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Abstract PL03-01: Origins of ovarian cancer, the biology of premalignancy, and cancer health disparities

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Epithelial ovarian cancer (EOC) is the 5th leading cause of cancer-related deaths in women in the United States1. High-grade serous carcinoma (HGSC) is the most aggressive EOC and women usually present at high-grade and high stage, leading to only a 30% 5 year survival rate after adjuvant platinum-based chemotherapy2. Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk (11%-60%) in developing high-grade serous cancer – the predominant histotype associated with hereditary breast-ovarian cancer3. The distal end of the fallopian tube is now the accepted site of origin of high-grade serous ovarian cancer4. It is known that factors related to parity, ovulation and hormone regulation have a dramatic effect on the risk of developing ovarian cancer in both BRCA mutation carriers and non-carriers. Recently, we have shown that the transcriptional profile of histologically normal fallopian tube epithelia of BRCA mutation carriers is different from wild type FTE and possibly hints at BRCA haploinsufficiency5,6. We propose that changes of the transcriptome in BRCA mutation carriers reflect an altered response to the microenvironment ovulatory stresses, which may include altered reproductive hormone levels and the ovulatory inflammatory response.

The prevalence of the BRCA mutation in the Bahamas where 23% of unselected breast cancer patients carry a mutation in the BRCA1 is the highest hereditary proportion in the world7,8. We are determining the importance of genetic founder effects in the two BRCA genes in the Caribbean basin – a region with a large African population (the Caymans, Barbados, Dominica and Jamaica). Epithelial ovarian cancer rates are low in the Caribbean and risk factors such as parity, age at menarche and menopause may be strong indicators of decreased risk in the population. The results of this extensive study will help direct health policies towards genetic testing in the Caribbean with implications for the immigrant US population, and should lead to regional policies regarding preventative strategies.

Abstract P4-10-11: An active approach to genetic counseling in Trinidadian women with breast cancer

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Introduction

Breast cancer (BC) is the leading cause of cancer death in Caribbean women. The prevalence of deleterious mutations in BRCA1/2, PALB2 and RAD51C among unselected BC patients in the Caribbean is 5-25%. We previously reported data on low usage of genetic counseling services by Bahamian women. In order to improve the dissemination of genetic testing results to Caribbean probands and their families we developed a structured approach to genetic test result dissemination and family counseling.

Methods

After approval by the University of Miami IRB and the Ethics Committee of the Ministry of Health of Trinidad & Tobago, we prospectively evaluated the active approach to genetic counseling in 32 BC mutation carriers in Trinidad & Tobago in 2015. The intervention consisted of: 1) initial appointment with referring oncologist for results discussion; 2) review of family tree with proband to identify all relatives at 25% or 50% risk (ARR) who should attend the genetic counseling session; 3) preschedule a counseling appointment for ARR within 2 weeks; 4) written invitation to genetic counseling session; 5) handouts of genetic information given to proband to distribute to family members; 6) offer assistance with contacting family members; 7) free genetic testing to ARR who attended the family counseling session.

Results

Twenty-five carriers (78%) consented to enroll in the study. At initial counseling, probands identified 158 ARR, however full family pedigree review at post-result counseling/consultation identified 225 ARR. 101 ARR (64%) attended the information sessions and 76 participants (75.2%) consented to be tested for BC gene mutations. Genetic sequencing revealed 35 ARR (46%) were carriers of at least one mutation. The most frequent reasons for ARR not attending the meetings were: living abroad (18%), unable to be contacted (17%), refusing to participate (17%), not showing up (17%), probands being estranged from ARR (12%) or being afraid to know the results (7%).

Conclusions

In Trinidad & Tobago, a structured approach to the dissemination of genetic test results leads to a significant improvement in the rate of family participation compared to previous efforts (64% in Trinidad & Tobago vs. 9% in the Bahamas).

