Clinical Utility of Routine Cardiac Monitoring in Breast Cancer Patients Receiving Trastuzumab.

BACKGROUND: Trastuzumab targets the human epidermal growth factor receptor-2 (HER2). Cardiotoxicity is a potential adverse effect, manifesting as either an asymptomatic decline in left-ventricular ejection fraction or infrequently as largely reversible symptomatic heart failure (HF). Monitoring recommendations differ between product labeling and 2012 guidelines, and the clinical utility of serial cardiac monitoring in patients with metastatic breast cancer remains controversial. OBJECTIVE: The objectives of this study were to describe the frequency of monitoring, incidence of symptomatic or asymptomatic HF, overall effect on treatment, and cost of monitoring for cardiotoxicity. METHODS: We preformed an institutional review board-approved retrospective chart review of breast cancer patients receiving trastuzumab from January 1, 2009, through January 1, 2014, at an academic medical center. RESULTS: Out of 154 treatments, 72% were adjuvant, and 28% were metastatic. In the adjuvant setting, a mean of 4.5 (interquartile range [IQR] = 4-5) echocardiograms (echos) over a mean of 11.5 (IQR = 11-12) months were performed. In the metastatic setting, a mean of 3.1 (IQR = 1-5) echos over a mean of 20.2 (IQR = 9-31) months were performed. Symptomatic HF events occurred in 4 adjuvant (3.6%) and 2 metastatic patients (6.5%); 10 patients (6.5%) had a treatment interruption, with 9 (90%) tolerating restart of trastuzumab. Two patients (1.3%) changed treatment as a result of cardiotoxicity. Using population incidence of HER2-positive breast cancer, $13 million could be saved if monitoring were reduced by 1 echo per patient. CONCLUSIONS: Given the low incidence of clinically significant HF and cost of monitoring, less frequent monitoring may be justified.

Genome-wide copy number alterations in subtypes of invasive breast cancers in young white and African American women.

Genomic copy number alterations (CNA) are common in breast cancer. Identifying characteristic CNAs associated with specific breast cancer subtypes is a critical step in defining potential mechanisms of disease initiation and progression. We used genome-wide array comparative genomic hybridization to identify distinctive CNAs in breast cancer subtypes from 259 young (diagnosed with breast cancer at <55 years) African American (AA) and Caucasian American (CA) women originally enrolled in a larger population-based study. We compared the average frequency of CNAs across the whole genome for each breast tumor subtype and found that estrogen receptor (ER)-negative tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.02) compared to ER-positive tumors. Triple-negative (TN) tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.003) than non-TN tumors. No significant difference in CNA frequency was observed between HER2-positive and -negative tumors. We also identified previously unreported recurrent CNAs (frequency >40%) for TN breast tumors at 10q, 11p, 11q, 16q, 20p, and 20q. In addition, we report CNAs that differ in frequency between TN breast tumors of AA and CA women. This is of particular relevance because TN breast cancer is associated with higher mortality and young AA women have higher rates of TN breast tumors compared to CA women. These data support the possibility that higher overall frequency of genomic alteration events as well as specific focal CNAs in TN breast tumors might contribute in part to the poor breast cancer prognosis for young AA women.

Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA.

BACKGROUND: Breast cancers with a triple negative tumor (TNT) subtype (as defined by lacking protein expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)) preclude the use of available targeted therapies and may contribute to poor outcome and to the historically poorest survival observed among African-American (AA) women. This study examines association of the ER/PR/HER2 subtypes with race and breast cancer survival. METHODS: Breast tumors from a population-based cohort of 116 AA and 360 white Atlanta women aged 20-54, diagnosed from 1990 to 1992 were centrally reviewed and tested by immunohistochemistry. Multivariate survival analyses within subtypes (TNT, ER-PR-HER2+, ER+/PR+HER2+, ER+/PR+HER2-) were conducted using weighted Cox regression and included socio-demographic, prognostic, and treatment factors. RESULTS: TNTs were more prevalent among young women and particularly among AA women (Odds Ratio [OR] = 1.9, 95% Confidence Interval [CI] 1.2-2.9), adjusting for age, stage, grade, and poverty index. Overall mortality was higher for AA women (Hazard Ratio [HR] = 1.9, 95% CI, 1.5-2.5) and differed by subtypes (P < 0.001). Within the TNT subtype, racial differences in survival persisted, after additional adjustment for treatment and comorbidities (HR = 2.0, 95% CI 1.0-3.7). TNTs were uniquely associated with high expression of p16, p53, and Cyclin E; and low Bcl-2 and Cyclin D1 expression. CONCLUSIONS: The high prevalence of TNTs among younger women and particularly younger AA women, along with unique protein expression patterns and poorer survival, suggests varying gene-environment etiologies with respect to age and race/ethnicity and a need for effective therapies.

