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Biomedical subjects

M Dowsett

Publications and source records attributed to M Dowsett.

At least 109 records · Page 6Linked to original sources
PubMed1997

A prospective study of endogenous serum hormone concentrations and breast cancer risk in post-menopausal women on the island of Guernsey.

The associations between serum concentrations of oestradiol, testosterone and sex hormone-binding globulin (SHBG) and risk of breast cancer in post-menopausal women were investigated in a prospective study on the island of Guernsey. Sixty-one women who developed breast cancer an average of 7.8 years after blood collection were matched for age, year of blood collection and number of years post-menopausal with 179 control subjects. Women using exogenous hormones at the time of blood collection were excluded from the study. Women who subsequently developed breast cancer had a 29% higher geometric mean oestradiol concentration than control women (P = 0.004). The odds ratio for breast cancer in the top third compared with the lowest third of the oestradiol concentration distribution was 5.03 (95% confidence interval 2.02-12.49, P for trend < 0.001). Adjusting for testosterone and SHBG concentrations did not substantially alter the odds ratio for oestradiol. Although testosterone and SHBG concentrations were associated with breast cancer risk, the concentrations of these hormones were correlated with those of oestradiol; the associations were not statistically significant after adjusting for oestradiol concentration. These data provide evidence that serum oestradiol concentrations in post-menopausal women may have a substantial effect on breast cancer risk.

Adult↗
PubMed1997

Absence of p21 expression is associated with abnormal p53 in human breast carcinomas.

The p53 tumour-suppressor gene is important in the regulation of cell growth and apoptosis, and loss of functional wild-type activity may be associated with tumour formation and resistance to therapy. Differentiation of functionally normal wild-type protein from mutant or abnormal protein remains difficult using either immunohistochemical assays or mutational DNA sequencing. p21(WAF1/CIP1) (p21) is induced by wild type p53 and plays an important role in promoting cell cycle arrest. To test the hypothesis that p21 protein expression may act as a downstream marker of tumours from patients with locally advanced breast cancer before treatment with doxorubicin, pretreatment p53 status had been characterized in 63 tumours by p53 protein immunostaining and DNA mutational analysis. There was a significant association between immunostaining for p53 and the presence of p53 mutations (P = 0.01). Of 56 patients available for determination of p21, 31 (55%) expressed p21 protein. Twenty-eight out of 31 patients (90%) positive for p21 had low negative p53 protein expression, whereas only 3 of 13 patients (23%) with high p53 expressed p21 (P = 0.009). No association was seen between p21 protein expression and p53 mutations (P = 0.24). The combination of p53 and p21 immunostaining results improved the specificity of the immunostaining but at a cost of significant reduction in sensitivity. Immunohistochemical assessment of p21 protein expression is inversely associated with abnormal p53 protein in human breast cancer. The detection of p21 protein expression in combination with p53 protein expression did not improve the ability of immunohistochemistry (IHC) to differentiate between normal and mutant p53 protein.

Adult↗
PubMed1997

Anastrozole--a new generation in aromatase inhibition: clinical pharmacology.

Use of the aromatase inhibitor aminoglutethimide is limited by its lack of selectivity for aromatase and its toxicity. Newer agents are more selective, but do not always offer improved inhibition of aromatase. Indirect comparison of their activity in inhibiting aromatase and suppressing plasma oestrogens indicates that aminoglutethimide, rogletimide, formestane, and fadrozole inhibited aromatase activity by 74-91%, with reported falls in oestradiol level of 58-76%. In contrast, the new-generation oral once-daily aromatase inhibitors anastrozole (Arimidex) and letrozole were of a similar activity, inhibiting aromatase activity by over 96%, with a concomitant fall in oestradiol and oestrone levels of at least 80%. Anastrozole at the recommended clinical dose of 1 mg daily also suppressed oestrone sulphate levels by 93.5%; activity with anastrozole 10 mg daily was not statistically significantly different. The new generation of aromatase inhibitors, as typified by anastrozole, thus offers effective and convenient aromatase inhibition which correlates well with decreases in the levels of plasma oestrogens.

Anastrozole↗
PubMed1997

A randomised comparison of oestrogen suppression with anastrozole and formestane in postmenopausal patients with advanced breast cancer.

