Biomedical subjects

W R Miller

Publications and source records attributed to W R Miller.

At least 37 records · Page 2Linked to original sources

PubMed2003

The therapeutic potential of aromatase inhibitors.

The third generation aromatase inhibitors are both remarkably potent and specific endocrine agents inhibiting aromatase activity and reducing circulating oestrogen levels in postmenopausal women to levels never previously seen. Their therapeutic potential is consequently much greater than the earlier prototype drugs. Their excellent side-effect profile also allows for potential wider indications in the treatment of oestrogen-related diseases, including breast cancer. It still remains to determine whether their potent endocrine effects translate into increased therapeutic benefit. In advanced breast cancer, aromatase inhibitors have been shown to have improved efficacy and toxicity profiles when compared with progestins, aminoglutethimide and tamoxifen. Aromatase inhibitors have also been used in the neoadjuvant setting, where they have been shown to achieve higher response rates than tamoxifen and to be more successful at downstaging tumours. Early results comparing an aromatase inhibitor with tamoxifen in the adjuvant setting in early breast cancer show anastrozole to be superior to tamoxifen in terms of both disease-free survival and a lower incidence of new contralateral tumours. There was also a more favourable side-effect profile, which has implications for potential future prophylactic treatment. Additionally, since aromatase inhibitors have different mechanisms of action, unlike antioestrogens, they may be particularly useful as chemopreventive agents if oestrogens are themselves genotoxic. Aromatase inhibitors have been used to date almost exclusively in postmenopausal women. The potential of combining them with luteinising hormone-releasing hormone analogues allows the possibility of treating premenopausal women with either oestrogen receptor-positive breast cancer or benign conditions such as cyclical breast pain, fibroadenomata, recurrent cystic disease or endometriosis. There is also the potential for their use in men with conditions such as gynaecomastia or prostate cancer. These new generation aromatase inhibitors may well have an increasing role in the future management of a number of conditions in addition to breast cancer.

Animals↗

PubMed2003

Safety issues surrounding the use of aromatase inhibitors in breast cancer.

Third generation aromatase inhibitors (AIs) are now established therapy in advanced oestrogen receptor (ER)-positive breast cancer. As the use of AIs expands to include adjuvant treatment of early breast cancer and breast cancer prevention, tolerability and effects on other organs such as bone will become as important as the antitumour properties of the drugs. In direct comparisons with tamoxifen, AIs have a better toxicity profile with fewer patients stopping therapy because of drug-related side effects. There is a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen. Although published information about the side effects of AIs is scarce, it is likely that they will have adverse effects on bone and possibly also on lipid metabolism. Subprotocols of ongoing adjuvant trials are investigating these effects. It is likely that the choice of which third generation AI to use will be largely determined by its tolerability and safety profile, since it is likely that the currently available drugs have similar efficacy.

Anastrozole↗

PubMed2002

Anastrozole ('Arimidex') blocks oestrogen synthesis both peripherally and within the breast in postmenopausal women with large operable breast cancer.

The effect of anastrozole on peripheral and tumour aromatase activity and oestrogen levels in postmenopausal patients with oestrogen receptor-rich breast tumours was investigated. Twenty-six patients were randomly allocated to treatment with anastrozole 1 mg (n=13) or 10 mg (n=13), once daily. Before and after 12 weeks' treatment, patients were infused with 3H-Delta4 androstenedione (20 MBq) and 14C-oestrone (E1) (1 MBq) for 18 h. Oestrogens were purified from excised tumours and plasma samples taken after each infusion. Peripheral and tumour aromatase activity and tumour E1 uptake were calculated from levels of 3H and 14C in purified E1 fractions from tumour and plasma. Endogenous tumour oestrogens were measured by radioimmunoassay. Twenty-three patients were available for analysis (1 mg group, n=12; 10 mg group, n=11). Following treatment, anastrozole (1 and 10 mg) markedly inhibited peripheral aromatase in all patients (the difference between pre- and on-treatment values being highly significant P<0.0001). In situ aromatase activity was also profoundly decreased by anastrozole treatment in 16 of 19 tumours (the difference with treatment also being highly significant P=0.0009). Most tumours were able to concentrate E1 beyond levels in the circulation; anastrozole treatment had no consistent effect on uptake of E1. Endogenous tumour levels of both E1 and oestradiol (E2) were significantly reduced with therapy (P=0.028 for E1 and P=0.0019 for E2). Anastrozole (1 and 10 mg daily) effectively suppresses aromatase activity, and subsequently oestrogen levels, within the breast tissue of postmenopausal women with large or locally advanced, operable, oestrogen receptor-rich breast cancers.

