Donna B. Jeffe

Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer: A Phase 2 Randomized Study

CONTEXT Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. DESIGN, SETTING, AND PATIENTS A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. INTERVENTION Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. MAIN OUTCOME MEASURES Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). SECONDARY OUTCOMES toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. RESULTS The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. CONCLUSIONS In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00324259.

Surgical Removal of the Primary Tumor Increases Overall Survival in Patients With Metastatic Breast Cancer: Analysis of the 1988–2003 SEER Data

BackgroundPrimary treatments for stage IV breast cancer are chemotherapy and radiation, with surgery usually reserved for tumor-related complications. We sought to determine whether surgical removal of the primary tumor provides a survival advantage for women with metastatic breast cancer.MethodsWe conducted a retrospective, population-based cohort study by using the 1988–2003 Surveillance, Epidemiology, and End Results (SEER) program data. By use of multivariate Cox regression models, overall survival in women with stage IV disease was compared between women who underwent surgical excision of their breast tumor with women who did not, controlling for potential confounding demographic, tumor- and treatment-related variables, and propensity scores (accounting for variables associated with the likelihood of having surgery).ResultsOf 9734 SEER patients with stage IV breast cancer, 47% underwent breast cancer surgery and 53% did not. Median survival was longer for women who had surgery than for women who did not, both among women who were alive at the end of the study period (36.00 vs. 21.00 months; P < .001) and among women who had died during follow-up (18.00 vs. 7.00 months; P < .001). After controlling for potential confounding variables and propensity scores, patients who underwent surgery were less likely to die during the study period compared with women who did not undergo surgery (adjusted hazard ratio, .63, 95% confidence interval, .60–.66).ConclusionsAnalysis of the 1988–2003 SEER data indicated that extirpation of the primary breast tumor in patients with stage IV disease was associated with a marked reduction in risk of dying after controlling for variables associated with survival.

Elevated Breast Cancer Mortality in Women Younger than Age 40 Years Compared with Older Women Is Attributed to Poorer Survival in Early-Stage Disease

BACKGROUND We investigated differences in breast cancer mortality between younger (younger than 40 years of age) and older (40 years of age and older) women by stage at diagnosis to identify patient and tumor characteristics accounting for disparities. STUDY DESIGN We conducted a retrospective study of women diagnosed with breast cancer in the 1988 to 2003 Surveillance, Epidemiology, and End Results Program data. Multivariate Cox regression models calculated adjusted hazard ratios (aHR) and 95% confidence intervals to compare overall and stage-specific breast cancer mortality in women younger than 40 years old and women 40 years and older, controlling for potential confounding variables identified in univariate tests. RESULTS Of 243,012 breast cancer patients, 6.4% were younger than 40 years old, and 93.6% were 40 years of age or older. Compared with older women, younger women were more likely to be African American, single, diagnosed at later stages, and treated by mastectomy. Younger women had tumors that were more likely to be higher grade, larger size, estrogen receptor/progesterone receptor-negative, and lymph-node positive (p < 0.001). Younger women were more likely to die from breast cancer compared with older women (crude HR = 1.39; CI, 1.34 to 1.45). Controlling for confounders, younger women were more likely to die compared with older women if diagnosed with stage I (aHR = 1.44; CI, 1.27 to 1.64) or stage II (aHR = 1.09; CI, 1.03 to 1.15) disease and less likely to die if diagnosed with stage IV disease (aHR = 0.85; CI, 0.76 to 0.95). CONCLUSIONS Higher breast cancer mortality in younger women was attributed to poorer outcomes with early-stage disease. Additional studies should focus on specific tumor biology contributing to the increased mortality of younger women with early-stage breast cancer.

