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Reproductive Risk Factor Patterns in the Caribbean Affecting Breast Cancer Age of Onset

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Background: Breast cancer is the leading cause of cancer in high-income (HIC) and low to middle-income countries (LMIC); and is the most common diagnosed cancer among women. Factors affecting breast cancer incidence include obesity, parity, age of menarche, age of first pregnancy and mutations in BRCA1/2 and genes involved in the homologous recombination repair pathway. These factors differ between HICs and LMICs including countries in the Caribbean. The majority of women from the Caribbean are of African ancestry and Black women have increased morbidity and mortality rates of breast cancer. Our goal is to study how reproductive patterns affect breast cancer age at presentation in Caribbean-born women. Methods: We conducted a prospective observational study recruiting patients from The Bahamas, Barbados, Cayman Islands, Dominica, Haiti, Jamaica and Trinidad and Tobago. Women were considered eligible if they were diagnosed with primary breast cancer at any age. The cohort was divided into four groups based on the year of birth ( < 1950, 1950 – 1959, 1960 – 1969, > 1970). The following data was collected: age at diagnosis of breast cancer, family history of cancer, age of first pregnancy, number of pregnancies, number of children, number of siblings, BMI at time of enrollment, age of menarche and menopause. Data analysis was conducted using the Chi-square test, ANOVA and logistic regression model. Results: A total of 1015 were enrolled and 995 met inclusion criteria. When comparing women born < 1950 to those > 1970, there was a statistically significant difference between means for the variables: Age at Breast cancer diagnosis (60.7 vs 35, p <.0001); number of siblings (4.5 vs 6.6, p <.0001); age of menarche (13.4 vs 12.3, p <.0001); number of pregnancies (4 vs 2.09); number of children (3.5 vs 1.6, p <.0001) and age of menopause at diagnosis (47.4 vs 37.5, p <.0001). When comparing women who were never pregnant to those who experienced pregnancy, mean age at breast cancer diagnosis was significantly reduced from 47.3 to 41.5 (p < 0.0001). Women who had n = 3 or more children were diagnosed older (mean of 49.9 years), compared to women with 2 or less children, (45.1 years, p < 0.0001). In multivariate analysis a higher likelihood for a positive mutation between year of birth 1960-1969 (aOR 2.19 [1.24 – 3.88], p = 0.007) and > 1970 (aOR 2.02 [1.06 – 3.88], p = 0.034) compared to < 1950. Conclusions: Our data shows that the Caribbean has undergone a rapid change in reproductive patterns in one generation. These changes provide an insight of risk factor patterns for breast cancer incidence which are associated with younger age of onset.

Comparing Breast Cancer Characteristics and Outcomes Between Black US-Born Patients and Black Immigrant Patients from Individual Caribbean Islands

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Background: Caribbean-born black immigrants (CBI) represent 57% of all black immigrants in the US; they come mainly from Haiti, Jamaica, Dominican Republic (DR), and Cuba. Breast cancer (BC) is the leading cause of cancer deaths in women living in the Caribbean, however, our previous retrospective cohort of 1131 black women with BC shows that CBI have a better overall survival compared with US-born black (USB). The Caribbean has a majority of African ancestry; nonetheless, different ancestral populations differ in genetic composition, making the Caribbean a distinct population with several health disparities within it. Therefore, we stratified our study by each Caribbean country compared to USB patients with the objective of further studying the difference in BC outcomes between USB patients and CBI. Methods: We identified BC patients through a Safety Net and Private Hospital Tumor Registries. We selected the most populace sites: Haiti, Jamaica, Bahamas, Cuba and DR; and used data from 1,082 patients to estimate hazard rations (HRs) using Cox proportional hazards regression and Kaplan Meier analysis for overall survival; Chi Squared and independent sample t-test to verify associations in categorical variables. Results: The study has 250 Haitian, 89 Jamaican, 43 Bahamian, 38 Dominican, 38 Cuban and 624 USB women. Haitians underwent less surgery (HB 61.2% vs USB 72.9%; P = 0.001) and had less triple negative BC (18% vs USB 27.8%; P = 0.006). Bahamians were the youngest at diagnosis (50.5 years vs. USB 57.6 P < 0.001) and presented at more advanced stages (stage 3/4, 54.3% vs USB 35.3%; P = 0.02). Jamaicans and DR underwent more radiation therapy (43.8%, P = 0.002 and 44.7%, P = 0.028 vs. USB 28%). Jamaican women had a better overall survival compared to USB patients (median of 154.93 months, 95% CI: 114.1-195.5 vs 98.63 months, 95% CI: 76.4-120.8; Log-Rank Mantel Cox P = 0.034). Favorable factors for survival were: radiation therapy in Haitian and USB (aHR = 0.45, 95% 0.27-0.77; P = 0.004); and surgery in USB (aHR = 0.26 (0.19-0.36), p < 0.001), Bahamians (aHR = 0.05 (0.01-0.47), p = 0.008) and Jamaicans (aHR = 0.08 (0.03-0.24), p < 0.001). Conclusions: This study underlines the vast heterogeneity in the Caribbean population and demonstrates that Jamaican immigrants with BC have a higher overall survival compared to USB patients, proposing that genetic and other cancer related factors inherent to country of origin impact survival within Caribbean immigrants and highlighting the need for further studies in this immigrant sub-group.

