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Mitch Dowsett

Publications and source records attributed to Mitch Dowsett.

At least 55 records · Page 3Linked to original sources
PubMed2005

Life following aromatase inhibitors--where now for endocrine sequencing?

The third-generation non-steroidal aromatase inhibitors (AIs) are challenging tamoxifen as treatments of choice for early and advanced breast cancer in postmenopausal women with estrogen receptor (ER)-positive disease. However, patients who initially respond to AIs eventually develop resistance to treatment and experience disease progression. To establish the optimal endocrine therapy following AI resistance, it is essential to understand the mechanisms that contribute to the loss of response. Data from in vitro models have suggested that acquired AI resistance is due to enhanced sensitization to low estrogen levels during long-term estrogen deprivation (LTED). Cross-talk between the ER and various growth-factor-receptor signaling pathways, including human epidermal growth factor receptor 2, and the insulin-like growth factor pathway, may also be implicated. Therefore, endocrine therapies that abolish estrogen signaling via removal of the ER could be effective in patients with AI-resistant disease. Fulvestrant ('Faslodex') is a new ER antagonist with no agonist effects that binds, blocks and degrades the ER. Due to its unique mode of action and lack of cross-resistance with existing treatments, fulvestrant is an effective therapeutic agent for use in sequential endocrine regimens. Fulvestrant has established efficacy in tamoxifen-resistant disease and there is a growing body of evidence demonstrating its efficacy in patients with AI-resistant disease. In preclinical models, MCF-7 cells undergoing LTED are refractory to tamoxifen but sensitive to fulvestrant, suggesting fulvestrant is a more appropriate choice following AI resistance. 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.

Anastrozole↗
PubMed2005

Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance.

There is an increasing rationale for effective combinations of endocrine therapy with novel drugs that target aberrant signal transduction pathways in estrogen receptor (ER) positive breast cancer. Prolonged endocrine therapy can be associated with an acquired increase in peptide growth factor signaling (EGFR, HER2), together with cross-talk activation of ER-dependent gene transcription and cell growth that leads to endocrine resistance. Current approaches to target these pathways include both the selective ER downregulator fulvestrant, and various signal transduction inhibitors (STIs). Fulvestrant can overcome resistance to tamoxifen (TAM-R) and long-term estrogen deprivation (LTED-R) in experimental models by reducing ER expression, and represents a current option for post-menopausal women with endocrine resistant ER+ve breast cancer. Emerging data suggest that fulvestrant's effect may be greater when combined with estrogen deprivation, and several phase III trials are assessing fulvestrant combined with aromatase inhibitors (AIs). Small molecule STIs such as tyrosine kinase inhibitors (TKIs), farnesyltransferase inhibitors (FTIs) and mTOR antagonists are also active in breast cancer. Pre-clinical data suggest that combined endocrine/STI therapy may result in greater growth inhibition than either therapy alone, and thus delay emergence of resistance. Several clinical trials are now examining STIs combined with AIs both in the tamoxifen-resistant and first-line advanced breast cancer setting, while pre-surgical studies are investigating the efficacy of combined endocrine/STI therapy utilising biological primary endpoints. This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area.

Antineoplastic Agents, Hormonal↗
PubMed2005

Mechanisms of resistance to aromatase inhibitors.

Aromatase inhibitors are rapidly becoming the first choice for hormonal treatment of steroid receptor positive breast cancer in postmenopausal women. An understanding of the resistance mechanisms to these agents is, therefore, important for the appropriate delivery of treatment to responsive patients and the rational development of new agents targeted at the resistance pathways. De novo resistance appears to be a quantitative rather than qualitative phenomenon with virtually all oestrogen receptor positive tumours showing an anti-proliferative response to the aromatase inhibitor anastrozole. While the expression of type 1 growth factor receptors reduces response to tamoxifen this appears to have little detrimental effect on response to aromatase inhibitors. Studies of acquired resistance in vitro have indicated that acquisition of hypersensitivity to oestrogenic stimulation is a key mechanism that is dependent on enhanced cross-talk of growth factor and oestrogen signaling pathways. Collection of resistant biopsy tissues from patients is important to determine if this mechanism is clinically relevant.

