M Dowsett

Publications (264)1353.5 Total impact

• Article: Enhanced expression of the PDGFR/Abl signaling pathway in aromatase inhibitor-resistant breast cancer.

  M T Weigel, S Banerjee, M Arnedos, J Salter, R A'hern, M Dowsett, L A Martin
  [show abstract] [hide abstract]
  ABSTRACT: Background We have found that the platelet-derived growth factor receptor (PDGFR)/Abl signaling pathway is up-regulated as a determinant of the acquisition of resistance to estrogen deprivation in vitro. We aimed to determine its clinical relevance in aromatase inhibitor (AI)-resistant breast cancer.Patients and methodsWe identified a cohort of 45 patients with estrogen receptor-positive breast cancer who had been treated with an AI, subsequently relapsed and had biopsy material available from both the presentation and post-AI recurrent lesion. PDGFRα, PDGFRβ and Abl expression was assessed in formalin-fixed paraffin-embedded sections.ResultsTumor protein expression of PDGFRα (1.39-fold, P = 0.0065), PDGFRβ (4.32-fold, P = 0.006) and Abl (1.8-fold, P = 0.001) was increased at the point of relapse. Tumor and stromal expression of PDGFRα as well as PDGFRβ was significantly correlated in pre-treatment and relapse samples. High post-treatment tumor and stromal PDGFRβ levels were associated with a short time to treatment failure (TTF). Expression of PDGFRα in relapsing tumor specimens was correlated with Abl expression and Ki67 levels. Furthermore, changes in Abl correlated significantly with changes in ER expression.Conclusions These clinical data support a role for enhanced PDGF/Abl signaling in AI-resistant disease and provide a rationale for targeting the pathway in endocrine-resistant breast cancer.
  Annals of Oncology 08/2012; · 6.43 Impact Factor
• Article: Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer.

  S Barton, L Zabaglo, R A'Hern, N Turner, T Ferguson, S O'Neill, M Hills, I Smith, M Dowsett
  [show abstract] [hide abstract]
  ABSTRACT: The immunohistochemical (IHC) 4+C score is a cost-effective prognostic tool that uses clinicopathologic factors and four standard IHC assays: oestrogen receptor (ER), PR, HER2 and Ki67. We assessed its utility in personalising breast cancer treatment in a clinical practice setting, through comparison with Adjuvant! Online (AoL) and the Nottingham Prognostic Index (NPI). We prospectively gathered clinicopathologic data for postmenopausal patients with hormone receptor-positive, HER2-negative, N0-3 resected early breast cancer treated consecutively at our institution. We retrospectively calculated and compared prognostic scores. The primary endpoint was the proportion of patients reclassified from AoL-defined intermediate-risk by application of the IHC4+C score. The median age of the 101 patients included in the analysis was 63. In all, 15 of the 26 patients classified as intermediate-risk by AoL were reallocated to a low-risk group by application of the IHC4+C score and no patient was reclassified as high-risk group. Of the 59 patients classified as intermediate-risk group by the NPI, 24 were reallocated to a low-risk group and 13 to a high-risk group. IHC4+C reclassifies more than half of the patients stratified as being in intermediate-risk group by the AoL and NPI. The use of IHC4+C may substantially improve decision-making on adjuvant chemotherapy.
  British Journal of Cancer 04/2012; 106(11):1760-5. · 5.04 Impact Factor
• Source

  Available from: breast-cancer-research.com

  Article: BRCA1, BRCA2 and pedigree genetic analysis to determine genetic risk in the UK Royal Marsden Hospital tamoxifen prevention trial

  Z Kote-Jarai, TP Powles, S Ashley, DF Easton, L Assersohn, N Sodha, M Dowsett, B Gusterson, A Tidy, G Mitchell, RA Eeles
  Breast Cancer Research 04/2012; 2:1-1. · 5.33 Impact Factor
• Source

  Available from: breast-cancer-research.com

  Article: Factors modulating integrin Beta I expression on the breast cancer cell lines MCF-7 and MDA-MB-231

  CJ Pogson, CMW Chan, L-A Martin, GPH Gui, M Dowsett
  Breast Cancer Research 04/2012; 2:1-1. · 5.33 Impact Factor
• Source

  Available from: Sunil Pancholi

  Article: The interaction of the ER with ERBB2 and PI3K results in elevated levels of AKT and p90RSK in tamoxifen-resistant MCF-7 cells

  S Pancholi, A Lykkesfeldt, SRD Johnston, M Dowsett, L-A Martin
  Breast Cancer Research 04/2012; 7:1-1. · 5.33 Impact Factor
• Source

  Available from: Sunil Pancholi

  Article: The anti-estrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF7 breast cancer cells refractory to long-term estrogen deprivation through downregulation of ER and IGF signalling

  L-A Martin, S Pancholi, I Farmer, SRD Johnston, M Dowsett
  Breast Cancer Research 04/2012; 7:1-2. · 5.33 Impact Factor
• Source

  Available from: breast-cancer-research.com

  Article: The involvement of the MAPK signalling pathway in the adaptation of MCF-7 cells to long-term oestrogen deprivation

  L-A Martin, CMW Chan, C Marshall, M Dowsett
  Breast Cancer Research 04/2012; 2:1-1. · 5.33 Impact Factor
• Article: An in vitro model showing adaptation to long-term oestrogen deprivation highlights the clinical potential for targeting kinase pathways in combination with aromatase inhibition.

