M Dowsett

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..This study evaluated changes in Ki-67 labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy...

..If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates...

..Little is known of the molecular effects of these agents on human breast carcinomas in vivo...

..The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy...

..Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges...

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..We retrospectively tested the hypothesis that this benefit might differ according to PgR status...

..Integration of each of these molecular profiles with classical clinicopathologic variables provided the most accurate prediction of outcome...

..To gain an understanding of current attitudes among oncologists and pathologists to prospective HER2 testing in breast cancer and to gauge whether a national consensus exists regarding extent and quality of testing...

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..We argue that these changes in proliferation and concurrent changes in apoptosis may be expected to be more predictive of adjuvant benefit from endocrine therapy than clinical response...

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..It provides a unique opportunity for detailed study of the determinants of response and resistance to estrogen deprivation as well as testing the role of presurgical therapy for improved biomarker-based estimates of prognosis...

..In contrast, tamoxifen can lead to markedly enhanced levels. In postmenopausal women aromatase inhibitors can achieve an almost complete inhibition of the aromatase enzyme...

..To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2)...

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..In this way, the treatments available should be efficiently and actively revised to incorporate new concepts of diagnosis, prognosis and treatment, to the benefit of women with breast cancer...

..These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice...

..Ultimately, the TA01 program has the potential to favorably impact treatment choices for breast cancer...

..Collection of resistant biopsy tissues from patients is important to determine if this mechanism is clinically relevant...

..7-2.3 by at least one center. Equivocal immunohistochemistry and borderline FISH cases are difficult to interpret, even for highly experienced and validated laboratories, highlighting the need for quality-control procedures...

..The resulting incorporation of new biomarkers and revised trial designs should promote the future development of more precise and increasingly active interventions directed towards the treatment of breast cancer...

..We therefore conducted an international Web-based consultation of breast cancer professionals to identify the topics most widely considered to be of highest priority...

..The importance of using appropriate methodology is discussed and illustrated with data demonstrating the disparity in the results obtained when low levels of oestradiol were quantified using direct and indirect methods...

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..To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy...

..There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors...

..To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy...

..Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of idoxifene, compared to tamoxifen...

..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...

..d., two at 800 mg b.d., and one at 1200 mg b.d. The most frequent side-effects were nausea and lethargy. One patient showed an objective response to treatment...

..This together with high baseline proliferation is likely to translate to poor clinical response...

..Thus, the resistance of these human breast cancer cells to oestrogen-deprivation appears to be due to acquired hypersensitivity which may be explained in part by increased levels of and phosphorylated ERalpha...

..To determine the effects of tamoxifen on the levels of hormone receptors and proliferation markers in the early phase of treatment and the relationship of the changes with tumor response in patients with primary breast cancer...

..05 < P < 0.10). Idoxifene was well tolerated in all patients. Idoxifene has an antiproliferative effect in ER-positive but not ER-negative breast cancers, and no significant effect on apoptosis in the short-term...

..Gene expression profiling (microarray analysis), i.e., genomic and proteomic studies, will probably advance the discovery of new biomarkers for breast cancer prevention and treatment...

..The objective of this clinical study was to examine in vivo changes in apoptotic index (AI), Bcl-2 expression, proliferation (Ki-67 and S-phase fraction [SPF]), and ploidy as potential indicators of chemoresponsiveness...

..This can be done using simple, widely available technology and provides the opportunity to perform large-scale retrospective analyses of archival materials...

..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...

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..CONCLUSION: Anastrozole did not have a detrimental effect on lipid profiles following 3 months of therapy. There was a significant increase in CTx with anastrozole in contrast to tamoxifen...

..3-11.3% by flow cytometry) and between different phases of treatment, and should provide a useful tool for further research on this process in solid tumours...

..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...

..The measurement of tumour biomarkers should allow better selection of patients for such treatment or for therapies such as aromatase inhibitors...

..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...

..The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients...

..Further investigation of the effects of aromatase inhibitors on prostatic biology, and bone metabolism in patients with metastatic prostate cancer, would appear worthwhile...

..2 +/- 9.1%, P < 0.025). This effect on Oe1S may be due to an influence of AG on oestrogen metabolism...

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..Existing clinical-pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness...

..We conclude that the slow release formulation of leuprorelin is effective in breast cancer treatment and that there is no major detriment to the use of the 3.75 rather than 7.5 mg dose...

..Hence, the effects of the nonsteroidal aromatase inhibitor anastrozole on serum oestrogen concentrations were compared in 24 healthy postmenopausal Japanese women and 24 healthy postmenopausal Caucasian women...