Effect of area poverty rate on cancer screening across US communities

Study objective: To analyse the contextual effect of area poverty rate on never having been screened for breast, cervical, and colorectal cancer by (1) describing the extent of the variation in screening behaviours among 98 US metropolitan areas; (2) determining if the variation in lack of screening can be explained by differences in the characteristics of the persons who resided in these areas; and (3) determining if living in a metropolitan area with a higher poverty rate increased the likelihood of never having been screened for cancer over and above individual characteristics. Design: Cross sectional survey using data from the 2002 Behavioral Risk Factor Surveillance System. Multilevel logistic regression included both individual level factors as well as area poverty rate. Setting: Ninety eight areas across the USA. Participants: Over 118 000 persons residing in 98 areas; a sample aimed at estimating 48.3% of the US population age 18 or older. Main results: After adjustment for individual level factors, increasing area level poverty rate (per 5%) remained associated with never having had a mammogram (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.03 to 1.37); clinical breast examination (OR = 1.28, 95% CI: 1.11 to 1.48), colonoscopy/sigmoidoscopy (OR = 1.10, 95% CI: 1.01 to 1.19), and a faecal occult blood test (OR = 1.19, 95% CI: 1.12 to 1.27). Poverty rate was not independently associated with never having had a Pap smear (OR = 1.12; 95% CI: 0.90 to 1.41). The size of the variance among metropolitan or micropolitan statistical areas (MMSAs) varied by type of screening test, with intraclass correlation coefficients ranging from 4.9% (never having had a Pap smear) to 1.2% (never having had a colonoscopy/sigmoidoscopy). Conclusions: Area poverty rate was independently associated with never having been screened for breast and colorectal cancer, but not cervical cancer. The size of the variance among MMSAs was modest at best.

National Survey of Burnout among US General Surgery Residents

BACKGROUND Burnout is a complex syndrome of emotional distress that can disproportionately affect individuals who work in health care professions. STUDY DESIGN For a national survey of burnout in US general surgery residents, we asked all ACGME-accredited general surgery program directors to email their general surgery residents an invitation to complete an anonymous, online survey. Burnout was assessed with the Maslach Burnout Inventory; total scores for Emotional Exhaustion (EE), Depersonalization (DP), and Personal Accomplishment (PA) subscales were calculated. Burnout was defined as having a score in the highest tertile for EE or DP or lowest tertile for PA. Chi-square tests and one-way ANOVA were used to test associations between burnout tertiles for each subscale and various resident and training-program characteristics as appropriate. RESULTS From April to December 2014, six hundred and sixty-five residents actively engaged in clinical training had data for analysis; 69% met the criterion for burnout on at least one subscale. Higher burnout on each subscale was reported by residents planning private practice careers compared with academic careers. A greater proportion of women than men reported burnout on EE and PA. Higher burnout on EE and DP was associated with greater work hours per week. Having a structured mentoring program was associated with lower burnout on each subscale. CONCLUSIONS The high rates of burnout among general surgery residents are concerning, given the potential impact of burnout on the quality of patient care. Efforts to identify at-risk populations and to design targeted interventions to mitigate burnout in surgical trainees are warranted.

Safe Medication Prescribing: Training and Experience of Medical Students and Housestaff at a Large Teaching Hospital

Purpose To assess medical students’ and housestaffs knowledge, attitudes, and behaviors regarding safe prescribing. Method In 2003, 214 housestaff (interns and residents) and 77 medical students in medicine and surgery at Barnes-Jewish Hospital, St. Louis, Missouri, were asked to complete an anonymous, self-administered questionnaire about safe prescribing. Questions asked about training in and attitudes about safe-prescribing and current prescribing behaviors. Fisher exact test was used to compare attitudes and behaviors among subgroups. Results Of the 175 (60%) respondents, 73 (59%) of 123 housestaff and eight (15%) of 52 students agreed that their safe-prescribing training was adequate (p < .001), and 145 (83%) total respondents agreed that prescribing errors were unacceptable. Respondents reported always doing the following: 156 (89%) checked prescribing information before prescribing new drugs, 131 (75%) checked for drug allergies, 103 (59%) double-checked dosage calculations, 98 (56%) checked for renal impairment, and 53 (30%) checked for potential drug–drug interactions. Conclusion Routine use of safe medication prescribing behaviors among housestaff and medical students was poor. Contributing factors may have included inadequate training and a culture that does not support safe prescribing. Effective strategies to increase safe medication prescribing need to be identified and implemented.