A Decoupled Multi-Stimulus Bioreactor for Studying Complex Chemo-Mechanical Microenvironments In Vitro

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In the body, cells exist in a complex chemo-mechanical microenvironment, which works to regulate the cell’s functional behavior. In recent years, many novel bioreactor systems have been developed to expose cells to individual stimuli such as fluid wall shear stress (WSS), cyclic stretching, hydrostatic pressure, substrate stiffness, substrate topography, and extracellular matrix proteins. These systems have led to the growing appreciation for the role mechanical forces have in regulating cellular behavior; however, few approaches are material independent and allow for the systematic variation of multiple combinations of forces in a single device. We have developed the Universal Mechano-Tester™, a unique, cost-efficient, bioreactor system for independently and dynamically varying WSS, flow regime, cyclic stretch, hydrostatic pressure, and cell culture substrate including the substrate’s stiffness, topography, and extracellular matrix (ECM) components.

Abstract P3-08-06: Demographics of breast cancer in a cohort of Afro-Caribbean women

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Objectives: In Latin America and the Caribbean, non – communicable chronic diseases are now the leading cause of premature mortality. The incidence of cancer has increased in the region as a result of population aging and growth but also as more people adopt lifestyle choices like smoking, physical inactivity, and ‘‘westernized’’ diets. In women, fertility factors such as decreased parity, earlier onset of menses and later age at time of first pregnancy are known epidemiologically to increase incidence of hereditary and sporadic breast cancer. Recently there has also been a strong link to a genetic etiology of the breast and ovarian cancer in the Bahamas (27% in unselected breast cancer cases). A study was designed to address the prevalence and spectrum of BRCA1 and BRCA2 mutations in the Afro-Caribbean population.

Methods: Demographic and clinical pathologic data was collected from 347 women of Afro-Caribbean decent. The cohort included women with breast cancer from the following countries: the Cayman Islands, Jamaica, Barbados, Dominica, Trinidad and Haiti. Summary statistics and t-tests and ANOVA were used to analyze population characteristics. A Bahamian mutation panel was created and detailed analyses of samples are ongoing.

Results: The mean age of onset in the cohort is 48.1 yrs with a mean BMI of 27.7. 70% of breast cancer cases ER+ (n=241 informative cases) and in Jamaica 27% (n=105) of breast cancer cases were Her2+. 67.8% cases were diagnosed at stages II/III (n=90). TAH-BSO delayed invasive breast cancer from 48 to 53 years, p=0.005. Parity was a statistically significant factor (p<0.0001), which delayed age of onset by 8 yrs. Additionally, pregnancy alone delayed age of onset (p<0.005) also by 8 yrs in our cohort (n=379). Only three women out of 347 were found to have a mutation.

Abstract DP-005: RNA-SEQUENCING OF FALLOPIAN TUBE–FIMBRIA AND HGSC FROM BRCA MUTATION CARRIERS

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Inheritance of a deleterious mutation in the BRCA1/2 genes increases the risk of the disease by up to 40%. The origin of the disease is still debated; however considerable evidence suggests the fallopian tube as the primary site of disease origin. The fallopian tube epithelium changes morphologically and genomically with the ovulatory cycle. To further understand the transcriptomic profile of the fallopian tube epithelium amongst patients with and without a BRCA mutation who have undergone prophylactic surgery, samples with clinically annotated ovulatory cycle status were analyzed by next-generation sequencing (RNA-Seq). The results from this study will provide an understanding of the origins of the disease and how new therapeutic and preventative interventions can be applied early in the development of the disease.

