Faculty Bibliography

BACKGROUND: Breast biopsy is essential for definitive breast cancer diagnosis, but may also play a role in determining eligibility for breast cancer preventive measures or clinical trials. In addition, the prevalence of a history of negative breast biopsy can be viewed as an indicator of the adequacy or intensity of health care in a given population. We therefore analyzed the association of a history of breast biopsy with race/ethnicity and other factors in a cohort of women without a cancer diagnosis who completed a risk assessment form for participation in the Study of Tamoxifen and Raloxifene (STAR) and a sociodemographic questionnaire. METHODS: Subjects were recruited at our large, urban teaching hospital. We developed a logistic regression model with biopsy (ever/never) as the outcome and age, race/ethnicity, educational attainment, and insurance coverage as the independent variables. RESULTS: Among 805 unaffected predominantly minority subjects, white women were more than three times as likely as black and Hispanic women (OR=3.3, 95% CI 1.9-5.9), and insured women were twice as likely as uninsured women (OR=2.0, 95% CI 1.4-2.9) to have had a biopsy. Biopsy results were also associated with race/ethnicity. DISCUSSION: We view these observations as hypothesis-generating rather than definitive. If confirmed, the associations we observed between negative biopsies and insurance status may reflect disparities in the timeliness and effectiveness of follow-up of suspicious lesions found via mammography. Our findings may also be relevant to the well-known association of breast cancer stage at diagnosis with low income and minority race/ethnicity.

In longitudinal studies with potentially nonignorable drop-out, one can assess the likely effect of the nonignorability in a sensitivity analysis. Troxel et al. proposed a general index of sensitivity to nonignorability, or ISNI, to measure sensitivity of key inferences in a neighbourhood of the ignorable, missing at random (MAR) model. They derived detailed formulas for ISNI in the special case of the generalized linear model with a potentially missing univariate outcome. In this paper, we extend the method to longitudinal modelling. We use a multivariate normal model for the outcomes and a regression model for the drop-out process, allowing missingness probabilities to depend on an unobserved response. The computation is straightforward, and merely involves estimating a mixed-effects model and a selection model for the drop-out, together with some simple arithmetic calculations. We illustrate the method with three examples.

BACKGROUND: Breast carcinoma prevention trials must recruit large cohorts of women who have an above-average risk of developing breast carcinoma. Recruitment for the Study of Tamoxifen and Raloxifene (STAR) trial required volunteers to complete a risk assessment questionnaire form (RAF). Women whose estimated risk of developing breast carcinoma in the next 5 years was > or = 1.67% based on the Gail model were invited to participate in STAR. Less than 4% of participants in the previously conducted P1 (tamoxifen vs. placebo) trial were minority women. We, therefore, studied barriers to minority participation in STAR among black, white, and Hispanic women who completed an RAF. METHODS: The authors analyzed the association of Gail model risk factors, education, and insurance with race/ethnicity using chi-square tests and two-sided P values. They developed logistic regression models of trial eligibility, controlling for the Gail model risk factors, education, and insurance status. RESULTS: Among 823 women who completed an RAF, white women were 10 times as likely as Hispanic women and 45 times as likely as black women to be eligible for STAR. Age at first birth (P = 0.04), having an affected first-degree relative (P < 0.0001), having had a biopsy (P < 0.0001), education (P < 0.0001), and insurance status (P < 0.0001) varied by race/ethnicity. All variables except insurance status were associated with eligibility when race was excluded from the model. In a model that included race/ethnicity, the same factors remained statistically significant. CONCLUSIONS: These findings suggested that both the race/ethnicity adjustment and socioeconomic factors were barriers to eligibility for and contribute to low minority participation in breast cancer prevention trials.

BACKGROUND: The objective of this study was to assess hormone receptor status as an independent predictor of survival in a population-based cohort of women with breast carcinoma who were followed for up to 11 years. METHODS: Since 1990, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program has collected data on hormone receptor status among patients with breast carcinoma. In a cohort of 205,736 women with breast carcinoma age > or = 20 years at diagnosis who were entered into the SEER data base between 1990 and 2000, the authors analyzed the association of hormone receptor status with year of diagnosis, patient age, disease stage, tumor histology, tumor grade, race/ethnicity, and metropolitan/statewide residence areas. Kaplan-Meier survival curves were compared according to hormone receptor status, and Cox proportional-hazards regression models were used to assess the association of hormone receptor status with breast carcinoma-specific and all-cause mortality controlling for age, disease stage, tumor grade, tumor histology, race/ethnicity, and SEER region. RESULTS: Women who had tumors that were positive for both estrogen and progesterone hormone receptors had significantly better survival than other women with breast carcinoma in the overall cohort, within each stage, and in the younger and older age groups, although the survival advantage was greater among women age < or = 50 years than among older women. Hormone receptor status was associated with mortality even when patient age, disease stage, tumor grade, tumor histology, race/ethnicity, and metropolitan/statewide residence areas were taken into account. CONCLUSIONS: Hormone receptor status was identified as an independent predictor of outcome in women with breast carcinoma. Data from clinical trials with long follow-up may shed light on whether and how the benefit of hormonal and other treatment varies with hormone receptor status.

