Lifetime changes in body mass index and risk of breast cancer in minority women

Introduction: Obesity is an epidemic in the United States, especially among Hispanics and African-Americans. Studies of obesity and breast cancer risk and subtype have been conducted primarily in non-Hispanic whites. Obesity is inversely associated with premenopausal breast cancer, but both obesity and weight gain increase the risk of postmenopausal disease. Obesity has been associated with breast cancer subtype in many studies. Methods: To assess the association between changes in body mass index (BMI) over the lifetime, weight gain, and breast cancer in Mexican-American women, we conducted a case-control study using 149 cases and 330 age-matched controls. In a second study, we identified 212 African-American and 167 Mexican-American women with breast cancer in the ongoing ELLA Bi-National Breast Cancer Study, abstracted medical charts to classify tumors as ER+/PR+, HER2+, or ER-/PR-/HER2-, and assessed the association between lifetime changes in body mass index, weight gain, and breast cancer subtype. In both studies, growth mixture modeling was use to identify trajectories of change in BMI over the lifetime, and these trajectories were used as exposures in a logistic regression model to calculate odds ratios (OR). Results: There was no association between trajectories of change in BMI and breast cancer risk in Mexican-American women. In addition, BMI at ages 15 and 30 and at diagnosis was not associated with breast cancer. However, adult weight gain was inversely associated with breast cancer risk (per 5kg, OR=0.92, 95% CI: 0.85-0.99). The case-only analysis found no association between obesity at ages 15 and 30 and at diagnosis and breast cancer subtype. Further, there was no association between adult weight gain (defined as weight change from age 15 to time of diagnosis) and breast cancer subtype. Conclusions: Obesity was not associated with breast cancer risk in Mexican-American women, while adult weight gain reduced the risk independently of menopausal status. These results are contradictory of those in non-Hispanic white women and suggest that the etiology of breast cancer may differ by race/ethnicity. Further, obesity was not associated with breast cancer subtype in African-American and Mexican-American women, contrary to results in non-Hispanic white women. ^

Breast cancer risk with aromatase inhibition and phytoestrogen-free diet

In this thesis a mouse model was used to examine the effect of pubertal estrogen inhibition and a phytoestrogen-free diet on the development of mammary glands. The study question was does treatment with aromatase inhibitor during puberty increase susceptibility to breast cancer among cohorts that consumed a diet free of phytoestrogens. The study design consisted of a cohort of mice treated with aromatase inhibitor, letrozole, during puberty and a vehicular group that was used as a control. Both groups were fed a diet free of phytoestrogens from the time of weaning until sacrifice during adulthood. The study aimed to assess mammary gland development in terms of breast cancer risk. The methods employed in this research included morphological and histological analysis of mammary glands, as well as estradiol, RNA and protein analysis. The main finding of the study was that mice exposed to aromatase inhibitor during puberty developed mammary glands with specific characteristics suggestive of vulnerability to oncogenesis such as increased lateral branching, increased number of glands, increase ductal hyperplasia, and diminished expression of TGFβ and p27 protein levels. The conclusions suggest that puberty is a critical period in which the mammary gland is susceptible to environmental threats that may result in deleterious epigenetic effects leading to an increased breast cancer risk in adulthood. This study has several public health implications; the most significant is that environmental threats during puberty may result in adverse mammary gland development and that phytoestrogen sources in the diet are necessary for normal maturation of the mammary glands.^