The Role of Poverty Rate and Racial Distribution in the Geographic Clustering of Breast Cancer Survival Among Older Women: A Geographic and Multilevel Analysis

The authors examined disparities in survival among women aged 66 years or older in association with census-tract-level poverty rate, racial distribution, and individual-level factors, including patient-, treatment-, and tumor-related factors, utilization of medical care, and mammography use. They used linked data from the 1992-1999 Surveillance, Epidemiology, and End Results (SEER) programs, 1991-1999 Medicare claims, and the 1990 US Census. A geographic information system and advanced statistics identified areas of increased or reduced breast cancer survival and possible reasons for geographic variation in survival in 2 of the 5 SEER areas studied. In the Detroit, Michigan, area, one geographic cluster of shorter-than-expected breast cancer survival was identified (hazard ratio (HR) = 1.60). An additional area where survival was longer than expected approached statistical significance (HR = 0.4; P = 0.056). In the Atlanta, Georgia, area, one cluster of shorter- (HR = 1.81) and one cluster of longer-than-expected (HR = 0.72) breast cancer survival were identified. Stage at diagnosis and census-tract poverty (and patients race in Atlanta) explained the geographic variation in breast cancer survival. No geographic clusters were identified in the 3 other SEER programs. Interventions to reduce late-stage breast cancer, focusing on areas of high poverty and targeting African Americans, may reduce disparities in breast cancer survival in the Detroit and Atlanta areas.

Effects of Hormone Replacement Therapy on Serum Lipids in Elderly Women: A Randomized, Placebo-Controlled Trial