  L-A Martin, Z Ghazoui, M T Weigel, Sunil Pancholi, A Dunbier, Stephen Johnston, M Dowsett
  [show abstract] [hide abstract]
  ABSTRACT: Aromatase inhibitors (AI) have improved the treatment of oestrogen receptor positive (ER+) breast cancer. Despite the efficacy of these agents over 40% of patients relapse with endocrine resistant disease. Here we describe an in vitro model of acquired resistance to long-term oestrogen deprivation (LTED). The LTED cells retain expression of the ER and appear hypersensitive to oestrogen as a result of altered kinase activity. Furthermore analysis of temporal changes in gene expression during the acquisition of resistance highlight growth factor receptor pathways as key mediators of this adaptive process.
  Steroids 07/2011; 76(8):772-6. · 2.83 Impact Factor
• Source

  Available from: Roger A'Hern

  Article: Relationship between estrogen receptor, progesterone receptor, HER-2 and Ki67 expression and efficacy of aromatase inhibitors in advanced breast cancer.

  H Anderson, M Hills, L Zabaglo, R A'hern, A F Leary, B P Haynes, I E Smith, M Dowsett
  [show abstract] [hide abstract]
  ABSTRACT: Surprisingly few data are published on the relevance of even commonly used biomarkers of response to aromatase inhibitors (AIs) in advanced breast cancer. Here, we aim to determine the effectiveness of AIs in that setting according to quantitative levels of estrogen receptor (ER), progesterone receptor (PgR) and Ki67 or human epithelial growth factor receptor-2 (HER-2) status. ER, PgR, HER-2 and Ki67 protein expressions were centrally assessed in 177 archival formalin-fixed paraffin-embedded primary or locally recurrent breast tumours from women who subsequently received AI treatment of advanced disease. Among ER-positive patients (n = 146), higher PgR, but not ER, levels were associated with increased time to AI treatment failure (TTF). Higher Ki67 staining was associated with decreased TTF. ER-positive/HER-2-positive patients showed a non-significant trend for decreased TTF compared with ER-positive/HER-2-negative patients. PgR level, but not Ki67, remained a significant predictor of TTF in multivariate analysis of ER-positive patients. Higher PgR and Ki67 levels are significantly associated with increased and decreased TTF, respectively, in ER-positive patients receiving AI treatment of advanced disease. The higher proliferation seen in PgR-negative tumours does not explain the poorer clinical responsiveness of this subgroup.
  Annals of Oncology 02/2011; 22(8):1770-6. · 6.43 Impact Factor
• Source

  Available from: Andrea Morandi

  Article: Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.

  I Plaza-Menacho, A Morandi, D Robertson, S Pancholi, S Drury, M Dowsett, L-A Martin, C M Isacke
  [show abstract] [hide abstract]
  ABSTRACT: Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERalpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERalpha. In this study, we show that in ERalpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERalpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERalpha transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM(R)-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERalpha-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors.
  Oncogene 08/2010; 29(33):4648-57. · 6.37 Impact Factor
• Source

  Available from: Sunil Pancholi

  Article: EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy.

  A H Evans, S Pancholi, I Farmer, A Thornhill, D B Evans, S R Johnston, M Dowsett, L-A Martin
  [show abstract] [hide abstract]
  ABSTRACT: Cross-talk between receptor tyrosine kinases and the oestrogen receptor (ER) is implicated in resistance to endocrine therapy. We investigated whether AEE788 (a combined inhibitor of EGFR, HER2 and VEGFR) plus tamoxifen or letrozole enhanced the individual anti-tumour effects of these agents. Breast cancer cell lines modelling endocrine-resistant and -sensitive disease were engineered to express aromatase (A) and examined using proliferation, western blotting and ER-alpha transcription assays. AEE788 enhanced the anti-proliferative effect of tamoxifen and letrozole in ER(+) cell lines (MCF-7 2A, ZR75.1 A3 and BT474 A3). This associated with an elevated G1 arrest and nuclear accumulation of p27. It is noteworthy that AEE788 alone or in combination with endocrine therapy increased the expression of progesterone receptor (PGR) and TFF1 in BT474 A3 cells. This may indicate a mechanism of resistance to AEE788 in ER(+)/HER2(+) breast cancers. In a ZR75.1 A3 xenograft, AEE788 alone or in combination with tamoxifen provided no further benefit compared with letrozole. However, letrozole plus AEE788 produced a significantly greater inhibition of tumour growth compared with letrozole alone. These data suggest that AEE788 plus letrozole in breast cancer overexpressing HER2 may provide superior anti-tumour activity, compared with single agents.
  British Journal of Cancer 04/2010; 102(8):1235-43. · 5.04 Impact Factor
• Article: Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC).

