Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

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International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate : A meta-analysis of 1446 patients

OBJECTIVE: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.Peer reviewe

Cervical Screening at Age 50-64 Years and the Risk of Cervical Cancer at Age 65 Years and Older: Population-Based Case Control Study

This work was supported by Cancer Research UK [C8162/10406 and C8162/12537]

Fusarium graminearum gene deletion mutants map1 and tri5 reveal similarities and differences in the pathogenicity requirements to cause disease on Arabidopsis and wheat floral tissue

The Ascomycete pathogen Fusarium graminearum can infect all cereal species and lower grain yield, quality and safety. The fungus can also cause disease on Arabidopsis thaliana. In this study, the disease-causing ability of two F. graminearum mutants was analysed to further explore the parallels between the wheat (Triticum aestivum) and Arabidopsis floral pathosystems. Wild-type F. graminearum (strain PH-1) and two isogenic transformants lacking either the mitogen-activated protein kinase MAP1 gene or the trichodiene synthase TRI5 gene were individually spray- or point-inoculated onto Arabidopsis and wheat floral tissue. Disease development was quantitatively assessed both macroscopically and microscopically and deoxynivalenol (DON) mycotoxin concentrations determined by enzyme-linked immunosorbent assay (ELISA). Wild-type strain inoculations caused high levels of disease in both plant species and significant DON production. The map1 mutant caused minimal disease and DON accumulation in both hosts. The tri5 mutant, which is unable to produce DON, exhibited reduced pathogenicity on wheat ears, causing only discrete eye-shaped lesions on spikelets which failed to infect the rachis. By contrast, the tri5 mutant retained full pathogenicity on Arabidopsis floral tissue. This study reveals that DON mycotoxin production is not required for F. graminearum to colonize Arabidopsis floral tissue

Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the ‘Arimidex™ and Tamoxifen Alone or in Combination’ (ATAC) trial

The ATAC trial evaluates in a randomized, double-blind design, Arimidex™ (anastrozole) alone or in combination with tamoxifen, relative to tamoxifen alone as 5-year adjuvant treatment in postmenopausal women with early breast cancer. Patients included in the pharmacokinetic (PK) sub-protocol had been in ATAC for ≥3 months, taking their medication in the morning and were 100% compliant for the preceding 14 days. Blood samples were collected 24 ± 4 h after last dose. Trough (Cmin) plasma concentrations of anastrozole, tamoxifen and desmethyltamoxifen (DMT) were measured by validated methods. The PK results were based on a total of 347 patients (131 anastrozole (1 mg o.d.), 111 tamoxifen (20 mg o.d.), 105 anastrozole and tamoxifen (1 and 20 mg o.d. respectively)). The geometric mean steady-state trough plasma concentrations of tamoxifen and DMT were statistically equivalent in patients receiving tamoxifen alone or in combination with anastrozole: geometric mean tamoxifen = 94.8 ng ml−1and 95.3 ng ml−1in tamoxifen alone and combination groups, respectively; geometric mean DMT = 265.1 and 277.6 ng ml−1in the tamoxifen and anastrozole and tamoxifen groups, respectively. The geometric mean anastrozole levels were 27% lower (90% Cl 20–33%;P< 0.001) in the presence of tamoxifen than with anastrozole alone. Baseline plasma oestradiol levels were not obtained in the PK sub-protocol, however, such information was available from a similar ATAC sub-protocol, which evaluated bone mineral density. Mean oestradiol levels were 21.3, 19.3, and 21.6 pmol l−1prior to treatment and 3.7, 20.9 and 3.6 pmol l−1after 3 months in the anastrozole, tamoxifen, and combination groups, respectively (n = 167). On-treatment values were below the detection limit (3 pmol l−1) in 43.6 and 38.5% of the anastrozole alone and anastrozole in combination with tamoxifen groups, respectively. As a result of (a) the lack of effect of anastrozole on tamoxifen and DMT levels and (b) the observed fall in blood anastrozole levels having no significant effect on oestradiol suppression by anastrozole, we conclude that the observed reduction in anastrozole levels by tamoxifen is unlikely to be of clinical significance when anastrozole and tamoxifen are administered together. © 2001 Cancer Research Campaign http://www.bjcancer.co

Anastrozole-Induced Carpal Tunnel Syndrome: Results From the International Breast Cancer Intervention Study II Prevention Trial

Supported in part by Cancer Research UK (C569/A5032) and the National Health and Medical Research Council Australia (GNT300755, GNT569213), and in part by AstraZeneca, who also provided anastrozole and matching placebo. This study was sponsored by Queen Mary University of London, London, United Kingdom

Participant-Reported Symptoms and Their Effect on Long-Term Adherence in the International Breast Cancer Intervention Study I (IBIS I)

Purpose: To assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I). IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the disease. Participants and Methods: Women were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279). After 456 exclusions, 3,823 women were included in this analysis. Adherence (< 4.5 years or ≥ 4.5 years) was calculated using data from six monthly clinical visits. Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatment. Results: Overall, 69.7% of women were adherent for at least 4.5 years (tamoxifen: 65.2% v placebo: 74.0%; P .05). In both treatment arms, we observed significant trends for lower adherence with increasing severity for all symptoms (P < .01) except headaches (P = .054). Conclusion: In the IBIS-I trial, experiencing predefined symptoms in the first 6 months reduced long-term adherence. Effects were similar between treatment arms, suggesting that women were attributing age-related symptoms to preventive therapy. Interventions were required to support symptom management

Barriers to preventive therapy for breast and other major cancers and strategies to improve uptake.

The global cancer burden continues to rise and the war on cancer can only be won if improvements in treatment go hand in hand with therapeutic cancer prevention. Despite the availability of several efficacious agents, utilisation of preventive therapy has been poor due to various barriers, such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. In this review, we discuss these barriers in detail and propose strategies to overcome them. These strategies include improving physician awareness and countering prejudices by highlighting the important differences between preventive therapy and cancer treatment. The importance of the agent-biomarker-cohort (ABC) paradigm to improve effectiveness of preventive therapy cannot be overemphasised. Future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms, and improvements in the safety profile of existing agents by experimentation with dose. We also highlight the role of drug repurposing for providing new agents as well as to address the current imbalance between therapeutic and preventive research. In order to move the field of therapeutic cancer prevention forwards, engagement with policymakers to correct research imbalance as well as to remove practical obstacles to implementation is also urgently needed.This study was partially supported by Gruppo Bancario Credito Valtellinese, and Cancer Research UK programme award (C569/A16891). Smith is supported by a Cancer Research UK Postdoctoral Fellowship (C42785/A17965)