Kent Hoskins

BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer

BACKGROUND To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families. METHODS Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer. Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations. RESULTS BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation. No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family. CONCLUSIONS Among women with breast cancer and a family history of the disease, the percentage with BRCA1 coding-region mutations is less than the 45 percent predicted by genetic-linkage analysis. These results suggest that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative.

Recent advances in breast cancer biology.

Approximately 1 in 10 US women will be diagnosed with breast cancer in her lifetime. With such a high incidence, breast cancer is a serious health concern for all American women. Within the past year, clues about the function of genes associated with breast cancer have been garnered, and novel genes that may contribute to breast tumorigenesis have been discovered. In addition, unique animal models and improvements in gene expression profiling technology have given researchers new tools to address previously unanswerable questions about this disease.

Body composition changes in females treated for breast cancer: a review of the evidence.

Body composition changes cannot be precisely captured using body weight or body mass index measures. Therefore, the primary purpose of this review was to characterize the patterns of body composition change in females treated for breast cancer including only studies that utilize imaging technologies to quantify adipose tissue and lean body mass (LBM). We reviewed PubMed for studies published between 1971 and 2012 involving females diagnosed with breast cancer where computed axial tomography , dual-energy X-ray absorptiometry, or magnetic resonance imaging were employed for body composition assessment. Of the initial 440 studies, 106 papers were evaluated and 36 papers met all eligibility criteria (15 observational and 21 intervention trials). Results of these studies revealed that body weight did not consistently increase. Importantly, studies also showed that body weight did not accurately depict changes in lean or adipose tissues. Further findings included that sarcopenic obesity as a consequence of breast cancer treatment was not definitive, as menopausal status may be a substantial moderator of body composition. Overall, the behavioral interventions did not exhibit consistent or profound effects on body composition outcomes; approximately half showed favorable influence on adiposity while the effects on LBM were not apparent. The use of tamoxifen had a clear negative impact on body composition. The majority of studies were conducted in predominantly white survivors, highlighting the need for trials in minority populations. Collectively, these studies were limited by age, race, and/or menopause status matched control groups, overall size, and statistical power. Very few studies simultaneously collected diet and exercise data—two potential factors that impact body composition. Future breast cancer trials should prioritize precise body composition methodologies to elucidate how these changes impact recurrence, prognosis, and mortality, and to provide clinicians with appropriate advice regarding lifestyle recommendations in this growing sector of the population.

The biology of breast cancer

The progression from normal breast epithelium to metastatic breast cancer is a complex, multistep process. Initially, genetic alterations are thought to confer a growth advantage to individual cells by decreasing tumor-suppressor gene activity or increasing oncogene activity, or both. Further alterations result in the development of cell clones that have the ability to invade adjacent tissue, establish metastatic deposits, and evade immune surveillance. At some point in this process, these malignant cell clones also lose the normal ability to respond to hormonal growth regulatory signals. Recent advances in understanding the genetic alterations, the loss of normal growth regulation, and the development of metastatic potential in breast cancer are reviewed. Factors related to the immunobiology of breast cancer are also discussed.

Racial and Ethnic Disparity in Symptomatic Breast Cancer Awareness despite a Recent Screen: The Role of Tumor Biology and Mammography Facility Characteristics

Background: In a racially and ethnically diverse sample of recently diagnosed urban patients with breast cancer, we examined associations of patient, tumor biology, and mammography facility characteristics on the probability of symptomatic discovery of their breast cancer despite a recent prior screening mammogram. Methods: In the Breast Cancer Care in Chicago study, self-reports at interview were used to define patients as having a screen-detected breast cancer or having symptomatic awareness despite a recent screening mammogram (SADRS), in the past 1 or 2 years. Patients with symptomatic breast cancer who did not report a recent prior screen were excluded from these analyses. Characteristics associated with more aggressive disease [estrogen receptor (ER)– and progesterone receptor (PR)–negative status and higher tumor grade] were abstracted from medical records. Mammogram facility characteristics that might indicate aspects of screening quality were defined and controlled for in some analyses. Results: SADRS was more common among non-Hispanic black and Hispanic than among non-Hispanic white patients (36% and 42% vs. 25%, respectively, P = 0.0004). SADRS was associated with ER/PR-negative and higher-grade disease. Patients screened at sites that relied on dedicated radiologists and sites that were breast imaging centers of excellence were less likely to report SADRS. Tumor and facility factors together accounted for two thirds of the disparity in SADRS (proportion mediated = 70%, P = 0.02). Conclusion: Facility resources and tumor aggressiveness explain much of the racial/ethnic disparity in symptomatic breast cancer among recently screened patients. Impact: A more equitable distribution of high-quality screening would ameliorate but not eliminate this disparity. Cancer Epidemiol Biomarkers Prev; 24(10); 1599–606. ©2015 AACR.