Antineoplastic Agents, Hormonal↗
PubMed2005

Treatment with high-dose estrogen (diethylstilbestrol) significantly decreases plasma estrogen and androgen levels but does not influence in vivo aromatization in postmenopausal breast cancer patients.

While growth factors and hormones are known to influence aromatase expression in experimental systems, little is know about potential factors influencing peripheral aromatization in postmenopausal women. The fact that peripheral aromatase activity is higher in old compared to young women and the finding of relatively high tissue estradiol (E2) concentrations after the menopause suggests peripheral aromatization could be influenced by estrogen concentration. To test this hypothesis, we determined plasma hormone levels (n=9) and in vivo aromatization (n=3) in postmenopausal women suffering from advanced breast cancer before and during treatment (4 weeks) with diethylstilbestrol (DES) 5mg three times daily. Plasma levels of cortisol (C), corticosteroid-binding globulin (CBG), and sex hormone binding globulin (SHBG) were significantly increased in all patients (P<0.05 for all). While we found no change in total body aromatization and plasma estrone (E(1)) levels, estradiol (E(2)) and estrone sulfate (E(1)S) were suppressed by a mean of 48.8 and 68.2%, respectively (P=0.043 and 0.008). Surprisingly, plasma levels of androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) were also suppressed by a mean in the range of 32.1 to 52.6% (P<0.05 for all androgens). In contrast, no change in plasma progesterone or 17alpha-hydroxyprogesterone was found. Thus, one possible explanation to our findings could be that DES administered in high doses reduces 17,20-lyase activity in the adrenal gland.

Aged↗
PubMed2005

Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men.

Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.

4-Butyrolactone↗
PubMed2005

Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation.

The knowledge that steroids play a pivotal role in the development of breast cancer has been exploited clinically by the development of endocrine treatments. These have sought to perturb the steroid hormone environment of the tumour cells, predominately by withdrawal or antagonism of oestrogen. Unfortunately, the beneficial actions of existing endocrine treatments are attenuated by the ability of tumours to circumvent the need for steroid hormones, whilst in most cases, retaining the nuclear steroid receptors. The mechanisms involved in resistance to estrogen deprivation are of major clinical relevance for optimal treatment of breast cancer patients and the development of new therapeutic regimes. We have shown that long-term culture of MCF7 cells in medium depleted of oestrogen (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of both ERalpha phosphorylated on Ser(118) and ERK1/ERK2. Our data suggest elevated ERK1/ERK2 activity results wholly or in part from enhanced ERBB2 expression in the LTED cells. These cells showed greater sensitivity to the tyrosine kinase inhibitor ZD1839 in both ERalpha-mediated transcription and growth assays compared with the wt-MCF7. Similarly the MEK inhibitor U0126 decreased basal ERalpha-mediated transcription and proliferation in the LTED cells by 50% and reduced their sensitivity to the proliferative effects of E2 10-fold, whilst having no effect on the wild type (wt). However, complete suppression of ERK1/ERK2 activity in the LTED cells did not inhibit ERalpha Ser(118) phosphorylation suggesting that the cells remained ligand-dependent. This was further confirmed by the increased sensitivity of the LTED cells to the growth suppressive effects of ICI 182,780 and suggested that the LTED cells remained wholly or partially dependent on oestrogen receptor (ER)/oestrogen responsive elements directed growth. These findings suggest that treatments targeted at growth factor signalling pathways may be useful in patients acquiring resistance to oestrogen deprivation with aromatase inhibitors and that the pure anti-oestrogen ICI 182,780 may also be effective by blocking or destabilizing ER and hence disrupting cross-talk.

Breast Neoplasms↗
PubMed2005

Phytoestrogen exposure correlation with plasma estradiol in postmenopausal women in European Prospective Investigation of Cancer and Nutrition-Norfolk may involve diet-gene interactions.

Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = -0.199 to -0.277, P <0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = -0.597 to -0.834, P < 0.03). The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women. There was no relationship between dietary isoflavones and plasma estradiol and no association was found between any of the dietary, urinary, and serum phytoestrogen and plasma SHBG or between these factors and polymorphisms in CYP19, SHBG, and COMT. We conclude that higher isoflavone exposure is associated with lower plasma estradiol in postmenopausal women and that this preliminary study is suggestive of the involvement of diet-gene interactions.

