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Biomedical subjects

Anthony Howell

Publications and source records attributed to Anthony Howell.

At least 55 records · Page 3Linked to original sources
PubMed2004

Strategies for managing breast cancer risk after the menopause.

Postmenopausal women in Western societies are conscious of breast cancer as a potential cause of death and ill health, which they wish to avoid with the advice of their doctors. Yet many factors that predispose women to the development of cancer will have been laid down before the menopause, in their genetic makeup or during their adolescent years. Even in middle age it is important to take account of the intrinsic level of risk, and to give women advice tailored to their own individual risk level. This results from their family history, previous diseases such as benign breast disease, and previous treatment for breast cancer or Hodgkin's disease. For those at the highest level of risk, strategies will include regular screening, prophylactic mastectomy, and the use of chemoprevention agents, such as tamoxifen. These women should avoid hormone replacement therapy (HRT) and control their menopausal symptoms and osteoporosis through the use of other agents now available - venlafaxine for menopausal symptoms and bisphosphonates for osteoporosis. Raloxifene is an agent under trial that may be valuable for breast cancer control as well as for osteoporosis. Women at standard population risk will require less robust preventive strategies, which will include screening and lifestyle modification. Their decisions regarding HRT should now be modified by recent evidence of associated risks. Recent studies show that tibolone causes less mammographic density and has a lower relative risk of breast cancer than combined estrogen/progestogen preparations. There is limited evidence that controlling obesity, participating in exercise and adopting a diet low in fats and high in fruit and vegetables will alter risk at this age. These precautions will, however, reduce the risk of other diseases common in this age group, such as hypertension, heart disease, stroke, and type 2 diabetes mellitus. Alcohol, even in small amounts, is a risk factor for breast cancer. Given the cardioprotective effect of moderate alcohol intake, advice on alcohol must reflect the individual relative risk of cardiovascular disease and breast cancer. Personal risk assessment is relevant for all women. Screening and a healthy lifestyle are worthwhile approaches for all, with the more aggressive approaches such as chemoprevention and prophylactic surgery reserved for those who have substantially elevated levels of risk. Once the menopause has passed, screening is probably the most effective evidence-based tool for breast cancer control by early diagnosis.

Breast Neoplasms↗
PubMed2003

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.

BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma.

Bone Diseases↗
PubMed2003

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials.

BACKGROUND: Fulvestrant (ICI 182,780) is a new type of estrogen receptor (ER) antagonist that down-regulates the ER and has no known agonist effects. The authors report the prospectively planned combined analysis of data from 2 Phase III trials comparing fulvestrant 250 mg monthly (n=428) and anastrozole 1 mg daily (n=423) in postmenopausal women with advanced breast carcinoma (ABC) who previously had progressed after receiving endocrine treatment. METHODS: The primary endpoint was time to progression (TTP). Secondary endpoints included objective response (OR), duration of response (DOR), and tolerability. The trials were designed to demonstrate superiority of fulvestrant over anastrozole. Noninferiority of fulvestrant versus anastrozole was determined using a retrospectively applied statistical test. RESULTS: At a median follow-up of 15.1 months, approximately 83% of patients in each treatment arm had progressed. The median TTP was 5.5 months in the fulvestrant group and 4.1 months in the anastrozole group, and the OR rates were 19.2% and 16.5% for fulvestrant and anastrozole, respectively (although the difference between treatments was not statistically significant). In patients who responded, further follow-up (median, 22.1 months) was performed to obtain more complete information on DOR; the median DOR (from randomization to disease progression) in patients who responded to treatment was 16.7 months in the fulvestrant group and 13.7 months in the anastrozole group. In a statistical analysis of DOR (using all randomized patients; from the start of response to disease progression), DOR was significantly longer for patients in the fulvestrant group compared with patients in the anastrozole group. Both drugs were tolerated well; withdrawals due to drug-related adverse events were 0.9% and 1.2% in the fulvestrant group and the anastrozole group, respectively. The incidence of joint disorders was significantly lower in the fulvestrant group (P=0.0036). CONCLUSIONS: Fulvestrant was tolerated well and was at least as effective as anastrozole in the second-line treatment of patients with ABC. This new hormonaltherapy may provide a valuable treatment option for ABC in postmenopausal women.