METHODS: In total a cohort of 68 archival formalin fixed paraffin embedded (FFPE) fallopian tube -fimbria was amassed: FTE-BRCA1 (n=32), FTE-BRCA2 (n=4), chemonaive HGSC-BRCA1 (n=9), FTE-nonBRCA (n=26). The pre-menopausal fallopian tube specimens were sub-divided by ovulatory cycle: normal-Follicular, normal-Luteal, BRCA-Follicular, BRCA-Luteal. The majority of the FTE specimen were obtained from pre-menopausal women (post-menopausal n=2). Laser capture microdissection was performed on the distal end of the fallopian tubes – the fimbria. Six-twelve, 10um FFPE sections were cut and stained with hematoxylin prior to LCM. RNA was extracted using the Roche High Pure FFPE Micro Kit and samples were processed using Illumina Tru-Seq Stranded Total RNA Kit with RiboGold ready and sequenced on the Illumina Hi-seq 2000 V3. Raw results, in FASTQ format, were then processed through the RNA sequencing pipeline to generate results including gene expression data.

RESULTS: Gene expression differences between carriers and non-carriers (FTE-BRCA1/2 and FTE-nonBRCA) revealed genes involved in metabolic pathways namely: oxidative phosphorylation, mitochondrial functions, glycolysis/gluconeogenesis and glycan biosynthesis and metabolism: UGT2A1, ST6GALNNAC6, Complex 1 (ND1, ND2, ND4, NDL4, ND5), ATP6/ATP8, and COX1-3. A comparison between the tumor and fimbria cases showed increased activity in the HMGBI Signaling (increase in HAT1, KAT2B, LIF, JAK3 and PIK3CA and decrease in RAP1A/B, ATM and HMGB1).

CONCLUSION: These results highlight BRCA1/2 distinct unique preneoplastic processes not previously identified. The fallopian tube epithelial in the fimbria in BRCA1 and BRCA2 mutation carriers have increased metabolic activity, indicated by their gene expression profiles. HGSC developed BRCA1 germline mutation carriers have an increased histone acetyltransferase activity shown to be involved in BRCA mediated DNA damage repair. Further analysis is required to understand how the ovulatory cycle influences the fallopian tube epithelium transcriptome, but preliminary results suggest that pathways altered include: metabolic pathways, apoptosis pathways, p53 pathways and mismatch repair pathways. These results support previous findings in addition to providing new insight into the early development of the disease.

Abstract C55: Presentation, treatment, and outcomes of Haitian women with breast cancer in Miami and Haiti: Disparities in breast cancer. A retrospective cohort study

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Abstract C27: Breast cancer presentation in a cohort of Afro-American women and Afro-Caribbean women diagnosed at University of Miami/Jackson Memorial Hospital

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Background: It is documented that socioeconomic factors, such as lack of access to health care and inadequate treatment after diagnosis contribute to disparities in breast cancer, but these factors alone do not explain breast cancer disparities. Several studies suggest that several other factors, such as environmental, biological and behavioral factors may play a significant role in the observed disparities in breast cancer outcomes in women in minorities. In this study we compare Afro-Caribbean (AC) women born in the Caribbean and living in the United States and Afro-American (AA) women born and living in the United States, with a diagnosis of breast cancer in order to evaluate the effect of immigration and place of residency.

Methods: We conducted a retrospective chart review study of black women of AA and AC origin diagnosed with breast cancer at University of Miami/Jackson Memorial Hospital between 2005 and 2015 (n = 745). For each of the groups, we collected demographic data including age, body mass index (BMI), menopausal state, and TNM stage, receptor expression of estrogen and progesterone, Her-2/neu expression, gravidity and parity. Continuous data were analyzed using independent samples t-tests when parametric and using Wilcoxon-Mann-Whitney tests when non-parametric; categorical and binary data were analyzed using Chi-squared tests.

Results: We analyzed data from 745 black female patients: AA (n = 281) AC (n = 422). Place of birth was not available for 42 women. Mean age was 54.9 and 53.7 in AC and AA women, respectively. AA women had higher BMI (32.1 vs 29.8, p = 0.0001), lower proportion of HER2 positive breast cancer (12% vs 19%, p = 0.027) and more children (3.1 vs 2.8, p = 0.023) than AC. There was no difference in age (54.9 vs 53.7), premenopausal status (33% vs 31%), stage 3 or 4 (38% vs 37%), ER+ (63% vs 62%) or triple negative breast cancer (27% vs 31%) in AC compared with AA women (Table 1).