Aged↗

PubMed2002

Effect of neoadjuvant treatment with anastrozole on tumour histology in postmenopausal women with large operable breast cancer.

Anastrozole is an orally active, non-steroidal aromatase inhibitor which appears effective as neoadjuvant treatment of breast cancer. Histological changes have been evaluated in biopsies from large, oestrogen-receptor rich, operable breast tumours in postmenopausal women following 12 weeks of neoadjuvant anastrozole treatment (1 mg (n=12) or 10 mg (n=11)). Of the 23 patients, 18 had a clinical response following treatment. Compared with pre-treatment biopsies anastrozole-treated specimens displayed decreased cellularity and/or increased fibrosis in 15 tumours; changes in gland formation, nuclear pleomorphism, or mitoses, in 12 cases; and a reduction in Mib1 score in all tumours. Marked changes in apoptotic scores were seen following treatment but the direction of effect was inconsistent. In all 17 tumours which were positive for progesterone receptors before therapy, treatment was associated with reduced staining for progesterone receptors. There was no consistent effect of treatment on oestrogen-receptor expression. It is concluded that neoadjuvant anastrozole treatment in this patient group has marked effects on tumour histopathology but these do not always correlate with clinical response.

Aged↗

PubMed2002

Outcome after extended follow-up in a prospective study of operable breast cancer: key factors and a prognostic index.

In 1990, 215 patients with operable breast cancer were entered into a prospective study of the prognostic significance of five biochemical markers and 15 other factors (pathological/chronological/patient). After a median follow-up of 6.6 years, there were 77 recurrences and 77 deaths (59 breast cancer-related). By univariate analysis, patient outcome related significantly to 13 factors. By multivariate analysis, the most important of nine independent factors were: number of nodes involved, steroid receptors (for oestrogen or progestogen), age, clinical or pathological tumour size and grade. Receptors and grade exerted their influence only in the first 3 years. Progestogen receptors (immunohistochemical) and oestrogen receptors (biochemical) were of similar prognostic significance. The two receptors were correlated (r=+0.50, P=0.001) and displaced each other from the analytical model but some evidence for the additivity of their prognostic values was seen when their levels were discordant.

Biomarkers, Tumor↗

PubMed2002

Expression of oestrogen receptor beta (ERbeta1) protein in human breast cancer biopsies.

Oestrogen action is mediated via specific receptors that act as ligand-activated transcription factors. A monoclonal antibody specific to the C-terminus of human oestrogen receptor beta has been characterized and the prevalence of expression of oestrogen receptor beta protein investigated in a well defined set of breast cancers. Reverse transcription-polymerase chain reaction analysis of RNA from tissue biopsies detected oestrogen receptor beta in all samples examined. The anti-oestrogen receptor beta antibody cross reacted specifically with both long (approximately 59 Kd) and short (approximately 53 Kd) forms of recombinant oestrogen receptor beta. Western blot analysis of breast tumours contained both forms of oestrogen receptor beta protein although in some samples lower molecular weight species (32--45 Kd) were identified. Fifty-one breast cancer biopsies were examined using immunohistochemistry; 41 (80%) were immunopositive for oestrogen receptor alpha, 48 (94%) were immunopositive for oestrogen receptor beta and 38 (74.5%) co-expressed both receptors. Expression of oestrogen receptor beta was exclusively nuclear and occurred in multiple cell types. There was no quantitative relationship between staining for the two ERs although in tumours in which both receptors were present immunoexpression of oestrogen receptor alpha was invariably more intense. The significance of oestrogen receptor beta protein expression in breast cancers to therapy remains to be determined but the availability of a well characterized antibody capable of detecting oestrogen receptor beta in archive material will facilitate the process.

Antibodies, Monoclonal↗

PubMed2002

Neoadjuvant endocrine therapy of breast cancer: a surgical perspective.