The epidemiology of triple-negative breast cancer, including race.

OBJECTIVE: Predictors of intrinsic breast cancer subtypes, including the triple-negative (TN) subtype, are largely unknown. We evaluated whether anthropometrics, demographics, and reproductive history were associated with distinct breast cancer subtypes. METHODS: Invasive breast tumors from a population-based case-control study of 476 (116 black and 360 white) Atlanta women aged 20-54, diagnosed between 1990 and 1992, were centrally reviewed and immunohistochemically analyzed for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2); then grouped [TN (ER-PR-HER2-); ER-PR-HER2+; ER/PR+HER2+; ER/PR+HER2- (case-only reference group)]. Data were from interviews and anthropometric measurements; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression, including both case-only and case-control comparisons. RESULTS: From the case-only analyses and compared with the ER/PR+HER2- subtype, women with TN tumors were more likely to be obese than normal/underweight [OR = 1.89 (95% CI = 1.22, 2.92)]. Regardless of HER2 status, ER-PR- tumors were associated with black race, young age at first birth, having a recent birth, and being overweight. CONCLUSIONS: Distinct breast cancer subtypes have unique sociodemographic, anthropometric and reproductive characteristics and possibly different pathways for development.

Oral contraceptives and survival in breast cancer patients aged 20 to 54 years.

Recent oral contraceptive (OC) use is associated with modestly higher breast cancer incidence among younger women, but its impact on survival is unclear. This study examined the relationship between OC use before breast cancer diagnosis and survival. A population-based sample of 1,264 women aged 20 to 54 years with a first primary invasive breast cancer during 1990 to 1992 were followed up for 8 to 10 years. OC and covariate data were obtained by interviews conducted shortly after diagnosis and from medial records. All-cause mortality was ascertained through the National Death Index (n = 292 deaths). Age- and income-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox regression methods. All-cause mortality was not associated with ever use of OCs or duration of use. Compared with nonusers, mortality estimates were elevated among women who were using OCs at diagnosis or stopped use in the previous year (HR, 1.57; 95% CI, 0.95-2.61). The HR for use of high-dose estrogen pills within 5 years before diagnosis was double that of nonusers (HR, 2.39; 95% CI, 1.29-4.41) or, if the most recent pill included the progestin levonorgestrel, compared with nonusers (HR, 2.01; 95% CI, 1.03-3.91). Because subgroup estimates were based on small numbers of OC users, these results should be cautiously interpreted. Overall, most aspects of OC use did not seem to influence survival, although there is limited evidence that OC use just before diagnosis, particularly use of some pill types, may negatively impact survival in breast cancer patients aged 20 to 54 years.

General and abdominal obesity and survival among young women with breast cancer.

Among postmenopausal women, obesity is linked to increased risk of breast cancer and poorer subsequent survival. For premenopausal women, obesity may reduce incidence, but less is known about its effect on prognosis, particularly for abdominal obesity. This study investigated whether general or abdominal obesity at diagnosis influenced survival in a cohort of young women with breast cancer. A population-based follow-up study was conducted among 1,254 women ages 20 to 54 who were diagnosed with invasive breast cancer between 1990 and 1992 in Atlanta or New Jersey. Women were interviewed within several months of diagnosis and asked about their weight and height at age 20 and in the year before diagnosis. Study personnel did anthropometric measures at the interview. With 8 to 10 years of follow-up, all-cause mortality status was determined using the National Death Index (n = 290 deaths). Increased mortality was observed for women who were obese [body mass index (BMI), > or =30] at the time of interview compared with women of ideal weight [BMI, 18.5-24.9; stage- and income-adjusted hazard ratio (HR), 1.48; 95% confidence interval (95% CI), 1.09-2.01]. A similar result was seen for the highest versus lowest quartile of waist-to-hip ratio (HR, 1.52; 95% CI, 1.05-2.19). Strong associations with mortality were found for women who were obese at age 20 (HR, 2.49; 95% CI, 1.15-5.37) or who were overweight/obese (BMI, > or =25) at both age 20 and the time of interview (HR, 2.22; 95% CI, 1.45-3.40). This study provides evidence that breast cancer survival is reduced among younger women with general or abdominal obesity.

