Human epidermal growth factor receptor family-targeted therapies in the treatment of HER2-overexpressing breast cancer.

Breast cancer characterized by overexpression of human epidermal growth factor receptor 2 (HER2) has been associated with more aggressive disease progression and a poorer prognosis. Although an improved understanding of breast cancer pathogenesis and the role of HER2 signaling has resulted in significant survival improvements in the past 20 years, resistance to HER2-targeted therapy remains a concern. A number of strategies to prevent or overcome resistance to HER2-targeted therapy in breast cancer are being evaluated. This article provides a comprehensive review of (a) the role of HER2 signaling in breast cancer pathogenesis, (b) potential receptor and downstream therapeutic targets in breast cancer to overcome resistance to HER2-targeted therapy, and (c) clinical trials evaluating agents targeting one or more members of the HER family and/or downstream pathways for the treatment of breast cancer, with a focus on metastatic disease.

Ovarian cancer: opportunity for targeted therapy.

Ovarian cancer is a common cause of cancer mortality in women with limited treatment effectiveness in advanced stages. The limitation to treatment is largely the result of high rates of cancer recurrence despite chemotherapy and eventual resistance to existing chemotherapeutic agents. The objective of this paper is to review current concepts of ovarian carcinogenesis. We will review existing hypotheses of tumor origin from ovarian epithelial cells, Fallopian tube, and endometrium. We will also review the molecular pathogenesis of ovarian cancer which results in two specific pathways of carcinogenesis: (1) type I low-grade tumor and (2) type II high-grade tumor. Improved understanding of the molecular basis of ovarian carcinogenesis has opened new opportunities for targeted therapy. This paper will also review these potential therapeutic targets and will explore new agents that are currently being investigated.

Early breast and prostate cancer and clinical outcomes (fracture).

Osteoporosis is a skeletal disorder characterized by low bone mass that is associated with increased risk of fracture. Nearly 40% of the 12 million cancer survivors in the United States were diagnosed with breast and prostate cancer. Therapy for these two diseases is not uncommonly associated with bone loss related to hormone-ablative therapy. In women, this includes the use of endocrine therapies and chemotherapy-related premature menopause. In men, hormone-ablative therapies include gonadotropin-releasing hormone analogs and bilateral orchiectomy. Fracture risk assessment includes bone mineral density determination in appropriate populations and integration of findings with identified risk factors. Strategies to prevent and treat bone loss include nonpharmacologic and pharmacologic interventions. In the former case, regular weight-bearing and muscle-strengthening exercise is encouraged along with smoking cessation, modulation of alcohol consumption, and fall prevention. Supplementation with calcium and vitamin D decreases fracture risk in subgroups. Pharmacologic interventions include use of oral or intravenous bisphosphonates, selective estrogen receptor modulators, and calcitonin. Estrogen/menopause hormone therapies are not recommended for use in breast cancer survivors related to potential influence on recurrence. Strategies for management of bone loss in breast and prostate cancer are outlined by guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

Differences in cause-specific mortality between Latino and white adults.

BACKGROUND: Understanding differences in cause-specific mortality between Latinos and whites is important for targeting future public health interventions and research aimed at eliminating health disparities. OBJECTIVES: We sought to determine the contribution of specific causes of death to Latino-white differences in mortality. RESEARCH DESIGN: Using nationally representative data, we estimated cause-specific mortality risks, which were then used in a simulation model to estimate mortality events for a cohort of persons starting at age 25 and followed until death or age 75. SUBJECTS: Subjects were 507,820 Latino and white adults, age 25 or older, who participated in the 1986-1994 National Health Interview Surveys. MEASURES: Outcomes were years of potential life lost before age 75 from specific causes of death and age-specific mortality rate ratios for Latinos compared with whites. RESULTS: Latinos had higher mortality rates than whites before age 45 and similar mortality rates at older ages. Latino women lost 315 (95% confidence interval [CI], 229-2423) more years of potential life (per 1000 persons before the age of 75) than white women and Latino men lost 595 (95% CI, 513-1675) more years than white men. For both men and women, whites lost substantially more years of potential life than Latinos from lung cancer. Homicide, diabetes, HIV, and liver disease contributed most to the excess years of potential life lost among Latino men, and diabetes and HIV contributed most to the excess years of potential life lost among Latino women. CONCLUSIONS: To eliminate health disparities between Latinos and whites, future health policy and public health efforts should target diabetes, homicide, HIV, and liver disease among Latinos and lung cancer among whites.

Physical activity decreases cardiovascular disease risk in women: review and meta-analysis.