Aged↗
PubMed2004

Deficits in plasma oestradiol measurement in studies and management of breast cancer.

The determination of plasma oestradiol has numerous applications in epidemiology, reproductive medicine and breast cancer management. Commercially available analytical methods, which measure the hormone levels without prior purification, have been successfully developed for measuring oestradiol in premenopausal women. The application of these methodologies to the quantification of the very low levels of oestradiol in postmenopausal women is more problematic in terms of accuracy and interpretation. 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.

Breast Neoplasms↗
PubMed2004

Endocrinology and hormone therapy in breast cancer: aromatase inhibitors versus antioestrogens.

Endocrine therapies act by either blocking or downregulating the oestrogen receptor or by reducing oestrogen concentrations around and within the cancer cell. In postmenopausal women, oestrogen suppression is achieved by inhibition of the enzyme aromatase by aromatase inhibitors (AIs). Modern AIs (anastrozole, letrozole and exemestane) are more potent than earlier ones and suppress oestradiol levels in plasma to virtually undetectable concentrations. Recent comparisons of AIs with the most widely used oestrogen receptor blocking drug tamoxifen indicate that, in general, AIs result in increased response rates and greater durations of response. Here, we summarize data supporting the difference between the two types of treatment and attempt to account for the underlying mechanisms that favour AIs.

Animals↗
PubMed2004

Polymorphisms associated with circulating sex hormone levels in postmenopausal women.

BACKGROUND: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them. METHODS: We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates. RESULTS: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained 1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk. CONCLUSION: Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r2 values may explain why these genes have given inconclusive results in breast cancer case-control studies.

17-alpha-Hydroxyprogesterone↗
PubMed2004

Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165].

INTRODUCTION: Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed. METHODS: A total of 205 women (age range 49-65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed. RESULTS: A total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean +/- standard deviation): TT isoflavone 1.4 +/- 12.3% and TT placebo -9.6 +/- 14.2%; CT isoflavone -5.2 +/- 12.0% and CT placebo -2.8 +/- 10.3%; and CC isoflavone -3.4 +/- 9.7% and CC placebo -1.1 +/- 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms. CONCLUSION: In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.

Adipose Tissue↗
PubMed2004

Translational research and the changing face of breast cancer.

Advances in our understanding of the molecular mechanisms underlying breast cancer have identified a considerable number of new molecular targets that may have significant roles in tumor behavior. The rapid and effective transition of these novel, preclinical scientific observations through into the clinic is described as translational research. Tumor markers are an important area of translational research, since they introduce the possibility of identifying groups of patients who possess particular diagnostic or prognostic characteristics. It is important that advances in translational breast cancer research are reviewed in order to determine how they may influence treatment. As part of this process, it is particularly important to identify how these advances may be rationally evaluated through the design of clinical trials, thereby ensuring that the resulting data are sufficiently robust in order to inform and direct clinical decision making. 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.

Biomarkers, Tumor↗
PubMed2004

Biomarker investigations from the ATAC trial: the role of TA01.

cDNA arrays and proteomic analyses have allowed the rapid identification of specific genes and proteins implicated in multiple tumor types. These molecules must then be validated as clinically relevant prognostic and predictive markers, and this translational research is best conducted in the context of clinical trials. Outcomes data and clinical specimens collected in the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) study, for example, can now be used to compare the expression of biomarkers with clinical outcomes. In this study, adjuvant tamoxifen and anastrozole ('Arimidex') were compared alone and in combination in more than 9000 women with breast cancer. Anastrozole was found to be superior to tamoxifen in terms of disease-free survival, time to recurrence, and reduction in the incidence of contralateral tumors. Importantly, tissue specimens from surgical excision, local relapse, and contralateral breast cancer were collected and paraffin-embedded for storage. In the TA01 (TransATAC) program, these specimens will be studied (after obtaining patient consent) using tissue microarrays; tissue biopsy cores 0.6 mm in diameter will be removed from donor blocks and placed on recipient blocks, which will be sectioned to allow the simultaneous analysis of the same samples for multiple biomarkers. These analyses can help determine differential benefits of treatment with anastrozole or tamoxifen, depending on the expression of particular biomarkers in tumor cells. This research also should clarify de novo and acquired resistance mechanisms, and the validation of relevant molecular pathways could guide the development of new drugs. Ultimately, the TA01 program has the potential to favorably impact treatment choices for breast cancer.