Eighty percent of deaths due to coronary heart disease (CHD) occur in persons older than 65 years of age, and CHD accounts for 50% of all deaths among persons older than 85 years of age (1). Coronary disease is the leading cause of death among older women (2). Because of the higher rates of CHD-related morbidity and death and the higher prevalence of cardiovascular risk factors among elderly persons, the attributable risk for any individual risk factor may be higher in elderly than in younger adults (3, 4). Modification of risk factors in this older age group therefore may strongly affect morbidity and mortality from CHD. Low serum levels of high-density lipoprotein (HDL) cholesterol are among the risk factors that have been predictive of death from CHD among adults older than 70 years of age, particularly among women (5). Therefore, interventions that target hypercholesterolemia may benefit older women. Observational studies have shown that postmenopausal women who receive hormone replacement therapy (HRT) have lower rates of CHD than women who do not receive HRT (6-8). Studies of the effects of HRT have focused primarily on women younger than 75 years of age, and little is known about the effects of HRT when it is initiated or re-instituted at an older age. We evaluated the effects of 9 months of HRT on serum lipid and lipoprotein levels in elderly women. We hypothesized that HRT would have beneficial effects on the lipid profile, particularly on HDL and low-density lipoprotein (LDL) cholesterol levels. Methods Participants Women 75 years of age or older, with or without a uterus, were recruited from the general community and congregate living sites. Participants provided written, informed consent to participate in this study, which was approved by the institutional review board of the Washington University School of Medicine, St. Louis, Missouri. Before enrollment, potential participants completed questionnaires on activities of daily living (ADLs) performance and underwent a medical history; chest radiography; blood and urine chemistries; physical examination, including gynecologic examination with transvaginal ultrasonography; mammography; a modified Physical Performance Test (modified PPT) (score range, 0 to 36); and a graded treadmill exercise test with measurement of peak aerobic power (VO2peak). The procedures for the ADL questionnaires, modified PPT, and measurement of VO2peak have been previously described [9]. Because we sought to enroll women with mild to moderate physical frailty for exercise training during the second 9 months of the study, women were eligible for this study if they met two of the following three criteria: 1) VO2peak of 11 to 18 mL/kg of body weight per minute (range of age-predicted VO2max for healthy sedentary women aged 75 to 80 years, 18 to 22 mL/kg per minute) [10], 2) self-reported difficulty or need for assistance with two instrumental ADLs or one basic ADL, and 3) a modified PPT score of 18 to 32. Exclusion criteria were estrogen or progestin use within the past year, history of breast cancer or any estrogen-dependent neoplasia, history of any other cancer within the past 5 years (except for an excised superficial skin lesion), current treatment for thromboembolic disease, corticosteroid use within 3 months, or active serious illness (unstable angina, congestive heart failure, myocardial infarction, or stroke or transient ischemic attack) within the past 6 months. Women who received thyroid hormone therapy but were not receiving a stable dose for 3 months or did not have a normal thyroid-stimulating hormone level were also excluded. Women receiving lipid-lowering agents were included because, to the extent possible, we wanted our results to apply to this age group of U.S. women, many of whom use such medications. Women who had not been taking a stable medication dose for at least 1 year were excluded from this analysis because we did not want to confound the effects of HRT on serum lipid levels over the study treatment period. Serum Lipid Measurements An overnight fasting blood sample was obtained at baseline and after 9 months for measurement of serum total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol levels. Samples were obtained at least 1 month after progestin ingestion. Samples were analyzed in the laboratory of the Washington University Lipid Research Center, as previously described (11). Diet Evaluation After receiving proper instruction, participants completed 3-day food records at baseline and at 9 months under supervision by a registered dietitian. We analyzed the food intake records by using Nutritionist IV software (First Databank, San Bruno, California). No specific diet was prescribed. Body Composition Total-body dual-energy x-ray absorptiometry was used to assess body composition (Hologic QDR1000/W, Waltham, Massachusetts). HRT and Randomization Women enrolled in the study were randomly assigned to receive either placebo or HRT, which consisted of conjugated estrogens, 0.625 mg/d (Wyeth-Ayerst, Philadelphia, Pennsylvania), and cyclic medroxyprogesterone acetate (MPA), 5 mg/d, for 13 consecutive days beginning at the end of the second month of treatment and then every third month thereafter (end of months 2, 5, and 8). The intent of the HRT regimen was to use the minimal effective progestin dose that would protect against the development of endometrial hyperplasia (12). Women who had undergone previous hysterectomy were not prescribed progesterone. Women with a uterus received active MPA if they were in the HRT group and received placebo MPA if they were in the placebo group. Eligible women were assigned to the placebo or HRT group in a 1:2 ratio, respectively, by using a computer-generated block random permutation procedure [13]. Twice as many women were assigned to the HRT group because 1) we had anticipated higher attrition in this group and 2) at 9 months, women receiving HRT were invited to continue HRT and to participate in an exercise training study. A member of the research team who did not interact with participants after screening assessments maintained the randomization log. All medications were taken orally. Active drugs and placebo were prepared as capsules in identical forms. Participants and study personnel who acquired data were blinded to group assignment. During a total of 9 months of treatment, participants had monthly visits to the research facility, at which time self-recorded medication calendars were reviewed. Participants completed a symptom checklist at baseline and at 1, 3, 6, and 9 months. Pills were counted every 3 months. Participants who could not tolerate the assigned medication because of side effects had their dosage decreased to one capsule every other day for 3 to 4 weeks. The dosage was then increased to one capsule daily. If intolerance persisted, the dosage was decreased to the highest tolerable dosage, which in most cases was three to four capsules per week. In all, dosages were adjusted for nine (15%) participants (two in the placebo group and seven in the HRT group). Exercise Program Because our volunteers had been recruited for studies of HRT or exercise (with or without HRT), all participants were instructed in a home-based exercise program of very low intensity that included flexibility and balance exercises. Statistical Analysis We performed primary analyses on changes in lipid levels from baseline to 9 months. Because we did not want to exclude women with missing lipid data and because we wanted to use a conservative analytic approach, we assumed that lipid values did not change among randomly assigned participants who did not provide 9-month lipid data. This approach yields conservative results because the assumption of no change among women without follow-up data reduces the between-group differences. A two-factor (treatment time) analysis of variance was used to determine the effects of HRT on the changes in lipid values. We calculated 95% CIs for between-group differences in the mean change from baseline to 9 months for each lipid measurement. Analyses of covariance were performed to adjust for clinically pertinent baseline characteristics (such as age at menopause onset, baseline lipid value, weight, percentage body fat, and waist circumference). Baseline characteristics of the two groups were compared by using Student t-tests for continuous data and chi-square tests for categorical data. Pearson product moment correlations were used to evaluate the relationship between baseline lipid levels and the change in lipid levels within each group. Statistical significance was defined as an level of 0.05 or lower. All data were analyzed by using SAS statistical software (SAS Institute, Inc., Cary, North Carolina). Data are presented as the mean (SD) unless otherwise stated. Role of the Funding Source The funding source and the product source had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Participant Characteristics Of 288 women who underwent pre-enrollment evaluations, 41 were excluded for medical reasons, 43 did not meet selection criteria, and 141 declined participation. Sixty-three women were randomly assigned to receive placebo (n = 22) or HRT (n = 41). Four women were excluded from our analysis because lipid-lowering medication dosage was not stable during the study period (2 each in the placebo and HRT groups). Therefore, we analyzed data on 59 participants: 20 in the placebo group and 39 in the HRT group. Women in the HRT group reported a younger age at menopause onset (P=0.02); no other baseline characteristics differed significantly between the two groups (Table 1). Table 1. Baseline Characteristics of Study Participants Eleven women (2 in the placebo group and 9 in the HRT group) discontinued use of study medication and also did not provide follow-up data at 9 months. Women who dropped out had dis