Neoadjuvant treatment with chemotherapy or endocrine agents is being used increasingly to downstage locally advanced and large operable breast cancers. Following these treatments, inoperable breast cancer often becomes fully resectable, and initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise neoadjuvant endocrine therapy: only patients with oestrogen receptor (ER)-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most. Such patients can expect a high probability of responses over a 3-month treatment period. Response to therapy should be monitored by clinical examination as well as by ultrasound, mammography, or other imaging procedures. Third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen in this treatment setting. In a large randomised trial of neoadjuvant endocrine therapy in postmenopausal women, letrozole achieved significantly higher response rates than tamoxifen, and a correspondingly higher rate of breast-conserving surgery was possible in the letrozole-treated patients. There is some evidence to suggest that the nature of the tumour response is different for preoperative endocrine therapy compared with chemotherapy. This difference may result in a higher rate of complete tumour excisions following breast-conserving surgery after neoadjuvant endocrine treatment. There appears to be a low rate of subsequent local recurrence in patients having breast-conserving therapy after neoadjuvant endocrine therapy.

Antineoplastic Agents, Hormonal↗

PubMed2002

Local uptake and synthesis of oestrone in normal and malignant postmenopausal breast tissues.

Uptake and local formation of oestrone (E1) were studied in vivo by a double isotopic technique in normal and malignant breast tissues from 24 postmenopausal women with breast cancer. Active uptake of radio-labelled E1 beyond plasma was found both in normal and malignant tissue, the effect being significantly greater in non-malignant compared with cancer tissue. The presence of local E1 formation was also demonstrated in most samples. Both uptake and synthesis positively correlated with total amount of radioactive E1 found in the tissues. Uptake appeared to make a greater contribution to E1 levels within the breast than in situ synthesis, although there were marked variations between specimens from different patients and the relative proportion of synthesis to uptake was higher in tumour compared with non-malignant tissue. These results demonstrate quantitative differences in the different compartments by which postmenopausal breasts obtain oestrogen and highlight variations between individual breasts. This may be important in optimising oestrogen deprivation therapy for postmenopausal patients with hormone-dependent cancers.

Aged↗

PubMed2002

MIB-1 assessments in breast cancers.

The variability of MIB-1 measurements in breast cancer was assessed in histological sections from core and excision biopsies taken simultaneously in 13 cases and sequentially (with an intervening period of 2-3 weeks) in 17 cases. Results showed no significant differences in values between cores and sections, whether taken simultaneously or sequentially. Individual pairs of cores and sections occasionally demonstrated substantial differences. The mean ratio of MIB-1 scores between cores and sections was 0.97 [95% confidence interval (CI)=0.68-1.38]. However 95% confidence intervals for ratios within individuals were 0.14-6.68. Although the two samples can be equivalent on an average over numerous patients, they cannot be taken as equivalent within individuals. Severe heterogeneity complicates the assessment of MIB-1 in individual breast cancers and limits utility in monitoring changes in proliferation with treatment.

Journal Article↗

PubMed2002

Anti-tumor effects of letrozole.

