Breast cancer and aging: results of the U13 conference breast cancer panel.

Breast cancer is predominantly a disease of older women, yet there is a knowledge gap due to the persisting misalignment between the age distribution of women with breast cancer and the age distribution of participants in clinical trials. The purpose of this report is to state the U13 conference breast cancer panel's recommendations regarding therapeutic clinical trials that will fill gaps in knowledge regarding the care of older patients with breast cancer. The U13 conference was a collaboration between the Cancer and Aging Research Group and the National Institute on Aging and the National Cancer Institute (NCI). Clinical trials should be developed for frail and vulnerable patients who would not enroll on the standard phase III trials, as well as efforts need to be made to increase enrollment of fit older patients on standard phase III trials. As a result of this conference, panel members are working with the NCI and cooperative groups to address these knowledge gaps. With the aging population and increasing incidence of breast cancer with age, it is essential to study the feasibility, toxicity, and efficacy of cancer therapy in this at-risk population.

Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score.

Tamoxifen (Tam), the major drug for estrogen receptor (ER)-positive breast cancer, is converted to its active metabolites, Z- and Z'-endoxifen and 4-OH-Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20 mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z-endoxifen levels increased while Z'-endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P ≤ 0.0004). The dosage in patients with endoxifen <40 nmol/l and/or CYP2D6 MPA scores of 0 was increased to 30 mg/day and their metabolite isomers were monitored for up to 90 days. Of the 24 patients on the increased dose, 90% showed an increase in active isomers by day 60; the rate of increase correlated with the MPA score. Notably, their antiestrogenic activity scores (AASs), which estimate total isomer biologic activity, increased from a baseline median of 17 to 26 at day 60. Further studies involving increasing/decreasing the Tam dosage based on the AAS may determine whether dose adjustment can optimize treatment and improve long-term survival.

The hedgehog pathway as a therapeutic target for treatment of breast cancer.

The Hedgehog (Hh) signaling pathway plays a key role in a variety of processes, such as embryogenesis and maintenance of adult tissue homeostasis. It is also becoming increasingly clear that this pathway can have a crucial role in tumorigenesis. Most recently, the Hh signaling pathway has been implicated in the development and maintenance of breast cancer. Here we review Hh signaling, advances in small molecule and antibody-based inhibitors targeting the Hh pathway, and dysregulation of the Hh signaling pathway in breast cancer.

The heat shock protein 90 chaperone complex: an evolving therapeutic target.

Hsp90 (heat shock protein 90) is a molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory, metabolism, organization, and signaling proteins. Binding to Hsp90 is required for normal function of many proteins. In addition, Hsp90 has an extra-cellular function. It is found in two isotypes: alpha which is inducible and beta which is constitutive. Tumor cells frequently over express Hsp90alpha, and Hsp90 is implicated in cancer progression. Hence Hsp90 has emerged as a potential target for cancer treatment. A variety of agents have been found to interfere with Hsp function, mainly by binding to an ATP binding site on the molecule. More recent agents interfere with protein binding or the dimerization of Hsp90 needed for function. Preclinical studies have demonstrated that disruption of the many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. As a result, agents which interfere with this protein's function are being tested in the clinic as a targeted method of interfering with malignant growth. We review the current clinical status of therapeutic efforts to perturb this pathway and discuss future directions.

Implications of applied research for prognosis and therapy of breast cancer.

Breast cancer is the one of leading causes of cancer-related deaths in women within economically developed regions of the world. The heterogeneity of the natural history of breast cancer complicates patient management in that there is tremendous variability in response to treatment and for survival. More recently, several biomarkers (hormone receptor status and HER2 expression) have been added to the risk evaluation and therapeutic assessments. Evolving knowledge of molecular biology and newer techniques, such as genomics and proteomics, offer the potential to better define the biologic nature of the disease process, both for risk and therapy. This review discusses classical as well as new prognostic and predictive techniques. These are leading to a paradigm shift from empirical treatment to an individually tailored approach, which may soon become a realistic option for patients, based on specific molecular profiles.

Heparin-induced thrombocytopenia complicating hemodialysis.

Hemodialysis complicated by heparin-induced thrombocytopenia (HIT) is a rare event requiring anticoagulation with direct-thrombin inhibitors. Contaminant calcific uremic arteriolopathy (calciphylaxis) further complicates this situation due to the possibility that warfarin anticoagulation may exacerbate skin necrosis. The authors report a patient with renal failure and calciphylaxis who developed HIT after starting hemodialysis. She was successfully treated with Argatroban.