Conclusion: Jackson Memorial Hospital is a Safety-Net hospital for the 2.4 million residents of Miami-Dade County. The average age of our cohort was 54 years, ER 63% positive, Stage 3 was 27% and triple negative breast cancer was 29%. Compared to SEER data, our patients developed breast cancer one decade earlier, had a higher rate of triple negative breast cancer and higher stage at presentation. This was not affected by immigration status although the AC women were thinner and had fewer children.

Abstract C060: The spectrum of germline mutation carriers in a cohort of breast and ovarian cancer patients in the Caribbean

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The Caribbean population is predominantly of African descent with an admixture of Indigenous, East Asian, Indian subcontinent, Western European and Middle Eastern descendants. This region has one of the highest burdens of cancer in the world, and breast cancer is the leading cause of cancer death in Caribbean women. We established a cohort of 1,019 people diagnosed with breast and ovarian cancer across 7 Caribbean countries (Cayman Islands, Bahamas, Barbados, Dominica, Haiti, Jamaica, Trinidad and Tobago)—Caribbean Women’s Cancer Study (CWCS). The primary objective was to identify deleterious mutations in the breast cancer genes in a cohort of Caribbean people with breast and/or ovarian cancer.

Methods: The study was conducted between 2004-2015 in the Bahamas, Cayman Islands, Jamaica, Barbados, Dominica, Trinidad and Tobago and Haiti. Following IRB approval, 1,019 women and men diagnosed with breast or ovarian cancer were identified through outpatient oncology clinicals, treating physicians and cancer societies on the islands. In addition, participants were recruited through radio, newspaper and TV advertisements. Inclusion criteria were pathologic diagnosis of breast (male or female) and/or ovarian cancer, at least 1 grandparent born in one of the participating countries and ability to provide saliva. NGS and MPLA (BRCA1/2) were performed on a panel of 31 genes. The following epidemiologic and anthropometric measures were collected: family pedigree; age of menarche, menopause, and first pregnancy; number of pregnancies; number of siblings; year of birth; age at cancer diagnosis; body mass index (BMI) at time of diagnosis; stage of cancer; mode of diagnosis; and tumor characteristics.

Results: The mean age of the mutation carriers was 45 (20-70) years and mean BMI was 29.0. 70% of the mutation carriers self-identified as Afro-Caribbean. 75% identified their cancer by palpation. The Bahamas has the highest incidence of hereditary breast cancer in the world due to founder mutations in the BRCA1 and BRCA2 genes (23% of unselected breast cancer). In Trinidad and Tobago 12% of women with breast cancer had a mutation in BRCA1/2, PALB2, RAD51C or CHEK2. Jamaica had 4.9% incidence of BRCA1/2, STK11, NBN and PALB2 mutations and 6.9% (5/94) of Haitian women have deleterious mutations in BRCA1/2, PALB2. In Barbados 17.9% (16/89) have deleterious mutations in BRCA1/2, PALB2. In Dominica (4/57) 8.8% of the cohort had BRCA2 or PALB2 deleterious mutations and 6.3% (4/63) in the Cayman Islands had a deleterious mutation in ATM, BRCA1/2. 64% of mutations carriers had a frameshift, nonsense, or large deletion in BRCA1, 23% in BRCA2 and 9% in PALB2. There were 29 unique mutations in BRCA1 in 92 individuals (64%) and 23 unique mutations in BRCA2 with recurring (founder) mutations predominantly in the Bahamas. 11 distinct mutations in PALB2 were seen in 13 individuals across 5 countries.

Conclusion: This initial Caribbean population-based study demonstrates that genetic causes of breast cancer are common in the Caribbean population.