The use of drugs, which inhibit estrogen biosynthesis, is an attractive treatment for postmenopausal women with hormone-dependent breast cancer. Estrogen deprivation is most specifically achieved using inhibitors which block the last stage in the biosynthetic sequence, i.e., the conversion of androgens to estrogens by the aromatase enzyme. Recently, a new generation of aromatase inhibitors has been developed. Among these, letrozole (Femara) appears to be the most potent. When given orally in milligram amounts per day to postmenopausal women, the drug almost totally inhibits peripheral aromatase and causes a marked reduction in circulating estrogens to levels that are often undetectable in conventional assays. Similarly, neoadjuvant studies demonstrate that letrozole substantially inhibits aromatase activity in both malignant and nonmalignant breast tissues, and markedly suppresses endogenous estrogens within the breast cancers. These studies also illustrate anti-estrogenic and anti-proliferative effects of letrozole in estrogen receptor (ER)-rich tumors. Thus, tumor expression of progesterone receptors and the cell-cycle marker Ki67 is significantly and consistently reduced with treatment. Additionally, clear pathological responses as evidenced by decreased cellularity and increased fibrosis are seen in the majority of cases. These results translated into clinical benefit in a series of 24 breast cancers treated neoadjuvantly with letrozole (either 2.5 or 10 mg): tumor volume reductions > 25% were observed in 23 women, and > 50% reductions in 18 patients. Pathological and clinical effects are seen much more consistently than with tamoxifen. Thus, in a multicenter randomized trial of letrozole vs. tamoxifen (PE 024), clinical study outcomes were superior for letrozole in comparison with tamoxifen with regard to overall tumor response and an increase in the proportion of patients treated by breast conserving surgery. Letrozole has also been used in advanced breast cancer, both as second-line hormone treatment following tamoxifen failure, and more recently as first-line therapy. Trials of second-line treatment in which letrozole has been compared with either older aromatase inhibitors or progestins have shown equivalent or superior clinical activity and improved tolerability favoring letrozole. In first-line comparison with tamoxifen in metastatic disease, a phase III trial of over 900 postmenopausal women showed letrozole to be significantly better than tamoxifen in terms of overall tumor response rates, clinical benefit, and time to treatment failure. In summary, letrozole is an exceptionally potent and specific endocrine agent. In patients with ER-rich tumors, high rates of pathological and clinical response have been documented, and large phase III trials against established treatments such as tamoxifen and progestin suggest superior (or at least equivalent) clinical efficacy. Letrozole is a drug of immense potential and in the future is likely to occupy a central role in the management of postmenopausal women with hormone-dependent breast cancer.

Antineoplastic Agents↗

PubMed2002

Regulatory subunits of PKA and breast cancer.

Overexpression of the R subunits of PKA (in particular, RI) is associated with high proliferation in normal breast, malignant transformation in the breast, poor prognosis in established breast cancer, and resistance to antiestrogens. These data, together with the observation that successful antiestrogen therapy is associated with reduced expression of RI mRNA, suggest that targeting R subunits is an appropriate therapeutic strategy for breast cancer. Initial experimental results, using antisense RI oligonucleotides, are promising in terms of reducing the growth rate of breast cancer cells and xenografts. While clinical trials designed to target RI subunits have yet to be established (and interventions as preventative measures are even more distant), the concept of these approaches to prevent and treat breast cancer should be developed and exploited.

Breast↗

PubMed2002

Atheists, agnostics and Alcoholics Anonymous.

OBJECTIVE: In spite of the strong emphasis in AA on spiritual beliefs and practices, findings are mixed about the importance of such beliefs in predicting AA affiliation. This study of the Project MATCH outpatient (N = 952) and aftercare (N = 774) samples tested three hypotheses about the role of client God belief and subsequent AA attendance and benefit, taking into account that some individuals may, in fact, deny the existence of a God. METHOD: Longitudinal analyses were conducted (N = 1,526) investigating client God beliefs, AA attendance, patterns of AA attendance and alcohol use. Assessments were conducted at intake and in 3-month intervals using the Form 90, Religious Behaviors and Background, and the Alcoholics Anonymous Inventory. RESULTS: 12-Step treatment was significantly more likely to promote pre-post shifts in client God beliefs, and atheist and agnostic clients attended AA significantly less often throughout follow-up relative to clients self-labeled as spiritual and religious. AA attendance, however, was significantly associated with increased abstinence and reductions in drinking intensity regardless of God belief. Finally, no differences in percent days abstinence and drinking intensity were found between atheist and agnostic versus spiritual and religious clients, but clients unsure about their God belief reported significantly higher drinking frequency relative to the other groups. CONCLUSIONS: God belief appears to be relatively unimportant in deriving AA-related benefit, but atheist and agnostic clients are less likely to initiate and sustain AA attendance relative to spiritual and religious clients. This apparent reticence to affiliate with AA ought to be clinically recognized when encouraging AA participation.

Adult↗

PubMed2001

Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.

PURPOSE: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively. PATIENTS AND METHODS: Postmenopausal patients with estrogen- and/or progesterone receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria. RESULTS: For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer patients underwent breast conservation (36%, P =.036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004). CONCLUSION: ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.

Antineoplastic Agents↗

PubMed2001

A multiple risk factor approach for predicting DWI recidivism.