ACCURACY OF THE BRCAPRO RISK ASSESSMENT MODEL IN MALES PRESENTING TO MD ANDERSON FOR BRCA TESTING

ACCURACY OF THE BRCAPRO RISK ASSESSMENT MODEL IN MALES PRESENTING TO MD ANDERSON FOR BRCA TESTING Publication No. _______ Carolyn A. Garby, B.S. Supervisory Professor: Banu Arun, M.D. Hereditary Breast and Ovarian Cancer (HBOC) syndrome is due to mutations in BRCA1 and BRCA2 genes. Women with HBOC have high risks to develop breast and ovarian cancers. Males with HBOC are commonly overlooked because male breast cancer is rare and other male cancer risks such as prostate and pancreatic cancers are relatively low. BRCA genetic testing is indicated for men as it is currently estimated that 4-40% of male breast cancers result from a BRCA1 or BRCA2 mutation (Ottini, 2010) and management recommendations can be made based on genetic test results. Risk assessment models are available to provide the individualized likelihood to have a BRCA mutation. Only one study has been conducted to date to evaluate the accuracy of BRCAPro in males and was based on a cohort of Italian males and utilized an older version of BRCAPro. The objective of this study is to determine if BRCAPro5.1 is a valid risk assessment model for males who present to MD Anderson Cancer Center for BRCA genetic testing. BRCAPro has been previously validated for determining the probability of carrying a BRCA mutation, however has not been further examined particularly in males. The total cohort consisted of 152 males who had undergone BRCA genetic testing. The cohort was stratified by indication for genetic counseling. Indications included having a known familial BRCA mutation, having a personal diagnosis of a BRCA-related cancer, or having a family history suggestive of HBOC. Overall there were 22 (14.47%) BRCA1+ males and 25 (16.45%) BRCA2+ males. Receiver operating characteristic curves were constructed for the cohort overall, for each particular indication, as well as for each cancer subtype. Our findings revealed that the BRCAPro5.1 model had perfect discriminating ability at a threshold of 56.2 for males with breast cancer, however only 2 (4.35%) of 46 were found to have BRCA2 mutations. These results are significantly lower than the high approximation (40%) reported in previous literature. BRCAPro does perform well in certain situations for men. Future investigation of male breast cancer and men at risk for BRCA mutations is necessary to provide a more accurate risk assessment.

Predictors of Contralateral Breast Cancer in BRCA Negative Women

Breast cancer is the most common cancer diagnosis and second leading cause of death in women. Risk factors associated with breast cancer include: increased age, alcohol consumption, cigarette smoking, white race, physical inactivity, benign breast conditions, reproductive and hormonal factors, dietary factors, and family history. Hereditary breast and ovarian cancer syndrome (HBOC) is caused by mutations in the BRCA1 and BRCA2 genes. Women carrying a mutation in these genes are at an increased risk to develop a second breast cancer. Contralateral breast cancer is the most common second primary cancer in patients treated for a first breast cancer. Other risk factors for developing contralateral breast cancer include a strong family history of breast cancer, age of onset of first primary breast cancer, and if the first primary was a lobular carcinoma, which has an increased risk of being bilateral. A retrospective chart review was performed on a select cohort of women in an IRB approved database at MD Anderson Cancer Center. The final cohort contained 572 women who tested negative for a BRCA1 or BRCA2 mutation, had their primary invasive breast cancer diagnosed under the age of 50, and had a BRCAPro risk assessment number over 10%. Of the 572 women, 97 women developed contralateral breast cancer. A number of predictors of contralateral breast cancer were looked at between the two groups. Using univariable Cox Proportional Hazard model, thirteen statistically interesting risk factors were found, defined as having a p-value under 0.2. Multivariable stepwise Cox Proportional Hazard model found four statistically significant variables out of the thirteen found in the univariable analysis. In our study population, the incidence of contralateral breast cancer was 17%. Four statistically significant variables were identified. Undergoing a prophylactic mastectomy was found to reduce the risk of developing contralateral breast cancer, while not having a prophylactic mastecomy, a young age at primary diagnosis, having a positive estrogen receptor status of the primary tumor, and having a family history of breast cancer increased a woman’s risk to develop contralateral breast cancer.

