.1158/1078-0432.CCR-09-2481 · 8.72 Impact Factor
  • Nicholas S Oscroft · Ian E Smith ·
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    ABSTRACT: Volume-assured non-invasive ventilation (NIV) theoretically guarantees minute ventilation with circuit leak compensation unlike other modes of NIV. Bench testing demonstrated that minute ventilation was maintained with varying lung compliance and resistance with minimal effect from circuit leak, confirming for the first time the core features of volume-assured NIV. Volume-assured non-invasive positive pressure ventilation (va-NIPPV) is a novel mode designed to adapt pressure support (PS) to achieve a target minute ventilation (TgV). This may optimize ventilation; however, no data confirm that va-NIPPV compensates appropriately for the changes in pulmonary mechanics and circuit leak seen in clinical practice. Bench testing assessed these principles. A ventilator featuring a va-NIPPV mode was studied. A test lung with varying compliance and resistance, and pneumotachograph were used. Eight lung model settings were chosen: (i) low resistance and high compliance; (ii) low resistance and low compliance; (iii) high resistance and high compliance; and (iv) high resistance and low compliance, all with and without additional circuit leak. An expiration valve, respiratory rate of 15, inspiratory time of 1 s and PS between 3 and 21 cm H2O were used. Va-NIPPV was tested with varying TgV after establishing the range of minute ventilation possible in a pressure preset mode. At a TgV of 10 L/min, va-NIPPV delivered minute ventilation of (median (interquartile range) ): 11 (10.9-11, 10.2 (10.2-10.3), 12.4 (12.4-12.4) and 11.2 (10.9-11.2) L/min in test lung settings 1, 2, 3 and 4, respectively. Additional leak between 8-33 L/min had little effect. Similar results were seen at other TgV, within the ventilator's PS capabilities. These data confirm that va-NIPPV is able to approximate a preset TgV with varying lung compliance and resistance, and that additional circuit leak has little effect on the delivered minute ventilation.
    Respirology 02/2010; 15(2):361-4. DOI:10.1111/j.1440-1843.2009.01691.x · 3.35 Impact Factor
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    Ian E Smith ·

    Breast cancer research: BCR 12/2009; 11 Suppl 3(Suppl 3):S18. DOI:10.1186/bcr2437 · 5.49 Impact Factor
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    Breast cancer research: BCR 12/2009; 11 Suppl 3(Suppl 3):S15. DOI:10.1186/bcr2434 · 5.49 Impact Factor
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    Ian E Smith ·

    Breast cancer research: BCR 12/2009; 11 Suppl 3(Suppl 3):S6. DOI:10.1186/bcr2425 · 5.49 Impact Factor
  • Amna Sheri · Nicholas C. Turner · Ian E. Smith ·
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    ABSTRACT: Substantial progress is being made in endocrine therapy for breast cancer. Here we review the results from recent trials, highlight key areas of current translational research, and discuss the potential for brief preoperative studies to identify molecular markers predicting outcome in the individual patient. A key challenge for translational research is to optimize endocrine therapy based on patient and tumor characteristics. A further challenge is to identify tumors with acquired or innate resistance and to develop the use of signal transduction inhibitors in combination with endocrine therapy as a means to overcome resistance. Key to the success of such approaches will be clinical trial designs that incorporate appropriate tumor selection and validation of biomarkers predicting benefit.
    Current Breast Cancer Reports 12/2009; 1(4):207-215. DOI:10.1007/s12609-009-0029-x
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    ABSTRACT: Oestrogen receptor (ER) negative breast cancers are more likely to achieve a pathological complete response (pCR) to neoadjuvant chemotherapy compared to those with ER positive tumours. ER positive tumours exhibit low proliferation and ER negative cancers high proliferation. The aim of this study was to determine to what extent the better response of ER negative cancers correlates with proliferation rate. A retrospective analysis of a prospectively maintained database identified 175 neoadjuvant chemotherapy patients with tissue available for Ki67 analysis. On univariate analysis, pre-therapy Ki67 (P=0.04), ER status (P=0.002), HER2 status (P=0.004) and grade (P=0.0009) were associated with a pCR. In a multivariate model, HER2 was the only significant predictor of pCR. No significant relationship between pre-therapy Ki67 and relapse-free and overall survival was demonstrated. Ki67 is not an independent predictor of clinical CR or pCR. Aspects of ER status beyond its inverse relationship with proliferation may contribute to its predictive value for pCR.
    Breast Cancer Research and Treatment 11/2009; 119(2):315-323. DOI:10.1007/s10549-009-0329-x · 3.94 Impact Factor
  • Ian E Smith · Susana Banerjee ·