A sample of DWI (driving while impaired) offenders was studied to compare various approaches for predicting reoffenses over a 4-year period. Logistic regression yielded multivariate predictor equations that were significant statistically, but were not helpful to clinicians in assessing risk for reoffending. As a different approach, five predictor variables that were consistently correlated with reoffense status were examined to determine the cut score at which the repeat offense rate exceeded the base rate. These were combined to yield the number of risk factors (from 0 to 5) for each offender. This method, used for the original and a hold-out sample, yields results as accurate as those derived from a logistic regression model that includes all the risk variables, and allows clinicians to classify offenders into low and high risk categories in a straightforward manner. Nearly half of offenders with four or five risk factors (age, years of education, arrest blood alcohol concentration (BAC), score on the receptive area scale of AUI and raw score on the MacAndrews scale of MMPI-2) were rearrested compared to the base rate (25%). However, this method is not sufficiently precise to accurately predict which individuals will and will not be rearrested. Although generalizability of specific algorithms across populations needs to be examined, this method appears promising as a clinically accessible way to classify, in a given offender population, those who are most likely to repeat the offense.

Adult↗

PubMed2001

The relative importance of proliferation and cell death in breast cancer growth and response to tamoxifen.

Changes in tumour volume depend on the relative balance between cell proliferation and cell loss. However, these processes are not independent, and it remains unclear which is more important in tumour progression and regression. For example, the anti-oestrogen tamoxifen, a mainstay in the therapy of breast cancer, has both antiproliferative and pro-apoptotic actions, and their relative importance in clinical efficacy is unknown. Thus, using a model system based on oestrogen receptor (ER)-positive ZR-75-1 breast cancer xenografts, both increased apoptosis and reduced proliferation have been previously shown to occur within 7 days of tamoxifen therapy (Cameron DA, Ritchie AA, Langdon S, Anderson TJ, Miller WR. Tamoxifen induced apoptosis in ZR-75 breast cancer xenografts antedates tumour regression. Breast Cancer Res Treat 1997, 45, 99--107). In the present study, Gompertzian growth curves have been fitted to individual breast cancer xenografts. This demonstrates that the growth rate of the untreated tumours is directly dependent only on the mitotic rate (P<0.001), whereas tumour response to tamoxifen correlates most strongly (P< 0.001) with the relative balance between apoptosis and mitosis, as evidenced by the apoptotic:mitotic ratio.

Animals↗

PubMed2001

Pharmacokinetics and metabolism of formestane in breast cancer patients.

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.

Aged↗

PubMed2001

Local endocrine effects of aromatase inhibitors within the breast.

To determine the effects of aromatase inhibitors on oestrogen uptake, in situ aromatase activity and endogenous oestrogens in the breast, postmenopausal women with large primary ER-rich breast cancers have been treated neoadjuvantly for 3 months with either letrozole (2.5 or 10mg daily) or anastrozole (1 or 10mg daily) or exemestane (25mg daily). Patients were given an infusion of 3H-androstenedione and 14C-oestrone for 18h before and at the end of the study period. Blood, tumour and non-malignant breast were taken immediately after each infusion; oestrogens were extracted and purified. Tumour volume was measured before and during treatment at monthly intervals so that endocrinological changes could be related to clinical response. Treatment with each of the aromatase inhibitors was associated with a profound reduction in peripheral aromatase (as monitored by the level of plasma 3H-oestrone). There was no consistent effect on uptake of radioactively labelled oestrogen into breast tumours but a tendency for levels to increase after treatment in non-malignant breast. Conversely, therapy was associated with a marked inhibition of in situ oestrogen synthesis in both tumour and non-malignant breast (in occasional tissues, inhibitors appeared to be less effective but the effect was not related to clinical or pathological responses). Similar decreases were apparent in endogenous levels of oestrone and oestradiol. The absence of in situ aromatase activity tended to be associated with lack of clinical response to aromatase inhibition but the relationship was not absolute, limiting the utility of measurements of tumour aromatase as a predictive indices. Ex vivo studies of tissue aromatase indicated that such measurements consistently underestimate the inhibitory potential of reversible non-steroidal agents (and occasionally paradoxical in vitro increases in aromatase activity were seen with treatment). However, in situ assays demonstrate that new aromatase inhibitors such as anastrozole, exemestane and letrozole have profound effects on the local endocrinology within the postmenopausal breast, these being compatible with the clinico-pathological changes which occur with treatment.

Anastrozole↗

PubMed2001

Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.

Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers.

Anastrozole↗