AIMS: The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel. MATERIALS AND METHODS: In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment. RESULTS: Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups. CONCLUSIONS: In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and procarcinogens that require activation by host metabolism. Metabolic activation of PAHs by aldo-keto reductases (AKRs) leads to formation of reactive and redox active o-quinones, which may cause oxidatively generated DNA damage. Spectrophotometric assays showed that NADPH caused PAH o-quinones to enter futile redox cycles, which result in the depletion of excess cofactor. Copper(II) amplified NADPH-dependent redox cycling of the o-quinones. Concurrent with NADPH oxidation, molecular oxygen was consumed, indicating the production of ROS. To determine whether PAH o-quinones can cause 8-oxo-dGuo formation in salmon testis DNA, three prerequisite experimental conditions were satisfied. Quantitative complete enzymatic hydrolysis of DNA was achieved, adventitious oxidation of dGuo was eliminated by the use of chelex and desferal, and basal levels of less than 2.0 8-oxo-dGuo/10(5) dGuo were obtained. The HPLC-ECD analytical method was validated by spiking the DNA with standard 8-oxo-dGuo and demonstrating quantitative recovery. HPLC-ECD analysis revealed that in the presence of NADPH and Cu(II), submicromolar concentrations of PAH o-quinones generated >60.0 8-oxo-dGuo adducts/10(5) dGuo. The rank order of 8-oxo-dGuo generated in isolated DNA was NP-1,2-dione > BA-3,4-dione > 7,12-DMBA-3,4-dione > BP-7,8-dione. The formation of 8-oxo-dGuo by PAH o-quinones was concentration-dependent. It was completely or partially inhibited when catalase, tiron, or a Cu(I) specific chelator, bathocuproine, was added, indicating the requirement for H(2)O(2), O(2)(-), and Cu(I), respectively. Methional, which is a copper-hydroperoxo complex [Cu(I)OOH] scavenger, also suppressed 8-oxo-dGuo formation. By contrast, mannitol, sodium benzoate, and sodium formate, which act as hydroxyl radical scavengers, did not block its formation. Sodium azide, which can act as both a hydroxyl radical and a (1)O(2) scavenger, abolished the formation of 8-oxo-dGuo. These data showed that the production of 8-oxo-dGuo was dependent on Cu(II)/Cu(I) catalyzed redox cycling of PAH o-quinones to produce ROS and that the immediate oxidant was not hydroxyl radical or Cu(I)OOH and that it is more likely (1)O(2), which can produce a 4,8-endoperoxide-dGuo intermediate.

BACKGROUND: Successful prevention of obesity and related cardiovascular risk factors requires a clear understanding of its determinants over the life course. Rapid infancy weight gain is associated with childhood obesity, whereas low infancy weight is associated with coronary heart disease. Our aim was to identify during which periods in infancy weight gain is associated with adult obesity. METHODS AND RESULTS: A cohort of European American formula-fed subjects, measured on 7 occasions during infancy as part of several infant formula studies, were contacted at age 20 to 32 years, when they reported usual adult weight and height. A life-course plot was used to identify critical periods of weight gain associated with adulthood overweight (body mass index > or =25 kg/m2). These associations were tested with logistic regressions. Data were available for 653 subjects (72% of eligible subjects). Approximately 32% of them were overweight adults. The period between birth and age 8 days was identified as potentially critical. After adjustment for important confounding factors, weight gain during the first week of life was associated with adulthood overweight status (OR for each 100-g increase 1.28, 95% CI 1.08 to 1.52), as was weight gain during the first 112 days of life (OR 1.04, 95% CI 1.01 to 1.08). Similar results were obtained after standardization with z scores from a reference population. CONCLUSIONS: In formula-fed infants, weight gain during the first week of life may be a critical determinant for the development of obesity several decades later. These results contribute to the understanding of chronic disease programming and suggest new approaches to obesity prevention.

BACKGROUND: African-American (AA) breast cancer patients consistently show a shortened survival when compared with Caucasian patients. This worse prognosis is most likely due to a combination of socioeconomic factors and differences in tumor biology. Previous studies have demonstrated that cyclin D1 overexpression is strongly associated with estrogen receptor (ER) expression in breast cancer, but these series either included primarily Caucasian patients or did not specify race. MATERIALS AND METHODS. We analyzed 200 breast cancer cases obtained from AA and Caucasian patients who were matched on age, stage, ER status, and year of diagnosis. We examined expression levels of cyclin D1, p53, p27Kip1 (p27), and p21Cip1 (p21), and correlated their expression with ER status. RESULTS: Cyclin D1, p53, p27, and p21 expression rates were similar in matched cases of AA and Caucasian breast cancer (p values>0.05). However, cyclin D1 overexpression was significantly associated with ER status in only the Caucasian (p=0.0005), and not the AA cases (p=0.07). CONCLUSION: This finding suggests a novel biological difference, which may contribute to the more aggressive phenotype of AA breast cancer.

HYPOTHESIS: Male breast cancer patients have better disease-specific survival than carefully matched female breast cancer patients. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS AND METHODS: Each man in the breast cancer database at Columbia-Presbyterian Medical Center (New York, NY) between the years 1980 and 1998 was matched with a woman. Matching was done based on age and date of diagnosis, stage, and primary histologic findings. MAIN OUTCOME MEASURES: The overall survivals and disease-specific survivals of the male breast cancer group and female breast cancer group were compared. RESULTS: Fifty-three male patients were matched with an equal number of female breast cancer patients. The Kaplan-Meier curves demonstrated that there was no significant difference in overall survival. The 5- and 10-year survivals for women were 0.77 and 0.51, and for men 0.77 and 0.56. When the Kaplan-Meier curves for breast cancer-specific survival were compared, however, there was a significant difference in the 5- and 10-year survivals (P = .05, log-rank test). For women, the 5- and 10-year disease-specific survival was 0.81 and 0.7, respectively, while for men it was 0.9 and 0.9, respectively. In a Cox regression analysis for time to death from breast cancer, stage was the only predictor of death that approached significance (P = .06). CONCLUSIONS: While the overall survivals were equivalent, male breast cancer patients had significantly better disease-specific survivals compared with their female counterparts. Male patients were 4 times more likely to die of other causes than their breast cancer