Race and Ethnicity Influence Survival Outcomes in Women of Caribbean Nativity With Epithelial Ovarian Cancer

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Background: Caribbean immigrants represent one of the largest groups of minorities in the United States (US), yet are understudied. Racial and ethnic disparities among women with ovarian cancer have been reported, but not in immigrant populations. Our objective was to evaluate differences in the clinicopathologic features and survival outcomes of Caribbean-born (CB) immigrants with ovarian cancer, with special focus on the influence of race and ethnicity on these measures.

Methods: A review of the institutional cancer registry was performed to identify women with known nativity treated for epithelial ovarian cancer between 2005 and 2017. Sociodemographic, clinical, and outcomes data were collected. Analyses were done using chi-square, Cox proportional hazards models, and the Kaplan-Meier method, with significance set at p < 0.05.

Results: 529 women were included in the analysis, 248 CB and 281 US-born (USB). CB women were more likely to have residual disease after debulking surgery (31.2 vs. 16.8%, p = 0.009) and be treated at a public facility (62.5 vs. 33.5%, p < 0.001). Black CB women less frequently received chemotherapy compared to White CB women (55.2 vs. 82.2%, p = 0.001). Among all CB women, Hispanic ethnicity was independently associated with improved survival when adjusting for other factors (HR 0.61 [95% CI 0.39–0.95], p = 0.03). White Hispanic CB women had a median overall survival (OS) of 59 months while Black, non-Hispanic CB women had a median OS of 24 months (log-rank p = 0.04).

Conclusion: Among Caribbean-born women with ovarian cancer, Hispanic ethnicity is significantly associated with improved survival outcomes, regardless of race.

BRCA Haploinsufficiency Promotes Gluconeogenesis in Fallopian Tube Epithelial Cells

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Introduction: High-grade serous ovarian cancer (HGSC) is one of the deadliest gynecologic malignancies due to presentation at advanced stages and the development of chemotherapy resistance. The recent discovery that HGSC arises from fallopian tube epithelia (FTE) and the analysis results obtained from TCGA study are helping in understanding the genes involved in the progression of the disease. HGSC is genetically unstable due to the loss of function mutations in BRCA1, BRCA2, PALB2, ATM, and RAD51 genes involved in DNA damage response. These genes also regulate cellular metabolism, antioxidant, and detoxification responses. Preliminary data show that phase II antioxidant enzymes are significantly reduced in HGSC and there is an increase in reactive oxygen species (ROS) in cells harboring p53 and BRCA1 mutations in precursor lesions of FTE and HGSC. We also observed differential mRNA expression of PCK1 and PCK2, GLUT1 genes involved in gluconeogenesis and glycolysis. Mitochondria are one of the major organelles for the production of ROS, and it is a well-known fact that metabolism is drastically changed in cancer cells compared to normal cells. Our aim was to determine the metabolic and fuel dependency in preneoplastic transformed cells, characterize the mitochondrial phenotype, and link these dependencies to transformation in FTE.

Methods: Fallopian tube specimens were obtained from the Biospecimen Shared Resources Core at SCCC. Patients undergoing risk reduction surgery were consent and FTE cells were obtained from BRCA and non-BRCA. Preneoplastic cell lines were then generated by hTERT, p53 mutation (R175H), and HPVE7. To mimic the genetic changes of in vivo HGSC, oncogenes CCNE1 and PIK3CA-H1047R were then overexpressed (OE) in these immortalized cell lines. Xenografts were generated from the transformed FTE cells lines. Agilent Seahorse assays were used to study the fuel dependency, oxidative phosphorylation, and glycolysis.

Results: FTE-BRCA1 and FTE-BRCA2 cells showed differences in both glycolytic and oxidative metabolism depending on the oncogenic type. The transformed cells had lower oxidative metabolism and there was also discrepancy in the dependency of metabolites utilized by these cell lines for energy. As seen by mRNA, FTE-BRCA cells had more PCK2 protein and were characterized by higher metabolic rates; these observations were augmented in the presence of PIK3CA-H1047R. However, these FTE preneoplastic and oncogene transformed cells showed no difference in their mitochondrial mass or membrane potential.

Conclusion: FTE-BRCA mutant cells utilize glycolysis or gluconeogenesis pathways to overcome metabolic stress depending on which oncogene is driving carcinogenesis. Further work is required to elucidate the mechanism of PCK2 and BRCA link in ovarian cancer carcinogenesis.