Adult↗
PubMed2003

International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations.

Primary systemic therapy (PST) represents the standard of care in patients with locally advanced breast cancer. In addition, there is increasing information on PST in operable breast disease that supports the use of PST in routine practice. However, current regimens and techniques vary. To address this concern, a group of representatives from breast cancer clinical research groups in France, Germany, Italy, the United Kingdom, and the United States reviewed all available data on prospective randomized trials in this setting. Recommendations are made regarding terminology, indications, regimen, diagnosis before treatment, monitoring of efficacy, tumor localization, surgery, pathologic evaluation, and postoperative treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

New approaches to the endocrine prevention and treatment of breast cancer.

All major endocrine prevention approaches act via the estrogen receptor (ER). A simple hypothesis concerning ER expression and breast cancer risk is outlined. We review breast cancer prevention trials with tamoxifen, raloxifene, aromatase inhibitors, and ovarian suppression. Current and planned endocrine prevention trials in populations of pre- and postmenopausal women at risk of breast cancer are summarized and endocrine therapy after primary surgery and for advanced disease discussed.

Breast Neoplasms↗
PubMed2003

Bayesian evaluation of breast cancer screening using data from two studies.

The mean sojourn time (the duration of the period during which a cancer is symptom free but potentially detectable by screening) and the screening sensitivity (the probability that a screen applied to a cancer in the preclinical screen detectable period will result in a positive diagnosis) are two important features of a cancer screening programme. Little data from any single study are available on the potential effectiveness of mammographic screening for breast cancer in women with a family history of the disease, despite this being an important public health issue. We develop a method of estimation, from two separate studies, of the two parameters, assuming that transition from no disease to preclinical screen detectable disease, and from preclinical disease to clinical disease, are Poisson processes. Estimation is performed by a Markov chain Monte Carlo algorithm. The method is applied to the synthesis of two studies of mammographic screening in women with a family history of breast cancer, one in Manchester and one in Kopparberg, Sweden.

Adult↗
PubMed2003

Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.

We assessed whether split dosing with the methylating agent DTIC is an effective strategy for inactivating the DNA repair protein O6-alkylguanine DNA-ATase in order to decrease tumour resistance to BCNU. ATase levels in PBMCs were used as a surrogate for tumour ATase depletion to determine whether this correlated with either the pharmacokinetics of DTIC and its major metabolite AIC or other clinical sequelae. Two 1 hr infusions of DTIC (400 mg/m(2)) 4 hr apart followed another 4 hr later by BCNU (75 mg/m(2)) were administered every 6 weeks in 7 patients with heavily pretreated advanced breast cancer. The extent and kinetics of ATase depletion and recovery in PBMCs varied not only between patients but also between cycles in the same patient. Serial FNAs showed heterogeneity in tumour ATase expression but no clear pattern of change in ATase activity. DTIC and AIC exhibited biphasic clearance from the blood, consistent with a 2-compartment pharmacokinetic model. The AUC of AIC was strongly correlated with the percentage decrease in PBMC ATase levels. There were no clinical responses, and toxicity in neutrophils and platelets was marked. Split-dose DTIC therefore does not appear to be a clinically effective approach to overcome O(6)-alkylating agent resistance in advanced breast cancer.

Adult↗
PubMed2003

Regulation of human breast epithelial stem cells.