The relative efficacy and tolerability of the aromatase inhibitors anastrozole (Arimidex) and formestane are assessed in a direct comparative trial in postmenopausal women with advanced breast cancer. Final results are available and reported here only for oestradiol suppression. Patients were randomised to receive either oral anastrozole, 1 mg once daily, or formestane, 250 mg every 2 weeks intramuscularly. In the anastrozole group, mean serum oestradiol levels fell from 32.1 pmol/l at baseline to 6.5 pmol/l at week 1, and similar levels of suppression were maintained over the next 3 weeks. In the formestane group, mean serum oestradiol levels fell from 31.0 pmol/l at baseline to 9.5 pmol/l at the week 1 assessment. In this group, serum oestradiol levels tended to rise by the 2- and 4-week measurements, i.e. immediately before the next injection was due. Based on the 2- and 4-week measurements, the mean falls in oestradiol levels were 79 and 58% in the anastrozole and formestane groups, respectively (p = 0.0001). More effective and consistent suppression of oestradiol was achieved with anastrozole at the therapeutic dose of 1 mg once daily, orally, than with formestane at the standard dose of 250 mg every 2 weeks, intramuscularly.

Adult↗
PubMed1997

Future uses for aromatase inhibitors in breast cancer.

Over recent years highly potent, well-tolerated aromatase inhibitors have been developed, which essentially obliterate peripheral aromatase activity in postmenopausal women. Their role as the optimal second-line agents (post-tamoxifen) for the treatment of advanced breast cancer has recently been established in large comparative clinical trials. Their testing as adjuvant therapy is warranted, but their eventual application in this (or the prophylactic) setting will be dependent on the currently unknown effects of profound oestrogen deprivation on the physiology of postmenopausal women as well as on its efficacy. It is also possible that these new compounds could suppress oestrogen synthesis in premenopausal women, but the consequences on ovarian folliculogenesis might prevent their widespread use in this group of patients.

Aromatase Inhibitors↗
PubMed1997

Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas.

Our aim was to determine whether biological molecular markers can predict response to neoadjuvant chemoendocrine therapy in patients with early breast cancer. Ninety patients (median age 56 years; range, 28-69 years) with primary operable breast carcinoma were studied. They were treated with four 3-weekly cycles of chemotherapy with mitozantrone, methotrexate (+/- mitomycin C), and tamoxifen prior to surgery. Fine-needle aspiration was used to obtain samples from patients prior to therapy, and the following parameters were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, Bcl-2, and c-erbB-2 measured by immunocytochemistry, and ploidy and S-phase fraction (SPF) by flow cytometry. The tumors of 78% of the subjects responded (complete response, 9%; partial response, 69%) and 22% did not (no change, 20%; progressive disease, 2%). Response rates according to disease stage and patient age were as follows: T1, 74%; T2, 79%; T3/T4, 78%; age </=50 years, 76%; >50, 79% (P = not significant). Response rates for other parameters were as follows: ER-positive, 82%, and -negative, 70%; PgR-positive, 86%, and -negative, 71%; p53-positive, 74%, and -negative, 81%; Bcl-2-positive, 85%, and -negative 61%; c-erbB-2-positive, 57%, and -negative, 93%; Ki67 high, 77%, and low, 81%; SPF high, 77%, and low, 77%; aneuploid, 71%; and diploid, 85%. Only the difference for c-erbB-2 was statistically significant (P = 0.007). A trend for higher response rates to neoadjuvant chemoendocrine therapy for tumors that were positive for ER, PgR, and Bcl-2 was observed but did not reach statistical significance. Tumors negative for c-erbB-2 had a higher response rate, which was statistically significant. In contrast, Ki67, ploidy, SPF, and p53 failed to predict for response.

Adult↗
PubMed1997

Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer.