Ovarian Hormones Regulate C/EBPD Induced EMT/MET Transition in the Human Fallopian Tube Epithelia

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Introduction: The histologically normal BRCA1 mutation carrier fallopian tube epithelia (FTE), compared to controls, showed that CEBPD was upregulated in the luteal phase of the ovulatory cycle. CEBPD is involved with the maintenance of genomic stability, promoting cellular differentiation, and regulating the cell cycle in response to cytotoxic stressors. In breast epithelial cells, CEBPD protein expression correlated with estrogen receptor (ER) and progesterone receptor (PR) and was found to be associated with increased progression-free survival in breast cancer patients. In fallopian tube epithelia (FTE), CEBPD was also found to modulate the epithelial-to-mesenchymal (EMT)/mesenchymal-to-epithelial transition (MET) by modulating target genes of this pathway. Given the hormonal response of this gene and its function in modulating an EMT/MET, the objective of this study was to determine whether sex hormones influence CEBPD regulation of EMT/MET in the fallopian tube and thus ovarian cancer.

Methods: Fresh fallopian tube (FTE) tissues were obtained from patients approved for collection by IRB. Immunohistochemical profiling on normal fallopian tube tissue and HGSC was performed using CEBPD, ER, and PR protein markers. FTE cell lines with a p53 mutation (R175H) were subjected to estradiol (50nM and 100nM) and 4-hydroxytamoxifen (10nM) and assayed using qRT-PCR and PCR. ANOVA and t-tests were conducted in GraphPad Prism software with significance set at p<0.05.

Results: E-cadherin in normal fallopian tube tissue was highly expressed in both the luteal and follicular phase whereas vimentin was highly expressed in the follicular phase but showed a range of expression (low expression to high expression) in the luteal phase. CEBPD overexpression increased SNAIL expression (p<0.0001), consistent with previous findings; treatment with 50nM estradiol (E2) resulted in increased SNAIL and SLUG mRNA expression in FTE cell lines overexpressing CEBPD (p<0.0001) relative to controls and decreased ZEB1 and ZEB2 mRNA expression. Addition of tamoxifen to cells overexpressing CEBPD increased SNAIL mRNA expression compared to cells without tamoxifen (p<0.0001); however, a combination of both tamoxifen and estradiol added to these cells decreased SNAIL expression relative to controls. IL6 mRNA expression level was increased in CEBPD overexpressing cells compared to controls (p<0.0001), which was further increased by E2 (p<0.0001).

Conclusion: Together these results demonstrate a role for CEBPD in modulating EMT/MET in normal FTE in a hormonally regulated manner, which during cancer formation and spread is critical for anoikis and metastasis. Furthermore, these data will facilitate an understanding of the early events of carcinogenesis in fallopian tube epithelia.

Thrombocytosis as a Biomarker in Type II, Non-Endometrioid Endometrial Cancer

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Thrombocytosis (platelets ≥ 400K) is a common hematologic finding in gynecologic malignancies and associated with worse outcomes. Limited data exist on the prognostic capability of thrombocytosis in women with high-grade endometrial cancer (EC). Our objective was to describe the associations between elevated platelets at diagnosis, clinicopathologic features, and survival outcomes among women with high-grade, non-endometrioid EC. A review of the institutional cancer registry was performed to identify these women treated between 2005 and 2017. Sociodemographic, clinical, and outcomes data were collected. Analyses were performed using chi-square tests, Cox proportional hazards models, and the Kaplan–Meier method. A total of 271 women were included in the analysis. A total of 19.3% of women had thrombocytosis at diagnosis. Thrombocytosis was associated with reduced median overall survival (OS) compared with those not displaying thrombocytosis (29.4 months vs. 60 months, p < 0.01). This finding was most pronounced in uterine serous carcinoma (16.4 months with thrombocytosis vs. 34.4 months without, p < 0.01). While non-White women had shorter median OS for the whole cohort in the setting of thrombocytosis (29.4 months vs. 39.6 months, p < 0.01), among those with uterine serous carcinoma (USC), this finding was reversed, with decreased median OS in White women (22.1 vs. 16.4 months, p = 0.01). Thrombocytosis is concluded to have negative associations with OS and patient race.

The Effects of Size and Shape of the Ovarian Cancer Spheroids on the Drug Resistance and Migration

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Graphical abstract

Formation of loose aggregates and compact spheroids using OVCAR-3 and OVCAR-8 cells, respectively.

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mRNA Expression in Low Grade Serous Ovarian Cancer: Results of a NanoString Assay in a Diverse Population

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An Investigation into the Influence of Electrically Conductive Particle Size on Electromechanical Coupling and Effective Dielectric Strain Coefficients in Three Phase Composite Piezoelectric Polymers

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Three phase epoxy/piezoelectric/conductive filler composites were fabricated. The volume fraction of the conductive filler, aluminum, was held constant at 20%, while the volume fraction of the piezoelectric material, PZT was varied from 0.10 to 0.70. Three sets of composites were examined, wherein, the size of the aluminum constituent was varied from micron in size (200 mesh) to nano -in size (∼18 nm). Both sets of composites presented enhanced loss factor (tan δ) and piezoelectric coefficient (d33) values for volume fractions of PZT above 0.30 volume fraction. Composites having micron size aluminum particles exhibited higher loss factor and strain coefficients than those that incorporated nano-size aluminum particles, which could be due to several factors: agglomeration, contact resistance between particles, and excess air voids in the samples.

Conduction in Multiphase Particulate/Fibrous Networks: Simulations and Experiments On Li-ion Anodes

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