Abstract B59: Analysis of High-Grade Serous Ovarian Cancer in a Cohort of Women diagnosed Epithelial Ovarian Cancer at University of Miami/Jackson Memorial Hospital

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Background: High-grade serous ovarian (HGSC) cancer is the most common and aggressive histotype of epithelial ovarian cancer in women, accounting for 75% of epithelial ovarian carcinomas. Most women present at advanced stages III/IV at diagnosis and 5-year survival for patients with advanced stage disease is approximately 20-30%. However, for patients with stage I disease, five-year survival rates exceed 90%.

Ovarian cancer risk factors include nulliparity, early age of menarche, late age of menopause, hormone replacement, obesity and strong family history of hereditary breast and ovarian cancer (HBOC). It is estimated that about 1 in 500 Americans have a mutation in BRCA1 or BRCA2. In women with a germline mutation there is a lifetime risk of: 40%-60% (BRCA1) and 11%-27% (BRCA2), of developing ovarian cancer. Recent studies of different immigrant populations in the United States and in their respective countries of origin have identified pockets of women who bare a similarly high genetic burden as the Ashkenazi Jewish population. Women of Bahamian and Trinidadian heritage are estimated to have 27.1% of breast cancer cases due to BRCA founder mutations. The ovarian cancer burden in these isolated high-risk populations is still unclear, but likely to be as high as those women of Ashkenazi descent.

South Florida has the highest Caribbean immigrant community in the US and nearly 4 out of 10 immigrants in Florida were born in the Caribbean. We sought to elucidate the patient demographic, pathologic, and outcome within a university health system between the safety net hospital – Jackson Memorial Hospital (JMH) and the Sylvester comprehensive cancer center (SCCC).

Methods: We conducted a retrospective chart review study of women diagnosed with epithelial ovarian cancer with the high-grade serous carcinoma histotype at Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital between 2011 and 2015. We collected data including date of diagnosis, age, body mass index (BMI), country of birth, ethnicity, germ-line and somatic genetic tests results, medical insurance, treatment and vital status. SPSS software was used to analyze using independent samples t-tests when parametric and using Wilcoxon-Mann-Whitney tests when non-parametric; and Chi-squared tests for categorical and binary data.

Results: 374 patients were diagnosed and treated for high-grade serous ovarian cancer (HGSC). 50.8% were non-Hispanic, 47.9% Hispanic and 1.3% Unknown. 12.% of the patient population was Black with a significantly higher BMI (39.1 vs 27.9, p=0.004). Mean age was 58 (Hispanic white 57.7yrs (17-93), non-Hispanic white 58.5yrs (17-93) and Black (53.7yrs (18-78), p=0.019)) compared to US national average of 63. At least 32.3% of patients were born in the US while, 60% of patients were born in Latin America and the Caribbean. 72.3% of patients born outside the US were diagnosed and treated at JMH (p<0.001). In a subset analysis of 102 patients, 31% had genetic or somatic testing, of these, 2 patients were Black, not of Afro-Caribbean descent. Patients at JMH presented with 8% Stage I vs 74.7% Stage III/IV, compared to 16.3% Stage I vs 73% Stage IV at SCCC. They had more advanced stage V – 42.7% vs 16.3% at SCCC. JMH patients were more likely to be on Medicaid or uninsured (68% vs 14.2%, p<0.001). Median survival was 47.0 months (44.1-49.9) at SCCC compared to 45.0 months (37.6-52.3) for women at JMH (p=0.392).

Conclusion: The majority of women sought care at the SCCC when diagnosed with HGSC had a higher likelihood of early stage diagnosis, were insured and born in the USA, there was no difference in outcome between patients treated at JMH versus SCCC. Genetic testing within the Black population was low compared to Hispanic and non-Hispanic white patients. This data indicate that the quality of care received in this university health system is similar at both sites. Further studies are indicated to explore uptake of genetic testing, disparities between safety net systems and comprehensive cancer centers, particularly with the shift toward targeted disease prevention and personalized therapy.