Expression of epidermal growth factor receptor (EGFR) or of c-erbB2 in primary breast cancer has been shown to predict for a poor chance of subsequent response of recurrent/metastatic disease to endocrine therapy. To assess the role of these receptors in the development of tamoxifen resistance, we examined their expression immunohistochemically on paraffin-embedded sections from breast cancers from 155 patients whose disease was progressing on tamoxifen therapy. Patients were categorized into those who initially responded to therapy (n = 56), those who never responded (n = 39), and those who relapsed while on adjuvant therapy and may or may not have "responded" (n = 60). In 61 cases, pretreatment specimens were also obtained for direct comparison with the resistance specimen for each patient. None of the 18 pretreatment samples from patients who responded to therapy expressed c-erbB2, and 1 of 18 expressed EGFR. Of the nonresponders, 7 of 18 expressed EGFR pretreatment, and 4 of 18 expressed c-erbB2 (1 patient expressed both receptors). Results confirmed previous findings that when considered independently, expression of either receptor pretreatment tended to predict for a poor chance of response (EGFR, P = 0.046; c-erbB2, P = 0.11). Importantly, patients who were either EGFR positive and/or c-erbB2 positive had a much poorer chance of response than "double negatives" (response rates of 1 of 11 and 17 of 25, respectively; P = 0.0039). At the time of disease progression compared to pretreatment, there was no significant change in expression of either receptor, irrespective of initial response. The inverse relationship between EGFR and estrogen receptor was maintained at relapse on tamoxifen. These data argue strongly against the acquired expression of these receptors during treatment playing a major role in the development of tamoxifen resistance in human breast cancer.

Adult↗
PubMed1996

Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer.

To test the antitumor effect of gonadotrophin-releasing hormone (GnRH) analogs, 32 consecutive patients with recurrent endometrial cancer that had progressed through conventional treatments were entered into an open observational trial of treatment with this class of compounds. Patients recruited had progressive, symptomatic, and measurable disease. Treatment was with monthly subcutaneous injections of GnRH analog. Measurements of gonadotrophins, sex hormones, and tumor dimensions were made together with repeat biopsy when possible to assess response to treatment. An objective response was seen in nine patients (28%, 95% CI 13-43%). Responses were seen within the first 2 months of treatment and included pelvic as well as distant sites of recurrence. Significantly greater response rates were seen in previously irradiated sites when compared with nonirradiated sites of recurrence (0.01 > P > 0.001). There was no significant difference between the response in patients with G3 lesions compared with patients with G1/G2 lesions (P > 0.5). Response did not correlate with previous progestogen exposure. No evidence of disease flare or drug toxicity was observed. GnRH analogs have a significant and durable antitumor effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.

Adult↗
PubMed1996

Effects of short-term antiestrogen treatment of primary breast cancer on estrogen receptor mRNA and protein expression and on estrogen-regulated genes.

Effects of the pure antiestrogen ICI182780 and tamoxifen on ER-protein, ER-mRNA, and estrogen-regulated mRNA expression were analysed using matched pretreatment core-cut biopsies and post-treatment mastectomy samples from 43 ER positive human breast cancers. Sixteen controls received either no preoperative treatment (n = 9) (7 days) or placebo (n = 7) (median 21 days) prior to primary surgery. Nineteen patients received ICI182780 6 mg/day (n = 10) or 18 mg/day (n = 9) for 7 days. Eight patients were given preoperative tamoxifen (4 x 40 mg-day 1, 20 mg/day thereafter, median 21 days). ER-protein expression was assessed on pre and post treatment samples by immunocytochemistry. ER, pS2, pLIV1, and actin-mRNA expression was determined by northern analysis on post-treatment samples only. ER-mRNA levels were similar to controls following ICI182780 or tamoxifen treatment. However ER-protein levels were significantly suppressed by ICI182780, particularly at the higher dosage (p = 0.0013). Tamoxifen had no significant effect on ER-protein levels. The ER-mRNA and ER-protein contents of control tumors were linearly related (Spearman r = 0.719, p = 0.006). A similar relationship between pretreatment protein and post ICI182780 treatment mRNA levels was observed (r = 0.652, p = 0.005). However, comparison of post ICI182780 treatment protein and mRNA results shows a loss of linearity through a reduction in protein without concurrent loss of mRNA (r = 0.28, p = 0.257). pS2 mRNA hybridization was lower in ICI182780 treated samples than controls (Mann-Whitney p = 0.035) but was unaffected by tamoxifen. pLIV1 mRNA hybridization was uninfluenced by either treatment. Short term exposure of breast tumors to ICI182780 appears to produce a greater inhibition of estrogen-induced transcriptional events than tamoxifen. These effects appear to occur without a concurrent reduction in ER mRNA levels.