Impact of a False-Positive Screening Mammogram on Subsequent Screening Behavior and Stage at Breast Cancer Diagnosis

Background: Experiencing a false positive (FP) screening mammogram is economically, physically, and emotionally burdensome, which may affect future screening behavior by delaying the next scheduled mammogram or by avoiding screening altogether. We sought to examine the impact of a FP screening mammogram on the subsequent screening mammography behavior. Methods: Delay in obtaining subsequent screening was defined as any mammogram performed more than 12 months from index mammogram. The Kaplan–Meier (product limit) estimator and Cox proportional hazards model were used to estimate the unadjusted delay and the hazard ratio (HR) of delay of the subsequent screening mammogram within the next 36 months from the index mammogram date. Results: A total of 650,232 true negative (TN) and 90,918 FP mammograms from 261,767 women were included. The likelihood of a subsequent mammogram was higher in women experiencing a TN result than women experiencing a FP result (85.0% vs. 77.9%, P < 0.001). The median delay in returning to screening was higher for FP versus TN (13 months vs. 3 months, P < 0.001). Women with TN result were 36% more likely to return to screening in the next 36 months compared with women with a FP result HR = 1.36 (95% CI, 1.35–1.37). Experiencing a FP mammogram increases the risk of late stage at diagnosis compared with prior TN mammogram (P < 0.001). Conclusions: Women with a FP mammogram were more likely to delay their subsequent screening compared with women with a TN mammogram. Impact: A prior FP experience may subsequently increase the 4-year cumulative risk of late stage at diagnosis. Cancer Epidemiol Biomarkers Prev; 26(3); 397–403. ©2017 AACR.

Individual breast cancer risk assessment in underserved populations: integrating empirical bioethics and health disparities research.

Research suggests that individual breast cancer risk assessment may improve adherence to recommended screening and prevention guidelines, thereby decreasing morbidity and mortality. Further research on the use of risk assessment models in underserved minority populations is critical to informing national public health efforts to eliminate breast cancer disparities. However, implementing individual breast cancer risk assessment in underserved patient populations raises particular ethical issues that require further examination. After reviewing these issues, we will discuss how empirical bioethics research can be integrated with health disparities research to inform the translation of research findings. Our in-progress National Cancer Institute (NCI) funded study, How Do Underserved Minority Women Think About Breast Cancer?, conducted in the context of a larger study on individual breast cancer risk assessment, is presented as a model.

Mediation of Racial and Ethnic Disparities in Estrogen/Progesterone Receptor–Negative Breast Cancer by Socioeconomic Position and Reproductive Factors

Hispanic and non-Hispanic black breast cancer patients are more likely than non-Hispanic white patients to be diagnosed with breast cancer that is negative for estrogen and progesterone receptors (ER/PR-negative). This disparity might be transmitted through socioeconomic and reproductive factors. Data on 746 recently diagnosed breast cancer patients (300 non-Hispanic white, 303 non-Hispanic black, 143 Hispanic) were obtained from the population-based Breast Cancer Care in Chicago Study (Chicago, Illinois, 2005-2008). Income, educational level, and census tract measures of concentrated disadvantage and affluence were combined into a single measure of socioeconomic position (SEP). Parity and age at first birth were combined into a single measure of reproductive factors (RPF). We constructed path models to estimate direct and indirect associations of SEP and RPF, and we estimated average marginal controlled direct associations. Compared with non-Hispanic white patients, non-Hispanic black patients and Hispanic patients were more likely to have ER/PR-negative disease (28% and 20% for non-Hispanic black patients and Hispanic patients, respectively, vs. 12% for non-Hispanic white patients; P ≤ 0.001). The ethnic disparity in ER/PR-negative breast cancer (prevalence difference = 0.13, 95% confidence interval: 0.07, 0.18) was reduced by approximately 60% (prevalence difference = 0.05, 95% confidence interval: -0.04, 0.13) after control for SEP and RPF. At least part of the ethnic disparity in the aggressiveness of breast tumors might be transmitted through social influences on tumor biology.

Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2

Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (< 1%) of patients tested for hereditary breast (BC) and ovarian cancer. It is unclear what factors predict BRACAnalysis Large Rearrangement Test (BART) positivity.

Selenium levels in human breast carcinoma tissue are associated with a common polymorphism in the gene for SELENOP (Selenoprotein P)

Selenium supplementation of the diets of rodents has consistently been shown to suppress mammary carcinogenesis and some, albeit not all, human epidemiological studies have indicated an inverse association between selenium and breast cancer risk. In order to better understand the role selenium plays in breast cancer, 30 samples of tumor tissue were obtained from women with breast cancer and analyzed for selenium concentration, the levels of several selenium-containing proteins and the levels of the MnSOD anti-oxidant protein. Polymorphisms within the genes for these same proteins were determined from DNA isolated from the tissue samples. There was a wide range of selenium in these tissues, ranging from 24 to 854ng/gm. The selenium levels in the tissues were correlated to the genotype of the SELENOP selenium carrier protein, but not to other proteins whose levels have been reported to be responsive to selenium availability, including GPX1, SELENOF and SBP1. There was an association between a polymorphism in the gene for MnSOD and the levels of the encoded protein. These studies were the first to examine the relationship between selenium levels, genotypes and protein levels in human tissues. Furthermore, the obtained data provide evidence for the need to obtain data about the effects of selenium in breast cancer by examining samples from that particular tissue type.