Breast epithelial stem cells are thought to be the primary targets in the aetiology of breast cancer. As breast cancers are predominantly oestrogen and progesterone receptor-positive (ERalpha/PR+), we investigated the biology of ERalpha/PR+ cells and their relationship to stem cells in normal human breast epithelium. Several complementary approaches were used to characterize the stem-cell population and relate it to ERalpha/PR+ cells, including dual label colocalization on tissue sections, isolation of a Hoechst dye-effluxing 'side population' using flow cytometry, and examination of DNA label retention. The intermediate or suprabasal population suggested by others to be breast stem cells comprises ERalpha/PR+ cells that coexpress the putative stem-cell markers including cytokeratin 19. Human breast epithelial cells with Hoechst dye-effluxing 'side population' properties characteristic of mammary stem cells in mice were demonstrated by lack of expression of myoepithelial and luminal cell-specific antigens such as CALLA and MUC1 to be undifferentiated cells. Using DNA radiolabelling of human tissue implanted into athymic nude mice, a population of label-retaining putative stem cells (LRC) were shown to be enriched for cells expressing the putative stem-cell markers p21CIP1/WAF1 and Musashi-1, which, interestingly, were expressed in separate subpopulations of ERalpha/PR+ cells. Finally, expression patterns of Musashi-1 and Notch-1 in relation to ERalpha/PR+ and adjacent proliferating cells suggest that the evolutionarily conserved Delta/Notch signalling pathway regulates asymmetric division of the putative stem-cell population. The data suggest a model in which ERalpha/PR+ cells scattered through the epithelium are stem cells that self-renew through asymmetric cell division and generate patches of transit amplifying and differentiated cells. ERalpha/PR+ breast cancers exhibit loss of the two key regulators of asymmetric cell division, Musashi-1 and Notch-1 and thus may arise from symmetric division of the ERalpha/PR+ stem cell.

Breast↗
PubMed2003

Do women understand the odds? Risk perceptions and recall of risk information in women with a family history of breast cancer.

OBJECTIVES: To describe and compare women's risk perceptions and recall of breast cancer risk information in a cohort of first-time attendees at a family history clinic. METHODS: We conducted a 1-year prospective study of 158 women aged 18-45 years with a confirmed lifetime risk of breast cancer of 1 in 6 or greater. Risk perception and recall were assessed using a self-report questionnaire, completed pre-counselling and 3, 6, 9 and 12 months post-counselling, and through interviews conducted at 3 and 12 months. RESULTS: The proportion of women with accurate personal risk perceptions based on 'gambling' odds ('1 chance in x') significantly improved after risk counselling from 12% pre-counselling to 67% 3 months post-counselling (p < 0.001), which was maintained for 1 year. This was the method of reporting perceived risk associated with the best level of risk accuracy and the women's preferred format for describing risk, but the concept of lifetime risk was understood by only 44% of women. Qualitative risk categories ('high', moderate' or 'low') correlated significantly with women's self-reported odds values, but each category comprised a wide range of women's perceived numeric risks. Describing risk as the 'likelihood of breast cancer' resulted in a broad and somewhat inaccurate reporting of risk, compared with numeric ratings made at the same time. There was an increase of up to 4-fold in the proportion of women who failed to recall their risk value over time, and women were unable to accurately put the breast cancer risk in context compared with other health threats. CONCLUSIONS: All methods of describing risk have limitations, but the results of the present study provide good support for women's accurate recall of numeric risk values and their preference for use of these 'gambling' odds. This may have been influenced by consistency of the use of this method both in risk communication and in personal summary letters. Descriptive risk formats reflected higher levels of perceived vulnerability to breast cancer, and genetic counsellors need to be aware of these different perceptions.

Adolescent↗
PubMed2002

Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy.

Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaN0) and 26% had cancer with spread (CaN+). Five-year survival was 100% for CIS, 94% for CaN0 and 72% for CaN+ (p = 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaN0 patients, mutation carriers had 75% 5-year disease-free survival vs. 96% for noncarriers (p = 0.01). Twenty-one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but 1 relapse occurred in the 15 who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p = 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking.

Adult↗
PubMed2002

Fulvestrant (Faslodex): current status in the therapy of breast cancer.

Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation. It appears to act as a pure antiestrogen and exhibits none of the negative side effects associated with the partial agonist activity of tamoxifen. It has been shown to be as effective as the oral aromatase inhibitor anastrozole in postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy, principally tamoxifen. It therefore provides the clinician with an alternative therapeutic strategy following the development of tamoxifen resistance. Fulvestrant might also have potential as a follow-on therapy after tamoxifen in an adjuvant setting and help alleviate some of the concerns surrounding long-term (up to 5 years) tamoxifen therapy.

Animals↗
PubMedDate not supplied

A roundtable discussion of aromatase inhibitors as therapy for breast cancer.

This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease.

Anastrozole↗