Interweaving Curriculum Committees: A New Structure to Facilitate Oversight and Sustain Innovation.

Undergraduate medical education curricula have increased in complexity over the past 25 years; however, the structures for administrative oversight of those curricula remain static. Although expectations for central oversight of medical school curricula have increased, individual academic departments often expect to exert control over the faculty and courses that are supported by the department. The structure of a governance committee in any organization can aid or inhibit that organization's functioning. In 2013, following a major curriculum change in 2007, the Emory University School of Medicine (EUSOM) implemented an "interwoven" configuration for its curriculum committee to better oversee the integrated curriculum. The new curriculum committee structure involves a small executive committee and 10 subcommittees. Each subcommittee performs a specific task or oversees one element of the curriculum. Members, including students, are appointed to two subcommittees in a way that each subcommittee is composed of representatives from multiple other subcommittees. This interweaving facilitates communication between subcommittees and also encourages members to become experts in specific tasks while retaining a comprehensive perspective on student outcomes. EUSOM's previous structure of a single committee with members representing individual departments did not promote cohesive management. The interwoven structure aligns neatly with the goals of the integrated curriculum. Since the restructuring, subcommittee members have been engaged in discussions and decisions on many key issues and expressed satisfaction with the format. The new structure corresponds to EUSOM's educational goals, although the long-term impact on student outcomes still needs to be assessed.

Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes: a population-based study and first report.

BACKGROUND: Although US year 2000 guidelines recommended characterizing breast cancers by human epidermal growth factor receptor 2 (HER2), national cancer registries do not collect HER2, rendering a population-based understanding of HER2 and clinical "triple subtypes" (estrogen receptor [ER] / progesterone receptor [PR] / HER2) largely unknown. We document the population-based prevalence of HER2 testing / status, triple subtypes and present the first report of subtype incidence rates. METHODS: Medical records were searched for HER2 on 1842 metropolitan Atlanta females diagnosed with breast cancer during 2003-2004. HER2 testing/status and triple subtypes were analyzed by age, race/ethnicity, tumor factors, socioeconomic status, and treatment. Age-adjusted incidence rates were calculated. RESULTS: Over 90% of cases received HER2 testing: 12.6% were positive, 71.7% negative, and 15.7% unknown. HER2 testing compliance was significantly better for women who were younger, of Caucasian or African-American descent, or diagnosed with early stage disease. Incidence rates (per 100,000) were 21.1 for HER2+ tumors and 27.8 for triple-negative tumors, the latter differing by race (36.3 and 19.4 for black and white women, respectively). CONCLUSIONS: HER2 recommendations are not uniformly adhered to. Incidence rates for breast cancer triple subtypes differ by age/race. As biologic knowledge is translated into the clinical setting eg, HER2 as a biomarker, it will be incumbent upon national cancer registries to report this information. Incidence rates cautiously extrapolate to an annual burden of 3000 and 17,000 HER2+ tumors for black and white women, respectively, and triple-negative tumors among 5000 and 16,000 respectively. Testing, rate, and burden variations warrant population-based in-depth exploration and clinical translation.

Parity and disparity in first course treatment of invasive breast cancer.