Antineoplastic Agents, Hormonal↗
PubMed1996

The control and biological importance of intratumoural aromatase in breast cancer.

The existence of aromatase activity in human breast carcinomas has been established for about 20 years but the clinical and biological importance of this remains unclear. A number of studies in clinical material suggest that aromatase activity may be a prerequisite of response to aromatase inhibitors and that aromatase activity may be enhanced in those tumours relapsing during treatment with one such inhibitor, aminoglutethimide. These results would carry more significance, however, if it was demonstrable that the growth of breast carcinomas is affected by the conversion of androgens to oestrogens by intratumoural aromatase. We have tried to address this by establishing model systems with aromatase-transfected MCF7 breast cancer cells. We have demonstrated that these cells can be stimulated mitogenically with androgen and that this proliferation is suppressible with aromatase inhibitors. Similarly the growth of aromatase transfected cells but not wild type cells as xenografts is supported by androstenedione and inhibitable by both the steroidal aromatase inhibitor, 4-hydroxyandrostenedione and non-steroidal inhibitor, CGS 20267. Work with the former of these, which is a suicide inhibitor allowed us to demonstrate that growth can proceed with aromatase activity approximating to the highest level seen in breast carcinomas indicating that at least at this extreme level the intratumoural conversion of androgens to oestrogens may indeed be able to support tumour growth. Further work with this mode system should allow us to define the minimal amount of intratumoural activity which can support tumour growth.

Adenocarcinoma↗
PubMed1996

Comparison of MIB-1 proliferation index with S-phase fraction in human breast carcinomas.

The MIB-1 antibody has been raised against recombinant parts of the Ki-67 antigen and, unlike Ki-67, has wider application to routinely fixed specimens. The aim of this study was to compare the usefulness of MIB-1 with S-phase fraction (SPF) as a measure of proliferation. A total of 75 patients with operable breast cancer were studied, 44 (median age 56 years) before any treatment and 31 (median age 68 years) after primary medical hormonal therapy. Sections from formalin-fixed paraffin-embedded tissue were stained with the MIB-1 antibody and a percentage score of positively stained cells obtained. SPF was measured by flow cytometry in fine-needle aspiration samples taken from the same lesion in each patient. Median MIB-1 score was 9% and median SPF was 11.1%. A close correlation was found between MIB-1 score and SPF (rho=0.59, P<0.0001). There was a difference in the strength of the correlation found between the no treatment group and the treatment group, however, 95% confidence intervals for the rho values overlapped, indicating that there was no significant statistical difference. When analysed for ploidy status a correlation was found only in aneuploid tumours. MIB-1 immunostaining can be used as an effective method of assessing proliferation in human breast carcinomas. This can be done using simple, widely available technology and provides the opportunity to perform large-scale retrospective analyses of archival materials.

Aged↗
PubMed1996

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer.

The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was evaluated in post-menopausal women with breast cancer. Twelve patients progressing after treatment with tamoxifen were randomised to receive anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded crossover design. In vivo aromatisation and plasma oestrogen levels were determined before commencing treatment and at the end of each 4-week period. Treatment with anastrozole 1 and 10 mg reduced the percentage aromatisation from 2.25% to 0.074% and 0.043% (mean suppression of 96.7% and 98.1% from baseline) and suppressed plasma levels of oestrone, oestradiol and oestrone sulphate by > or = 86.5%, > or = 83.5% and > or = 93.5% respectively, irrespective of dose. Notably, several patients had their oestrone and oestradiol values suppressed beneath the sensitivity limit of the assays. In conclusion, anastrozole was found to be highly effective in inhibiting in vivo aromatisation with no difference in efficacy between the two drug doses. Contrary to previous studies on other aromatase inhibitors, this study revealed an internal consistency between the percentage aromatase inhibition and suppression of plasma oestrone sulphate.

Anastrozole↗
PubMed1996

Therapeutic effects of the aromatase inhibitor fadrozole hydrochloride in advanced breast cancer.