Trastuzumab use and risk of congestive heart failure in older breast cancer patients

Trastuzumab is a humanized-monoclonal antibody, developed specifically for HER2-neu over-expressed breast cancer patients. Although highly effective and well tolerated, it was reported associated with Congestive Heart Failure (CHF) in clinical trial settings (up to 27%). This leaves a gap where, Trastuzumab-related CHF rate in general population, especially older breast cancer patients with long term treatment of Trastuzumab remains unknown. This thesis examined the rates and risk factors associated with Trastuzumab-related CHF in a large population of older breast cancer patients. A retrospective cohort study using the existing Surveillance, Epidemiology and End Results (SEER) and Medicare linked de-identified database was performed. Breast cancer patients ≥ 66 years old, stage I-IV, diagnosed in 1998-2007, fully covered by Medicare but no HMO within 1-year before and after first diagnosis month, received 1st chemotherapy no earlier than 30 days prior to diagnosis were selected as study cohort. The primary outcome of this study is a diagnosis of CHF after starting chemotherapy but none CHF claims on or before cancer diagnosis date. ICD-9 and HCPCS codes were used to pool the claims for Trastuzumab use, chemotherapy, comorbidities and CHF claims. Statistical analysis including comparison of characteristics, Kaplan-Meier survival estimates of CHF rates for long term follow up, and Multivariable Cox regression model using Trastuzumab as a time-dependent variable were performed. Out of 17,684 selected cohort, 2,037 (12%) received Trastuzumab. Among them, 35% (714 out of 2037) were diagnosed with CHF, compared to 31% (4784 of 15647) of CHF rate in other chemotherapy recipients (p<.0001). After 10 years of follow-up, 65% of Trastuzumab users developed CHF, compared to 47% in their counterparts. After adjusting for patient demographic, tumor and clinical characteristics, older breast cancer patients who used Trastuzumab showed a significantly higher risk in developing CHF than other chemotherapy recipients (HR 1.69, 95% CI 1.54 - 1.85). And this risk is increased along with the increment of age (p-value < .0001). Among Trastuzumab users, these covariates also significantly increased the risk of CHF: older age, stage IV, Non-Hispanic black race, unmarried, comorbidities, Anthracyclin use, Taxane use, and lower educational level. It is concluded that, Trastuzumab users in older breast cancer patients had 69% higher risk in developing CHF than non-Trastuzumab users, much higher than the 27% increase reported in younger clinical trial patients. Older age, Non-Hispanic black race, unmarried, comorbidity, combined use with Anthracycline or Taxane also significantly increase the risk of CHF development in older patients treated with Trastuzumab. ^

Correlates of post-diagnosis weight management among female breast cancer survivors: An Internet survey

Objective. Weight gain after cancer treatment is associated with breast cancer recurrence. In order to prolong cancer-free survivorship, interventions to manage post-diagnosis weight are sometimes conducted. However, little is known about what factors are associated with weight management behaviors among cancer survivors. In this study, we examined associations of demographic, clinical, and psychosocial variables with weight management behaviors in female breast cancer survivors. We also examined whether knowledge about post-diagnosis weight gain and its risk is associated with weight management behaviors. ^ Methods. 251 female breast cancer survivors completed an internet survey. They reported current performance of three weight management behaviors (general weight management, physical activity, and healthy diet). We also measured attitude, elf-efficacy, knowledge and social support regarding these behaviors along with demographic and clinical characteristics. ^ Results. Multiple regression models for the weight management behaviors explained 17% of the variance in general weight management, 45% in physical activity and 34% in healthy dieting. The models had 9–14 predictor variables which differed in each model. The variables associated with all three behaviors were social support and self-efficacy. Self-efficacy showed the strongest contribution in all models. The knowledge about weight gain and its risks was not associated with any weight management behaviors. However, women who obtained the knowledge during cancer treatment were more likely to engage in physical activity and healthy dieting. ^ Conclusions. The findings suggest that an intervention designed to increase their self-efficacy to manage weight, to be physically active, to eat healthy will effectively promote survivors to engage in these behaviors. Knowledge may motivate women to manage post-diagnosis weight about risk if information is provided during cancer treatment.^