BACKGROUND: Adherence to first course treatment guidelines for breast cancer may not be uniform across racial/ethnic groups and could be a major contributing factor to disparities in outcome. In this population-based study, we assessed racial differences in initial treatment of breast cancer. METHODS: Surveillance, Epidemiology, and End Results (SEER) program data were used to study all primary invasive breast cancers diagnosed during 2000-2001 among Black (n = 877) and White (n = 2437) female residents of the five Atlanta SEER counties, counties with several large teaching hospitals. Differences in treatment delay, cancer directed surgery, and receipt of chemotherapy, radiotherapy, or hormonal therapy were analyzed according to guidelines for treatment. Analyses utilized frequency distributions, chi(2) tests of independence and statistics in and across strata. RESULTS: Black women experienced longer treatment delays, regardless of stage at diagnosis, and were 4-5 fold more likely to experience delays greater than 60 days (P < 0.001). For local-regional disease, more Black women did not receive cancer directed surgery (7.5% vs. 1.5% of white women, P < 0.001), but did receive breast conserving surgery (BCS) equivalently. Only 61% of Black vs. 72% of White women received radiation with BCS (P < 0.001). Black women eligible for hormonal therapy were less likely to receive it (P < 0.001). CONCLUSION: Our findings suggest treatment standards are not adequately or equivalently met among Black and White women, even in an area where teaching hospitals provide a substantial portion of breast cancer care. Treatment differences can adversely affect outcome and reasons for the differences need to be addressed.

Factors associated with advanced disease stage at diagnosis in a population-based study of patients with newly diagnosed breast cancer.

Breast cancer is diagnosed at a younger age and a more advanced stage in African-American women than in White women. The authors investigated the effects of several factors, including race, on stage of breast cancer in women aged 20-54 years living in Atlanta, Georgia, and diagnosed between 1990 and 1992. A total of 251 African-American and 580 White women were interviewed and their medical records reviewed. By use of polytomous logistic regression, factors possibly influencing stage and racial differences in stage were studied. In African-American women, the odds of stage III/IV breast cancer at diagnosis were almost four times the odds in White women (odds ratio = 3.79, 95% confidence interval: 2.45, 5.89) and approximately two and one-half times for stage IIA or stage IIB disease (odds ratio = 2.57, 95% confidence interval: 1.66, 3.99; odds ratio = 1.94, 95% confidence interval: 1.31, 2.86, respectively). These racial differences appeared to be largely explained by insurance status, poverty, history of mammography, method of tumor detection, and obesity. Interventions targeting these factors could potentially lower the stage at diagnosis for African-American breast cancer patients and, in doing so, improve their survival and other outcomes.

Association between reproductive factors and breast cancer survival in younger women.

This analysis investigated whether reproductive factors such as age at menarche, parity, and timing and outcomes of pregnancies were associated with survival among women with breast cancer younger than 55 years. Female residents of Atlanta, Georgia, and central New Jersey who were diagnosed with a primary, incident invasive breast cancer between 1990 and 1992 and enrolled in a population-based study (n = 1,264) were followed for 8-10 years. Detailed exposure and covariate information was collected via in-person interviews administered shortly after diagnosis. Vital status as of January 1, 2000 was ascertained through the National Death Index via the state cancer registries (n = 292 deaths). Cox regression methods were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for confounders. Parity of 4 or more births, as compared with nulliparity, was positively associated with all-cause mortality, [HR (95% CI) = 1.71 (1.09-2.67)]. Increased mortality was associated with having given birth within 5 years prior to diagnosis (5 years) [1.78 (1.28-2.47)], and was more pronounced among women with a pre-diagnostic body mass index of <25 kg/m2 [2.54 (1.61-4.00)]. Early age at menarche and early age at first birth also modestly increased mortality; history of miscarriage, induced abortion, and ever breastfeeding were not related to survival. These results may help elucidate breast cancer progression mechanisms and enable a better understanding of how reproductive characteristics influence breast cancer survival.

Recreational physical activity and survival among young women with breast cancer.

BACKGROUND: Most epidemiologic studies report a reduced risk of developing breast cancer associated with higher levels of recreational physical activity, but little is known regarding its effect on prognosis. METHODS: In this study, the authors investigated whether activity undertaken prior to diagnosis influenced breast cancer survival in a population-based cohort. A follow-up study was conducted among 1264 women ages 20 to 54 years who were diagnosed with invasive breast cancer between 1990 and 1992. Women in the study were interviewed within several months of diagnosis and were asked about their average frequency of moderate and vigorous activity at age 13 years, age 20 years, and during the year before diagnosis. With 8 to 10 years of follow-up, all-cause mortality status was determined by using the National Death Index (n = 290 deaths). RESULTS: A modest reduction in the hazards ratio (HR) was observed for the highest quartile of activity in the year before diagnosis compared with the lowest quartile (stage-adjusted and income-adjusted HR, 0.78; 95% confidence interval [95% CI], 0.56-1.08). High activity was associated with a reduced HR among women who were overweight or obese at the time of diagnosis (HR, 0.70; 95% CI, 0.49-0.99) but not among ideal weight or underweight women (HR, 1.08; 95% CI, 0.77-1.52). A reduced HR was not evident for activity at age 13 years or 20 years or for average activity across the 3 periods studied. CONCLUSIONS: The results of this study provided some suggestive evidence for a beneficial effect on survival of recreational physical activity undertaken in the year before diagnosis, particularly among women who are overweight or obese near the time of diagnosis.