OBJECTIVE: To review and quantify the dose-response relationship of physical activity (PA) in initially healthy women on cardiovascular disease (CVD) outcomes, especially coronary heart disease (CHD) and stroke, and to assess the minimum amount of PA to reduce CVD risk. DATA SOURCES: Studies on PA and CVD were searched in MEDLINE (January 1966-March 2003) with additional manual searches. DATA SELECTION: Studies were included if they (1) provided data on women; (2) assessed PA (exposure) as either a continuous variable or a categorical variable with three or more levels, and CVD (outcome); and (3) provided information on relative risks (RRs) and 95% confidence intervals. DATA EXTRACTION: Studies were reviewed, abstracted, and rated for quality by each author. DATA SYNTHESIS: Thirty articles met the inclusion criteria. When studies were combined according to relative PA levels, the RRs showed a dose-response relationship for CHD (RR=1 [reference], 0.78, 0.53, 0.61, respectively; p for trend was <0.0001 for studies with four PA levels, n =5); for stroke (RR=1 [reference], 0.73, 0.68, p for trend was <0.0001 for studies with three PA levels, n =7); and for overall CVD (RR=1 [reference], 0.82, 0.78, p for trend was <0.0001 for studies with three PA levels, n =6). When studies were combined by absolute walking amount, even 1 hour/week walk was associated with reduced risk of CVD outcome. CONCLUSIONS: Physical activity was associated with reduced risk of CVD among women in a dose-response fashion. Inactive women would benefit by even slightly increasing their PA (e.g., walking 1 hour per week or possibly less) and even more from additional PA.

Resident-to-resident violent incidents in nursing homes.

CONTEXT: Little is known about nursing home residents' injuries that are inflicted by other residents. OBJECTIVE: To assess risk factors for violent injury to nursing home residents by other residents. DESIGN, SETTING, AND SUBJECTS: Case-control study using data from the Massachusetts Department of Public Health's Complaint and Incident Reporting System and from Minimum Data Set assessments for Massachusetts nursing home residents. Cases had an injury sustained from an incident with another nursing home resident between January 1, 2000, and December 31, 2000, which left visible evidence (ie, fracture, dislocation, bruise or hematoma, laceration, and reddened area) (median age, 81 years). Controls were randomly selected from all residents who had a Minimum Data Set assessment completed in 2000 (n = 101 429) and no injury report (median age, 83 years). A total of 1994 controls were included in the analyses. MAIN OUTCOME MEASURES: Injury type and risk of being injured by resident-to-resident aggressive physical behaviors based on the specific characteristics of the injured resident. RESULTS: During the first incident, 294 residents sustained fractures (n = 39), dislocations (n = 6), bruises or hematomas (n = 105), lacerations (n = 113), and reddened areas (n = 31). Injured residents (cases) were more likely to be cognitively impaired, exhibit symptoms of wandering, be verbally abusive, and have socially inappropriate behavior than the controls. Residents who were classified as needing extensive assistance (adjusted odds ratio [AOR], 0.3; 95% confidence interval [CI], 0.2-0.6) and being severely dependent (AOR, 0.12; 95% CI, 0.05-0.27) had a significant reduction in being injured. Residents in an Alzheimer disease unit were almost 3 times as likely to be injured than those living in other units (AOR, 3.2; 95% CI, 1.4-7.5). CONCLUSIONS: Injured residents were more likely, perhaps unknowingly, to "put themselves in harm's way," be verbally aggressive, and be cognitively impaired. Interventions to prevent these incidents should focus on the behavior of the injured persons.

Firearm availability and female homicide victimization rates among 25 populous high-income countries.

OBJECTIVE: to determine the association between firearm availability and female homicide victimization among high-income countries. METHODS: Data were assembled for the most recent available year (1994-1999) from the official reports of the ministries of health for those countries that had more than 2 million inhabitants and were dassified as high income by the World Bank. Twenty-five nations provided sufficient information for the analysis. Rates of female victimization from homicide, firearm homicide, and nonfirearm homicide were compared with a validated proxy for household firearm ownership (the percentage of total national suicides that are committed with firearms). Possible confounding variables included in the analysis were the percentage of the population living in urban areas and income inequality. RESULTS: The United States is an outlier. It had the highest level of household firearm ownership and the highest female homicide rate. The United States accounted for 32% of the female population in these high-income countries, but for 70% of all female homicides and 84% of all female firearm homicides. Female homicide victimization rates were significantly associated with firearm availability largely because of the United States. CONCLUSION: Among high-income countries, where firearms are more available, more women are homicide victims. Women in the United States are at higher risk of homicide victimization than are women in any other high-income country.