Identifying factors associated with disability-related differences in breast cancer screening (United States)

Objective: The purpose of this study was to identify factors that could explain breast cancer underutilization among women age 40 and older with disabilities. Methods: The data are part of the 1996 Medical Expenditure Panel Survey (MEPS), a nationally representative sample of medical care use and expenditures in the United States. Two different definitions of disability were used: limitations in activities of daily living (ADL) and limitations in instrumental activities of daily living (IADL). Annual mammography was used as the outcome measure. The data are restricted to noninstitutionalized women at least 40 years of age. Results: Crude odds ratios showed that women with long-term limitations in their ADLs or IADLs were less likely to be screened for breast cancer compared to those without such limitations. These associations remained while controlling for possible confounders and were observed among women age 40 or older, those 50–69, and among women 70 years of age and older. Conclusions: Reasons for the underutilization of breast cancer screening among women with long-term disabilities remain elusive. Future studies need to examine additional factors in order to improve screening use, especially among women with long-term disabilities who are 50–69 years of age, for whom screening has been shown to be beneficial in terms of reduced risk of mortality from breast cancer.

Accuracy of ultrasonography and mammography in predicting pathologic response after neoadjuvant chemotherapy for breast cancer.

BACKGROUND Neoadjuvant chemotherapy reduces tumor size before surgery in women with breast cancer. The aim of this study was to assess the ability of mammography and ultrasound to predict residual tumor size following neoadjuvant chemotherapy. METHODS In a retrospective review of consecutive breast cancer patients treated with neoadjuvant chemotherapy, residual tumor size estimated by diagnostic imaging was compared with residual tumor size determined by surgical pathology. RESULTS One hundred ninety-two patients with 196 primary breast cancers were studied. Of 104 tumors evaluated by both imaging modalities, ultrasound was able to size 91.3%, and mammography was able to size only 51.9% (chi(2)P < .001). Ultrasound also was more accurate than mammography in estimating residual tumor size (62 of 104 [59.6%] vs 33 of 104 [31.7%], P < .001). There was little difference in the ability of mammography and ultrasound to predict pathologic complete response (receiver operating characteristic, 0.741 vs 0.784). CONCLUSIONS Breast ultrasound was more accurate than mammography in predicting residual tumor size following neoadjuvant chemotherapy. The likelihood of a complete pathologic response was 80% when both imaging modalities demonstrated no residual disease.