A workshop to teach medical students communication skills and clinical knowledge about end-of-life care.

We describe a half-day workshop to teach third-year medical students three focused end-of-life care skills: breaking bad news, discussing advance directives, and assessing and managing pain. Our workshop included a readers' theater exercise and three role-play exercises. In two of the workshops, faculty members played the role of patients. We used readers' theater to engage the students on an emotional level and set a reflective tone for the workshop. Evaluations reflected that most respondents felt that the workshop enhanced their understanding and ability to address these skills with patients. By 6 months, many students reported applying these skills to patient care in a way they thought was effective.

Racial differences in the expression of cell cycle-regulatory proteins in breast carcinoma.

BACKGROUND: African-American (AA) women are more likely to be diagnosed with an advanced stage of breast carcinoma than are white women. After adjustment for disease stage, many studies indicate that tumors in AA women are more likely than tumors in white women are to exhibit a high level of cell proliferation and features of poor prognosis. The purpose of the current study was to compare tumor characteristics and cell cycle alterations in AA women and white women that might affect the aggressiveness of breast carcinoma. METHODS: The study included 124 AA and 397 white women, ages 20-54 years. These women were enrolled in a case-control study in Atlanta, Georgia, between 1990 and 1992. Breast tumor specimens obtained from these women were centrally reviewed for histologic characteristics and evaluated for expression of estrogen and progesterone receptors (ER/PR), c-ErbB-2, Ki-67, p53, cyclin E, cyclin D1, p27, p16, pRb, and p21 by immunohistochemistry. Logistic regression models were used to assess the age- and stage-adjusted associations of various tumor characteristics with race. RESULTS: The odds of a breast carcinoma diagnosis at a younger age and at a later stage were higher for AA women than for white women. After adjustment for disease stage and age at diagnosis, AA women also were found to have increased odds of having a higher-grade tumor, a higher mitotic index, marked tumor necrosis, ductal histology, loss of ER and PR, overexpression of cyclin E, p16, and p53 and low expression of cyclin D1 at diagnosis. CONCLUSIONS: The observed differences between tumor specimens obtained from AA women and tumor specimens obtained from white women, independent of stage and age at diagnosis, indicated that race may be a determinant, or a surrogate for other determinants, of aggressive breast carcinoma and specific cell cycle defects.

Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma.

BACKGROUND: Few studies have addressed the issue of whether delays in the interval between medical consultation and the diagnosis and treatment of breast carcinoma are greater for African American women than for white women. The authors examined differences with respect to these delays and analyzed the factors that may have contributed to such differences among women ages 20-54 years who had invasive breast carcinoma diagnosed between 1990 and 1992 and who lived in Atlanta, Georgia. METHODS: A total of 251 African American women and 580 white women were interviewed and had their medical records reviewed. The authors estimated racial differences in delay times and used polytomous logistic regression to determine the contributions of various factors (socioeconomic and other) to these differences. RESULTS: Although most women in both groups were treated within 3 months of initial consultation, 22.4% of African American women and 14.3% of white women had clinical delays of > 3 months. Compared with white women, African American women were more likely to experience delays in diagnosis and treatment. Access to care (as represented by method of detection and insurance status) and poverty index partially accounted for these differences in delay time; however, racial differences in terms of delayed treatment and diagnosis remained even after adjustment for contributing factors. CONCLUSIONS: The findings of the current study suggest that among women ages 20-54 years who have breast carcinoma, potentially clinically significant differences in terms of delayed diagnosis and treatment exist between African American women and white women. Improvements in access to care and in socioeconomic circumstances may address these differences to some degree, but additional research is needed to identify other contributing factors.