  M Arnedos, A Nerurkar, P Osin, R A'Hern, I E Smith, M Dowsett
  [show abstract] [hide abstract]
  ABSTRACT: Analysis of estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC) is increasingly being conducted in core needle biopsies (CNBs) taken at diagnosis but the concordance with the excisional biopsy (EB) is poorly documented. Patients with EBC presenting to The Royal Marsden Hospital from June 2005 to September 2007 who had CNB and subsequent EB were included. ER and PgR were determined by immunohistochemistry (IHC) and graded from 0 to 8 (Allred score). HER2 was determined by IHC and scored from 0 to 3+. FISH analysis was carried out in HER2 2+ cases and in discordant cases. In all, 336 pairs of samples were compared. ER was positive in 253 CNBs (75%) for 255 EBs (76%) and was discordant in six patients (1.8%). PgR was positive in 221 CNBs (66%) and 227 (67.6%) EBs being discordant in 52 cases (15%). HER2 was positive in 41 (12.4%) of the 331 CNBs in which it was determined compared with 44 (13.3%) EBs and discordant in four cases (1.2%). CNB can be used with confidence for ER and HER2 determination. For PgR, due to a substantial discordance between CNB and EB, results from CNB should be used with caution.
  Annals of Oncology 08/2009; 20(12):1948-52. · 6.43 Impact Factor
• Source

  Available from: Anita K Dunbier

  Article: Biomarkers and predictive factors of response to neoadjuvant treatment.

  M Dowsett, A Dunbier, H Anderson, J Salter, S Detre, R Jones, A Skene, M Dixon, Ie Smith
  Breast cancer research: BCR 06/2009; 11 Suppl 1:S11. · 5.24 Impact Factor
• Source

  Available from: Sarah E Pinder

  Article: HER2 testing in the UK: further update to recommendations.

  R A Walker, J M S Bartlett, M Dowsett, I O Ellis, A M Hanby, B Jasani, K Miller, S E Pinder
  [show abstract] [hide abstract]
  ABSTRACT: These guidelines update the previous UK HER2 testing guidelines and have been formulated to give advice on methodology, interpretation and quality assurance to ensure that HER2 testing results are accurate, reliable and timely with the expansion of testing to all patients with breast cancer at the time of primary diagnosis. The recommendations for testing are the use of immunohistochemistry but with analysis of equivocal cases by in situ hybridisation to clarify their HER2 status or the use of frontline fluorescence in situ hybridisation (FISH) testing for those laboratories wishing to do so; the inclusion of a chromosome 17 probe is strongly recommended. Laboratories using chromogenic or silver in situ hybridisation should perform an initial validation against FISH. For immunohistochemistry and in situ hybridisation there must be participation in the appropriate National External Quality Assurance scheme.
  Journal of clinical pathology 08/2008; 61(7):818-24. · 2.43 Impact Factor
• Source

  Available from: cnrs.fr

  Article: A randomised study of the effects of letrozole and anastrozole on oestrogen receptor positive breast cancers in postmenopausal women.

  J Murray, O E Young, L Renshaw, S White, L Williams, D B Evans, J St J Thomas, M Dowsett, J M Dixon
  [show abstract] [hide abstract]
  ABSTRACT: Changes in proliferation as measured by Ki67 occur within 14 days of starting treatment with an aromatase inhibitor and these changes have been shown to be predictors of long term outcome. This study aimed to compare changes in proliferation following 14 days of treatment with anastrozole and letrozole. Two hundred and six women with 209 estrogen receptor (ER) positive operable breast cancers (three bilateral) were randomly allocated to receive either 14 days treatment with 2.5 mg of letrozole or 1 mg of anastrozole prior to surgery. Changes in expression of estrogen (ER) and progesterone receptors (PgR) as assessed by ALLRED scores and proliferation as assessed by Ki67 were analysed. The HER2 status of each tumour was also assessed using a combination of the Hercept test and FISH. Both letrozole and anastrozole reduced ER expression (ALLRED score) by a mean of 0.32 (0.20-0.44), P<0.001 and PgR fell by a mean of 2.54 (2.20-2.89) P<0.0001. Letrozole reduced proliferation from a geometric mean of 6.37% to 0.81%, P<0.0001 and anastrozole reduced proliferation from 5.81% to 0.77%, P<0.0001. There was no differences between drugs in the fall in ER, PgR or proliferation. Both letrozole and anastrozole produced significant falls in proliferation in both HER2 positive and HER2 negative cancers, all P<0.001. 14 days of both letrozole and anastrozole reduces proliferation, ER and PgR expression. No significant difference between these two drugs was identified.
  Breast Cancer Research and Treatment 04/2008; 114(3):495-501. · 4.43 Impact Factor
• Article: Aromatase inhibitors and male breast cancer.