..These data support an algorithm in which FISH testing is restricted to IHC 2+ tumours in reference centres. The results may not extrapolate to laboratories with less experience or using different methodologies...

..These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor...

..A consistent effect of letrozole on serum lipids has not been demonstrated...

..In addition, the oestradiol suppressant effects of anastrozole appear unaffected by tamoxifen...

..In contrast, early data from the neoadjuvant setting suggest that responses to aromatase inhibitors may be maintained in patients with HER2 overexpression...

..We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial...

..Pretreatment proliferation and GI are however predictive of response to chemotherapy in breast cancer...

..The drug's reduced agonist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment...

..The use of biotinylated nucleotides to identify DNA strand breaks is a commonly reported method of estimating cells numbers undergoing apoptosis; however, investigators report inconsistent results for a variety of reasons...

..As aromatase inhibitors work by inhibiting the conversion of androgens to estrogens in adipose tissue, we hypothesized that anastrozole may be more effective in women with a high body mass index (BMI)...

..These results show that ARZ is an effective antagonist of E2-stimulated breast cancer growth with similar growth-inhibitory and pharmacodynamic effects to TAM in this model...

..We conclude that any prophylactic effect of letrozole is not likely to be dependent on antiproliferative effects on normal breast. Studies in healthy patients will need to recognize the potential for enhanced bone resorption...

..Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors...

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..We conclude that changes in ploidy and SPF detected by flow cytometry may predict initial response and the likelihood of relapse of breast tumours to tamoxifen before clinical changes become evident. These data justify a larger study...

..The possibility is considered that the apparent small differences between the triazoles may be associated with differences in clinical effectiveness. These new compounds merit consideration for studies of breast cancer prevention...

..02) and overall survival (P = 0.03) when measured by this immunohistochemical assay, but was not significant when measured by ligand-binding assay...

..No serious adverse events were reported. In conclusion, fadrozole is a clinically active aromatase inhibitor with a low incidence of side-effects and phase III clinical trials in post-menopausal women are currently under way...

..We investigated the effects of anastrozole and tamoxifen over time on serum VEGF and sVEGFR-1...

..The modest degree of gene change suggests that intermediate markers of chemoprevention may be difficult to identify...

..Larger validation studies are necessary to define and refine patterns for different agents...

..The steroidal AI, exemestane is also an option in non-steroidal AI-resistant disease. Clinical trials are underway to compare fulvestrant with exemestane as an appropriate therapy following the onset of AI resistance...

..Three microarray-based single sample predictors (SSPs) have been used to define molecular classification of individual samples. We aimed to establish agreement between these SSPs for identification of breast cancer molecular subtypes...

..Their use is sometimes extended to younger women after chemotherapy-induced amenorrhoea; we have audited this in one institution's breast unit, and we propose guidelines for use in such circumstances...

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..Continuing work using cDNA microarrays may yield new, more reliable indices of likely response and an improved insight into biological processes related to chemotherapeutic response...

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..Early HER-2 directed therapy (such as the monoclonal antibody trastuzumab) as a part of multimodal treatment may improve outcome in this poor prognosis cancer...

..CONCLUSION: Ki67 is unlikely to be useful as a predictive marker in individual patients. Further molecular markers that predict lack of response continue to be required...

..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...

..Neither anastrozole nor letrozole have any effect on plasma concentrations of tamoxifen when given in combination with it...

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..The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets...

..This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area...

..The experimental and clinical evidence supporting these mechanisms of tamoxifen resistance are discussed in this review...

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..This article reviews the safety profile of AIs, discussing events related to their chemical structure, their specificity, and the effects of estrogen deprivation on target organs...

..The aim of this proof-of-principle study was to assess whether NEUROD1 DNA methylation is able to predict the response to neoadjuvant and adjuvant chemotherapy...

..In most cases, the clinical effectiveness of these agents remains to be fully established and their optimal therapeutic application is yet to be determined...

..We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study...

..Rigorous comparison of these emerging markers with current treatment selection criteria will be required to determine whether they offer significant benefit to justify their use...

..However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs...

..These observations support the need for further evaluation of these markers in breast tumors as predictors of TAM resistance...

..These compounds promise a new era of disease prevention in the aging woman and their therapeutic potential is currently being evaluated in large-scale clinical trials...

..It is concluded that incomplete hormonal resistance results from co-expression of HER-2 and ER and that this may differ between different hormonal agents...

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