    Breast (Edinburgh, Scotland) 10/2009; 18 Suppl 3:S74-7. DOI:10.1016/S0960-9776(09)70277-2 · 2.38 Impact Factor
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    ABSTRACT: Purpose To compare the prognostic significance of proliferation, as assessed by Ki67 expression, in breast cancer before and after neoadjuvant chemotherapy. Methods A retrospective search of a prospectively maintained clinical database was performed to identify patients treated with neoadjuvant chemotherapy at the Royal Marsden Hospital. The expression of Ki67 was assessed using immunohistochemistry in pre-therapy core-needle biopsy and post-therapy surgical excision specimens. The following factors were considered pre- and post-chemotherapy for their relationship with relapse-free and overall survival: age, menstrual status, T and N stage, pre-therapy operability, Ki67, ER, PgR, HER2, grade, histological subtype, vascular invasion, clinical response, chemotherapy regimen, type of surgery performed, adjuvant therapy, pathological tumour size and nodal involvement. Results In a matched cohort of 103 patients, on multivariate analysis of relapse-free survival, post-therapy Ki67 was the only significant independent prognostic factor. On multivariate analysis for overall survival, both pre- and excision Ki67 were significant independent predictors but the latter showed a stronger prognostic impact. The highest and lowest tertiles of excision Ki67 had different prognosis for both 5-year relapse-free (27% vs. 77%) and overall (39% and 93%) survival. In a cohort of 284 patients with only excision samples, post-therapy Ki67 was a significant independent prognostic factor on multivariate analysis. Conclusion Post-chemotherapy Ki67 is a strong predictor of outcome for patients not achieving a pathological complete response.
    Breast Cancer Research and Treatment 07/2009; 116(1):53-68. DOI:10.1007/s10549-008-0081-7 · 3.94 Impact Factor

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    ABSTRACT: We analysed the clinical features, distribution of basal markers, prevalence of oncogene amplification, and outcome of triple negative (TN) compared to those of non-TN cancers in a series of adjuvant-anthracycline treated breast cancer patients. We examined the prognostic impact of the TN and BL phenotype in 245 breast cancer patients uniformly treated with adjuvant anthracycline-based chemotherapy following primary surgery, with regards to local relapse-free (LRFS), metastasis free (MFS), and breast cancer specific survival (BCSS). A comparative analysis of the clinicopathological characteristics, expression of basal markers (cytokeratins (Cks) 5/6, 14, 17, EGFR, and caveolin 1 and 2), MIB-1, p53 and topoisomerase II alpha, and prevalence of CCND1, MYC and TOP2A amplification in TN and non-TN breast tumours was performed. TN cancers were significantly associated with the expression of basal markers (all P < 0.0001). However 19.4% of TN tumours were negative for basal markers, whilst 7.3% of non-TN tumours expressed basal markers. TN phenotype was significantly associated with p53, MIB-1 and topoisomerase II alpha (all, P < 0.01) expression. No TN cancer harboured amplification of CCND1 or TOP2A. In univariate analysis, TN and BL phenotype were significantly associated with shorter MFS (both, P < 0.01) and BCSS (both, P < 0.005) but not LRFS. Despite treatment with standard dose anthracycline-based chemotherapy, the clinical outcome of TN and BL cancers remains poor. Alternative chemotherapeutic regimens and/or novel therapeutic approaches are warranted. Although a significant phenotypic overlap exists between TN and basal-like tumours, the TN phenotype is not an ideal surrogate marker for basal-like breast cancers.
    Breast Cancer Research and Treatment 09/2008; 111(1):27-44. DOI:10.1007/s10549-007-9756-8 · 3.94 Impact Factor
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    ABSTRACT: Ovarian failure and infertility following adjuvant chemotherapy for early breast cancer are major concerns for some young women. Techniques for oocyte harvesting are associated with delay in starting treatment, potentially undesirable estrogen stimulation and a relatively low success rate. We report an audit of our experience with the luteinising hormone-releasing hormone agonist, goserelin, to achieve transient ovarian suppression during chemotherapy as a means of preserving ovarian function. Pre-menopausal women were offered goserelin 3.6 mg by subcutaneous injection every 28 days during chemotherapy, starting 0-14 days prior to treatment. The primary end-point was recovery of menstruation. Serum luteinising hormone, follicle stimulating hormone and oestradiol were measured at recovery of menstruation or at first year follow-up if amenorrhoea persisted. Subsequent pregnancies were recorded. Fifty-one evaluable women were audited. Amenorrhoea occurred in all but one. All received combination anthracycline-containing chemotherapy regimens with a mean cumulative cyclophosphamide dose of 3.9 g/m(2). Forty-five (90%) recovered menstruation during the first year of follow-up; mean time to recovery 5 months. Eight pregnancies in 10 women attempting this so far. Using goserelin concurrently with chemotherapy is associated with a high rate of ovarian function preservation.
    Breast Cancer Research and Treatment 09/2008; 110(3):411-6. DOI:10.1007/s10549-007-9745-y · 3.94 Impact Factor

Publication Stats

7k Citations
1,382.97 Total Impact Points


  • 1988-2015
    • The Royal Marsden NHS Foundation Trust
      • Breast Unit
      Londinium, England, United Kingdom
  • 2014
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2005-2014
    • Institute of Cancer Research
      Londinium, England, United Kingdom
    • Bournemouth University
      Bournemouth, England, United Kingdom
  • 2001-2014
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2010
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 2008
    • Imperial College London
      Londinium, England, United Kingdom
  • 2007
    • Hospital Clínico Universitario Lozano Blesa, Zaragoza
      Caesaraugusta, Aragon, Spain
  • 2006
    • Haukeland University Hospital
      • Department of Medicine
      Bergen, Hordaland, Norway
  • 1999
    • Cancer Research UK
      Londinium, England, United Kingdom