Note: This abstract was not presented at the conference.

Abstract B50: Breast cancer in the Caribbean–A six-country cohort

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Introduction: In Low and Middle Income Countries (LMIC) non-communicable chronic diseases are now the leading cause of premature mortality. Breast cancer is the leading cause of cancer death in Caribbean women. A Caribbean wide study was launched to determine the demographics of breast cancer and the contribution of breast cancer gene mutations to its incidence.

Methods: Breast and ovarian cancer patients were recruited from public and private clinics in the Cayman Islands, Jamaica, Barbados, Dominica, Trinidad & Tobago, Haiti and at the University of Miami/ Jackson Memorial Hospital between 2010 and January 2015. Study participants had to have at least 1 grandparent born in one of the participating countries. All women provided written consent. The study was approved by the ethics review board in all participating institutions and/or countries. A saliva sample was taken. A pedigree was drawn and demographic and clinical pathologic data was collected from 855 women and men. Summary statistics and t-tests and ANOVA were used to analyze study population characteristics.

Results: Afro Caribbean women have a young age of onset of breast cancer mean age 49.1 yrs. Within the cohort, Trinidad & Tobago had significantly p<0.0001) younger participants – mean age 43 (19 – 80 yr, 95%CI 41.9-44.0); Barbados mean age 46.4 (p<0.05) compared to Cayman Islands (51.4), Dominica (52) and Haiti (51.1).

The mean BMI for the cohort was 28.2: Barbados 27.5, Cayman lslands 30.3, Dominica 28.7, Haiti 25.9, Jamaica 28.2 and Trinidad & Tobago 27.4.

Estrogen receptors were found in 62% (95%CI 51.6-72.6) of AC women although in Dominica and Haiti they were seldom done and all therapy was empirically guided. AC women had Her-2 overexpression in 19% (95%CI 10.7-) although it was higher in Haiti and Jamaica, 38% and 27%.

Stage at presentation was skewed to stages III and IV in 5/6 countries studied (except in Cayman Islands). 30-40% of participants presented at an advance stage compared to their American counter parts where Stage III and IV account for 12%.

In the cohort, women who were nulliparous had an earlier age at presentation of invasive breast cancer by 7 years (p<0.0001) compared to women with 1 or more children. Similarly 1 or more pregnancies, increased the age at invasive breast cancer diagnosis (p<0.0001). Women who underwent a TAH-BSO had a later age of onset of diagnosis by 5.1yrs (p=0.0001)

Deleterious mutations in the breast cancer genes were a frequent cause of breast cancer in the Bahamas (28% of unselected patients) and Trinidad & Tobago (12% of unselected patients).

94% of breast cancers were detected by the patient.

Conclusions: This population-based study provides information on the tumor stage and characteristics as well as risk factors such as genetic, weight and fertility factors that contribute to the incidence of breast cancer in AC women. AC women develop breast cancer at an earlier age than either European American (EA) or African American (AA) women (AC 49.1, AA 58, EA 62). 60% of AC women were diagnosed between the ages of 35-54 compared to 30% of AA women. Breast cancer in AC women presents at a higher stage than in AA or EA women (30-40% Stage III&IV vs 12%). Genetic factors play a large role in the etiology of breast cancer in the Bahamas and Trinidad & Tobago. Fertility factors have a direct effect on the age of onset of breast cancer. Mammography is not readily available and most cancers are detected by palpation. Financial constraints limit diagnostic capacity, treatment options and genetic testing.

Breast cancer is the leading cause of cancer death in the Caribbean and as the countries in the Caribbean move rapidly from the third world into the first world, the breast cancer incidence will increase. Understanding the factors that contribute to the cause of breast cancer will enable the countries to strategy.