Social and economically influenced factors associated with breast cancer treatment among blacks and whites. A qualitative study

Background: Despite the fact breast cancer mortality has declined in recent years, the mortality gap between African-American and white women continues to grow. A part of these disparities may be due to either inadequately following guideline recommended treatment or treatment delays. Although racial/ethnic disparities in breast cancer treatment and mortality have been extensively documented, the mechanisms by which these disparities occur remain largely unknown. Social and economically influenced factors such as choice of providers, distance of treatment facility, transportation, health insurance, and job related factors may also contribute to racial differences in breast cancer treatment; however, these have not been explored sufficiently in previous research. ^ Aim: The purpose of this study was to evaluate the role of social and economically influenced factors that may contribute to racial disparities in the receipt of guideline recommended treatment using the Health Disparities Model. ^ Methods: In this qualitative comparative case study, data from medical records, structured telephone interviews, and in-depth patient interviews explored the relationship between social and economically influenced factors and breast cancer treatment. Transcripts were analyzed using standard iterative process followed by immersion/crystallization approach. Participants were identified through rapid ascertainment from the New Jersey Cancer Registry and this study included 8 African-American and 8 white women aged 20-85 years old diagnosed with early stage breast cancer between 2003-2007, matched on age, race, and physician recommended treatment. ^ Results: We did not identify differences by race in factors that influenced the receipt of breast cancer treatment among the individual matched pairs. Four prominent themes emerged among women from both groups who experienced similar difficulties influenced by socioeconomic factors. Choice of providers, distance of facility, health insurance, and job related factors all contributed to breast cancer treatment experience among these women. Conclusions: We identified common issues influenced by socioeconomic factors and its relation with the receipt of breast cancer treatment, regardless of race. However, more research is needed to study the additional factors conveying racial differences affecting breast cancer treatment. ^

Developing the follow-up schedules for women with breast cancer

Background: The follow-up care for women with breast cancer requires an understanding of disease recurrence patterns and the follow-up visit schedule should be determined according to the times when the recurrence are most likely to occur, so that preventive measure can be taken to avoid or minimize the recurrence. Objective: To model breast cancer recurrence through stochastic process with an aim to generate a hazard function for determining a follow-up schedule. Methods: We modeled the process of disease progression as the time transformed Weiner process and the first-hitting-time was used as an approximation of the true failure time. The women's "recurrence-free survival time" or a "not having the recurrence event" is modeled by the time it takes Weiner process to cross a threshold value which represents a woman experiences breast cancer recurrence event. We explored threshold regression model which takes account of covariates that contributed to the prognosis of breast cancer following development of the first-hitting time model. Using real data from SEER-Medicare, we proposed models of follow-up visits schedule on the basis of constant probability of disease recurrence between consecutive visits. Results: We demonstrated that the threshold regression based on first-hitting-time modeling approach can provide useful predictive information about breast cancer recurrence. Our results suggest the surveillance and follow-up schedule can be determined for women based on their prognostic factors such as tumor stage and others. Women with early stage of disease may be seen less frequently for follow-up visits than those women with locally advanced stages. Our results from SEER-Medicare data support the idea of risk-controlled follow-up strategies for groups of women. Conclusion: The methodology we proposed in this study allows one to determine individual follow-up scheduling based on a parametric hazard function that incorporates known prognostic factors.^

The Role of Type I Insulin-Like Growth Factor Receptor Signaling in Breast Cancer Brain Metastasis

Brain metastasis is a common cause of mortality in cancer patients. Approximately 20-30% of breast cancer patients acquire brain metastasis, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF- IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that the IGF-IR signaling axis is constitutively active in brain-seeking sublines of breast cancer cells, driving an increase in in vitro metastatic properties. We demonstrate that IGF-IR signaling is activated in an autocrine manner as a result of IGFBP3 overexpression in brain-seeking cells. Transient and stable knockdown of IGF-IR results in a downregulation of IGF-IR downstream signaling through phospho-AKT, as well as decreased in vitro migration and invasion of MDA- MB-231Br brain-seeking cells. Using an in vivo experimental brain metastasis model, we show that IGF-IR ablation attenuates the establishment of brain metastases and prolongs survival. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