  E Arriola, E Hui, M Dowsett, I E Smith
  [show abstract] [hide abstract]
  ABSTRACT: The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.
  Clinical and Translational Oncology 03/2007; 9(3):192-4. · 1.33 Impact Factor
• Source

  Available from: Jean-Yves Pierga

  Article: Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy.

  J-Y Pierga, J S Reis-Filho, S J Cleator, T Dexter, A Mackay, P Simpson, K Fenwick, M Iravani, J Salter, M Hills, C Jones, A Ashworth, I E Smith, T Powles, M Dowsett
  [show abstract] [hide abstract]
  ABSTRACT: We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approximately 5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11-12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21-q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3-q4 and 18p11.31 and gains of 6p25.1-p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2-11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.
  British Journal of Cancer 02/2007; 96(2):341-51. · 5.04 Impact Factor
• Article: Oncogene Products and Other Diagnostic Markers in Human Breast Cancer Patients

  M. DOWSETT, A. MAKRIS, P. ELLIS, S. R. D. JOHNSTON, J. SALTER, S. DETRE, S. HUMPHRIES, G. SACCANI-JOTTI, T. J. POWLES, I. E. SMITH
  Annals of the New York Academy of Sciences 12/2006; 784(1):403 - 411. · 3.15 Impact Factor
• Source

  Available from: PubMed Central

  Article: Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?

  A Leary, M Dowsett
  [show abstract] [hide abstract]
  ABSTRACT: Long-term endocrine therapy with either aromatase inhibitors (AIs) or tamoxifen may lead to endocrine resistance and disease progression. Recent years have seen advances in our understanding of the complex biological mechanisms associated with resistance. Growth factor signaling pathways appear to be upregulated in hormone-resistant tumours and interact with oestrogen-receptor (ER) signaling, which remains functional even after long-term endocrine deprivation. Signaling through the human epidermal and insulin-like growth-factor receptor (HER and IGFR, respectively) pathways may promote ligand-independent ER gene transcription and stimulate growth factor signaling. Therapeutic agents that inhibit these signal transduction pathways, when combined with AIs, may offer breast cancer patients new hope for more robust, longer-term remissions. Preliminary data from phase II studies of combination therapies are encouraging. There is a large programme of ongoing randomised, controlled trials, the results of which should pave the way for integrating combination therapies into clinical practice. To identify which patients will respond best to particular combinations of treatments, biomarkers and gene expression profiles are being investigated as predictors of sensitivity or resistance. In time, breast cancer treatment will become truly individualised because physicians will be able to match patients with a variety of disease phenotypes to optimal combination therapies.
  British Journal of Cancer 10/2006; 95(6):661-6. · 5.04 Impact Factor
• Article: Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status.

  M Dowsett, J Houghton, C Iden, J Salter, J Farndon, R A'Hern, R Sainsbury, M Baum
  [show abstract] [hide abstract]
  ABSTRACT: Most women with oestrogen receptor (ER) positive primary breast cancer receive adjuvant tamoxifen after surgery. The measurement of tumour biomarkers should allow better selection of patients for such treatment or for therapies such as aromatase inhibitors. Histopathological blocks of primary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature randomised clinical trials were retrieved. Immunohistochemical staining for ER, progesterone receptor (PgR), HER2 and epidermal growth factor receptor (EGFR) was undertaken. The primary endpoint was relapse free survival. 813 patients were included in the study. Benefit from tamoxifen was seen in ER-positive patients [Relative risk (rr) 0.77, ci 0.63-0.93]. ER-negative patients also showed a strong trend to benefit from tamoxifen (rr 0.73, ci 0.52-1.02) which was largely confined to the PgR-positive group. Amongst the ER-positive group, PgR-positive and PgR-negative patients showed similar benefit (rr 0.81; ci 0.65-1.02 and 0.70; ci 0.49-0.99, respectively). Patients positive for HER2 did not benefit significantly (rr 1.14; ci 0.75-1.73) but this group was small. Measurement of PgR status in ER-negative patients defines a group of patients that benefit from tamoxifen but would be excluded from tamoxifen therapy on the basis of ER status alone. The data are consistent with HER2 positive tumours being resistant to tamoxifen.
  Annals of Oncology 06/2006; 17(5):818-26. · 6.43 Impact Factor