Anastrozole↗
PubMed2004

Designing the future shape of breast cancer diagnosis, prognosis and treatment.

Translational research is intended to efficiently and accurately validate the most promising preclinical biomarkers and ensure that their diagnostic or prognostic potential is rapidly adopted in the clinic. Translational research therefore needs to take into account the biological complexity that is inherent in all cellular pathways, such as the estrogen and progesterone receptor pathways, and yet produce conclusions that will have sufficient statistical power to define and shape clinical practice. This will be achieved through the incorporation of new concepts of trial design, including neoadjuvant or preoperative hypothesis-generating studies, and the increasing use of high-throughput proteomic and genomic approaches. Clinical trials will be increasingly designed to incorporate biomarker analyses, and ongoing trials may employ the retrospective collection of archival tissues to allow the use of prospectively planned biomarker analyses. This approach is being utilized in the TA01 program, which is based upon the 'Arimidex', tamoxifen, alone or in combination (ATAC) trial. 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.

Biomarkers, Tumor↗
PubMed2004

Circulating tumour cells in breast cancer.

By use of modern immunological and molecular analytical techniques, cells with the characteristics of tumour cells can be detected in the blood of many patients with breast cancer. The ability to detect and characterise such cells routinely could have a profound influence on the early diagnosis of breast cancer, risk stratification in the adjuvant setting, early detection of relapse, and the development of new targeted strategies. In this review we discuss current techniques to detect circulating breast-cancer cells and the limitations of these approaches. We also review the clinical studies in breast cancer and discuss the potential relevance of this research to the future management of the disorder.

Breast Neoplasms↗
PubMed2004

The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Isoflavone phytoestrogen therapy has been proposed as a natural alternative to hormone replacement therapy (HRT). HRT has a beneficial effect on bone, but few trials in humans have investigated the effects of isoflavones on bone. OBJECTIVE: The objective of the study was to determine the effect on bone density of a red clover-derived isoflavone supplement that provided a daily dose of 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein for 1 y. Effects on biochemical markers of bone turnover and body composition were also studied. DESIGN: Women aged 49-65 y (n = 205) were enrolled in a double-blind, randomized, placebo-controlled trial; 177 completed the trial. Bone density, body composition, bone turnover markers, and diet were measured at baseline and after 12 mo. RESULTS: Loss of lumbar spine bone mineral content and bone mineral density was significantly (P = 0.04 and P = 0.03, respectively) lower in the women taking the isoflavone supplement than in those taking the placebo. There were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, but bone formation markers were significantly increased (P = 0.04 and P = 0.01 for bone-specific alkaline phosphatase and N-propeptide of collagen type I, respectively) in the intervention group compared with placebo in postmenopausal women. Interactions between treatment group and menopausal status with respect to changes in other outcomes were not significant. CONCLUSION: These data suggest that, through attenuation of bone loss, isoflavones have a potentially protective effect on the lumbar spine in women.

Aged↗
PubMed2004

Mechanisms of tamoxifen resistance.

The anti-oestrogen tamoxifen is the most commonly used treatment for patients with oestrogen-receptor (ER)-positive breast cancer. Although many patients benefit from tamoxifen in the adjuvant and metastatic settings, resistance is an important clinical problem. The target of tamoxifen in vivo is the ER. Over the last decade many advances have been made in our understanding of the biology of the ER which may help to explain how resistance to tamoxifen develops. Such mechanisms may include changes in the expression of ERalpha or ERbeta, alterations in co-regulatory proteins, and the influences of cellular kinase signal transduction pathways. The experimental and clinical evidence supporting these mechanisms of tamoxifen resistance are discussed in this review.

Antineoplastic Agents, Hormonal↗