Mechanisms of HER2/{\it neu\/} proto-oncogene overexpression in breast cancer cells

Overexpression and amplification of HER2/neu have been documented in many primary tumors, most notably in breast. Not only do approximately 30% of breast cancer patients carry tumors that overexpress the gene, but those that do generally have shorter overall and disease-free survival times than patients with tumors expressing low levels of HER2/neu. Thus, overexpression of HER2/neu plays an important role in the pathogenesis of breast cancer. We have examined the mechanisms that result in HER2/neu overexpression in breast cancer by using, as a model system, established breast cancer cell lines that express much higher levels of HER2/neu mRNA than normal breast tissue while maintaining a near normal HER2/neu gene copy number. Nuclear run-on experiments indicate that the breast cancer cell lines MDA-MB453, BT483, and BT474 have an increased HER2/neu gene transcription rate. By using HER2/neu promoter-CAT constructs, we have found that the enhanced HER2/neu transcription rate in MDA-MB453 cells is due to activation of the gene in trans, while the enhanced transcription rate in BT483 cells is due to activation of the gene in either trans or cis. In BT474 cells, transcriptional upregulation is primarily due to gene amplification. Since the levels of increased transcription are not as high as the levels of HER2/neu mRNA in any of these three lines, post-transcriptional deregulation that increases HER2/neu expression must also be functioning in these cells. The half-life of HER2/neu mRNA was measured and found to be equivalent in these lines as in a control. Thus, the post-transcriptional deregulation is not increased stability of the HER2/neu transcript.^ Much work has been performed in characterizing the altered trans-acting factor involved in increased HER2/neu transcription in MDA-MB453 cells. Using promoter deletion constructs linked to a reporter gene, the region responsive to this factor was localized in the rat neu promoter. When human HER2/neu promoter constructs were used, the homologous sequence in the human promoter was identified. Furthermore, a number of protein/DNA complexes are detected when these promoter regions are used in gel mobility shift assays. UV-crosslinking experiments indicate DNA-binding proteins of roughly 110 kDa, 70 kDa, and 35 kDa are capable of interacting with the human promoter element. ^

Breast cancer -specific activation of topoisomerase IIalpha and its application in the tumor -targeting gene therapy

To ensure the success of systemic gene therapy, it is critical to enhance the tumor specificity and activity of the promoter. In the current study, we identified the breast cancer-specific activity of the topoisomerase IIα promoter. We further showed that cdk2 and cyclin A activate topoisomerase IIα promoter in a breast cancer-specific manner. An element containing an inverted CCAAT box (ICB) was shown to respond this signaling. When the ICB-harboring topoisomerase IIα minimal promoter was linked with an enhancer sequence from the cytomegalovirus immediate early gene promoter (CMV promoter), this composite promoter, CT90, exhibited activity comparable to or higher than the CMV promoter in breast cancer cells in vitro and in vivo, yet expresses much lower activity in normal cell lines and normal organs than the CMV promoter. A CT90-driven construct expressing BikDD, a potent pro-apoptotic gene, was shown to selectively kill breast cancer cells in vitro and to suppress mammary tumor development in an animal model of intravenously administrated, liposome-delivered gene therapy. Expression of BikDD was readily detectable in the tumors but not in the normal organs of CT90-BikDD-treated animals. Finally, we demonstrated that CT90-BikDD treatment potentially enhanced the sensitivity of breast cancer cells to chemotherapeutic agents, especially doxorubicin and taxol. The results indicate that liposomal CT90-BikDD is a novel and effective systemic breast cancer-targeting gene therapy, and its combination with chemotherapy may further improve the current adjuvant therapy for breast cancer. ^