Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.

Sununary 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. Breast cancer is the most common malignancy among women in the western hemisphere. Many of these patients develop metastatic disease, for which no cure is currently available. Because endocrine treatment causes fewer side-effects than chemotherapy, such therapy is first-line treatment in patients with metastatic disease and hormone receptor-positive tumours. While the anti-oestrogen tamoxifen is first choice of therapy in post-menopausal patients with metastatic breast cancer. increasing use of tamoxifen as adjuvant therapy focuses on the need for alternative endocrine treatment options on relapse in breast cancer patients.While ovarian oestrogen synthesis ceases at the menopause, oestrogens are synthesised in peripheral tissue from circulating androgens by the process called aromatisation (Grodin et al., 1973). The main pathway is conversion of androstenedione (A) into oestrone (El), with a minor contribution from conversion of testosterone into oestradiol (E2) (L0nning et al., 1990).Aromatase inhibitors are drugs that inhibit the peripheral conversion of androgens to oestrogens (Santen et al., 1982a), thereby suppressing plasma oestrogen levels in postmenopausal women. The first-generation aromatase inhibitor, aminoglutethimide, was implemented in breast cancer treatment more than 20 years ago (Cash et al., 1967). While the drug is effective in hormone-sensitive breast cancer, lack of specificity (inhibition of adrenal steroid-synthesising enzymes) and side-effects (such as skin rash and lethargy) provoked the development of new aromatase inhibitors (Coombes et al., 1984;Evans et al., 1992;Johnston et al., 1994;Lipton et al., 1995; Santen et al., 1989).Anastrozole (Arimidex; 2,2'[5-(1H-1 ,2,4-triazol-1-ylmethyl) -1,3-phenylene]bis-(2-methylpropiononitrile, Figure 1) is a new, potent and selective aromatase inhibitor belonging to the triazole class. Pilot studies in post-menopausal women have shown the drug to suppress plasma E2 by > 80% (Plourde et al., 1994), and preclinical studies as well as observations in women suggest the drug to be highly specific with no influence on adrenal steroid synthesis (Plourde et al., 1995). A major problem in evaluating the biochemical efficacy of aromatase inhibitors has been the lack of internal consistency between the percentage aromatase inhibition and degree of plasma oestrogen suppression. While aminoglutethimide as well as the second-generation aromatase inhibitor formestane and the third-generation inhibitor fadrozole (L0nning et al., 1991) ...

IntroductionExperimental and clinical data show that the oral bisphosphonate clodronate (Bonefos®) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival.Methods1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated.ResultsOral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event.ConclusionThese results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.

Although molecular prognostics in breast cancer are among the most successful examples of translating genomic analysis to clinical applications, optimal approaches to breast cancer clinical risk prediction remain controversial. The Sage Bionetworks–DREAM Breast Cancer Prognosis Challenge (BCC) is a crowdsourced research study for breast cancer prognostic modeling using genome-scale data. The BCC provided a community of data analysts with a common platform for data access and blinded evaluation of model accuracy in predicting breast cancer survival on the basis of gene expression data, copy number data, and clinical covariates. This approach offered the opportunity to assess whether a crowdsourced community Challenge would generate models of breast cancer prognosis commensurate with or exceeding current best-in-class approaches. The BCC comprised multiple rounds of blinded evaluations on held-out portions of data on 1981 patients, resulting in more than 1400 models submitted as open source code. Participants then retrained their models on the full data set of 1981 samples and submitted up to five models for validation in a newly generated data set of 184 breast cancer patients. Analysis of the BCC results suggests that the best-performing modeling strategy outperformed previously reported methods in blinded evaluations; model performance was consistent across several independent evaluations; and aggregating community-developed models achieved performance on par with the best-performing individual models.