The endocrine and therapeutic effects of the aromatase inhibitor fadrozole hydrochloride have been assessed in 80 post-menopausal patients with recurrent breast cancer after tamoxifen failure. Treatment allocation was randomly 0.5, 1.0 or 2.0 mg orally b.d. Eight patients were not assessable for response. All patients were evaluated for toxicity (intent-to-treat analysis). In general, the patients' characteristics were well balanced between the three randomised groups. The endocrine data from this study previously reported suggest a dose-related suppression of oestrone, but not oestradiol or oestrone sulphate. The objective response rate was 17% (95% CI 8.9-27.3%) with no complete responders. Fifteen patients (21%) had stable disease (NC) and 45 patients (63%) had progressive disease (PD). The median duration of objective response was 36 weeks. The median time to treatment failure was 12.7 weeks. The log-rank test showed no statistical difference between the dosage groups. The main adverse events reported were mild to moderate severity: nausea in 11 patients (15%), hot flashes in four (5%) and somnolence in three (4%). 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.

Adult↗
PubMed1996

Arimidex (ZD1033): a selective, potent inhibitor of aromatase in postmenopausal female volunteers.

Two multiple-dose studies were conducted in healthy post-menopausal female volunteers to investigate the pharmacokinetics and effects on endocrinology of Arimidex (ZD1033). Volunteers in the first trial were dosed with 3 mg of ZD1033 daily over 10 days to assess the effects on endocrinology of ZD1033 and establish a pharmacokinetic profile. In the second trial volunteers received 14 daily doses of either 0.5 or 1.0 mg of ZD1033 to assess the pharmacokinetics of ZD1033 and the effects of low doses of ZD1033 on serum oestradiol concentrations. Following multiple dosing a significant reduction in the concentration of serum oestradiol of approximately 80% of baseline was obtained with all three doses; no recovery in oestradiol was apparent for up to 144 h after the last dose. There was no overall difference in the level of oestradiol suppression between the 0.5 or 1.0 mg doses of ZD1033. However, comparison of the number of volunteers with oestradiol concentrations below the limits of detection of the assay, 24 h after the last dose of ZD1033, suggested that 1.0 mg was the minimal dose required for maximal suppression of oestradiol. No significant effect was recorded on serum concentrations of gonadotrophins over the dosing period. Serum concentrations of a range of adrenal steroids were not affected by administration of ZD1033; furthermore, steroid response to standard adrenocorticotrophic hormone (ACTH) challenge was unimpaired by ZD1033. Together these data demonstrate the potency, tolerability and selectivity of ZD1033. The pharmacokinetic profile of ZD1033 supports its use as a once-daily treatment given orally.

Adrenocorticotropic Hormone↗
PubMed1996

Endocrine treatment of advanced breast cancer.

Endocrine treatment is the preferred first-line therapy for advanced breast cancer because of its good tolerability. There are several groups of agents which differ in their mode of action but almost all in some way reduce stimulation by oestrogen. Over recent years, there has been a substantial increase in the number of medical agents in clinical trial. New antioestrogens with reduced or no agonist activity, and potent, more specific, aromatase inhibitors are now reaching the clinic. In most cases, the clinical effectiveness of these agents remains to be fully established and their optimal therapeutic application is yet to be determined.

Antineoplastic Agents, Hormonal↗
PubMed1996

Endocrine resistance in advanced breast cancer.

Although about half of patients with advanced breast cancer show either an objective response or disease stabilization on first line endocrine therapy, virtually all eventually relapse. Few of those patients that fail to respond to first-line treatment, respond to challenge with a second agent. In most cases, the cause of this de novo resistance appears to be the presence of only very low levels of oestrogen receptor (ER) and presumed growth dependence on other pathways. Patients who develop acquired resistance after an initial response, have approximately a 50% chance of responding to a further agent. The most frequently used first-line agent is tamoxifen, and the understanding of acquired endocrine resistance mainly relates to this agent. Selection of ER-ve clones of cells does not appear to occur frequently, and there is little clinical evidence to support the role of ER variants or mutants. There is evidence, however, that in some patients the intratumoural concentration of tamoxifen is substantially reduced at relapse, despite no change in plasma levels.

Antineoplastic Agents, Hormonal↗