Gene sequencing for pathogenic variants among adults with breast and ovarian cancer in the caribbean

Importance: Rates of breast and ovarian cancer are high in the Caribbean; however, to date, few published data quantify the prevalence of inherited cancer in the Caribbean population. Objective: To determine whether deleterious variants in genes that characterize the hereditary breast and ovarian cancer syndrome are associated with the development of breast and ovarian cancer in the English- and Creole-speaking Caribbean populations. Design, Setting, and Participants: This multisite genetic association study used data from germline genetic test results between June 2010 and June 2018 in the Bahamas, Cayman Islands, Barbados, Dominica, Jamaica, Haiti, and Trinidad and Tobago. Next-generation sequencing on a panel of 30 genes and multiplex ligation-dependent probe amplification (BRCA1 and BRCA2) were performed. Medical records were reviewed at time of study enrollment. Women and men diagnosed with breast and ovarian cancer with at least 1 grandparent born in the participating study sites were included; 1018 individuals were eligible and consented to participate in this study. Data were analyzed from November 4, 2019, to May 6, 2020. Exposures: Breast and/or ovarian cancer diagnosis Main Outcomes and Measures: Rate of inherited breast and ovarian cancer syndrome and spectrum and types of variants. Results: Of 1018 participants, 999 (98.1%) had breast cancer (mean [SD] age, 46.6 [10.8] years) and 21 (2.1%) had ovarian cancer (mean [SD] age, 47.6 [13.5] years). Three individuals declined to have their results reported. A total of 144 of 1015 (14.2%) had a pathogenic or likely pathogenic (P/LP) variant in a hereditary breast and ovarian cancer syndrome gene. A total of 64% of variant carriers had P/LP variant in BRCA1, 23% in BRCA2, 9% in PALB2 and 4% in RAD51C, CHEK2, ATM, STK11 and NBN. The mean (SD) age of variant carriers was 40.7 (9.2) compared with 47.5 (10.7) years in noncarriers. Individuals in the Bahamas had the highest proportion of hereditary breast and ovarian cancer (23%), followed by Barbados (17.9%), Trinidad (12%), Dominica (8.8%), Haiti (6.7%), Cayman Islands (6.3%), and Jamaica (4.9%). In Caribbean-born women and men with breast cancer, having a first- or second-degree family member with breast cancer was associated with having any BRCA1 or BRCA2 germline variant (odds ratio, 1.58; 95% CI, 1.24-2.01; P \u3c.001). A BRCA1 vs BRCA2 variant was more strongly associated with triple negative breast cancer (odds ratio, 6.33; 95% CI, 2.05-19.54; P =.001). Conclusions and Relevance: In this study, among Caribbean-born individuals with breast and ovarian cancer, 1 in 7 had hereditary breast and ovarian cancer. The proportion of hereditary breast and ovarian cancer varied by island and ranged from 23% in the Bahamas to 4.9% in Jamaica. Each island had a distinctive set of variants.

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

Abstract 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. Summary demographics of Caribbean women with breast cancerCountryNo. of ParticipantsMean age at diagnosis (yrs)ER+Her2+BRCA1/2 +BMICayman Islands6651.429/443/431/2730.3Barbados8946.652/739/734/8727.5Dominica6052.29/132/70/4628.7Jamaica13748.669/10528/105128.7Trinidad and Tobago645.54/61/51/527.4Haiti3448.5NANANA24.9 Reproductive Characteristics of Caribbean women with breast cancerNMean Agep-valueTAH-BSOPerformed71530.005Not Performed30448ParityNulliparous6042⟨ 0.0001Multiparous31950PregnancyNone4843⟨ 0.0001More than 133150 Conclusions: This population-based study provides an insight into pattern of risk factors – both genetic and environmental of breast cancer incidence and subtype across the Caribbean. In conclusion 1) genetic causes of breast cancer appear rare outside of the Bahamas, 2) fertility factors appear important in the development of breast cancer, 3) TAH-BSO is common as both a form of contraception and because of the high incidence of fibroids in the Caribbean and it may be protective, 4) BMI may impact on breast cancer development and 5) screening mammography is rare and the vast majority of mammography performed is diagnostic in nature. Citation Format: Sophia HL George, Talia Donenberg, Mohammed Akbari, Cheryl Alexis, Gillian Wharfe, Sook Yin, Hedda Dyer, Theodore Turnquest, Vincent DeGennaro, Steven Narod, Judith Hurley. Demographics of breast cancer in a cohort of Afro-Caribbean women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-08-06

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

Abstract 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. Citation Format: Sophia HL George, Talia Donenberg, Mohammad Akbari, Cheryl Alexis, Gilian Wharfe, Hedda Dyer, Sook Yin, Theodore Turnquest, Jameel Ali, Vincent DeGennaro, Jr., Steven A. Narod, Judith Hurley. Breast cancer in the Caribbean – A six-country cohort. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B50

Abstract B81: Changing fertility factors affecting breast cancer in the Bahamas

Abstract Introduction: There are many factors that affect breast and ovarian cancer incidence. Genetics, obesity, parity, age at menarche, age at first pregnancy, and family size are all determinants of breast and ovarian cancer risk and factors that differ between well-resourced countries and low- and middle-income countries (LMIC). These factors can be subject to rapid change. In addition, there are risks that are associated with the development of breast and ovarian cancer that are associated with race and ethnic group that are less well understood. The Caribbean is home to more than 20 million women, the majority of whom are of African ancestry. The demographics of the Caribbean basin in terms of finance, diet, and exposures are rapidly changing and these factors will, no doubt, be reflected in the rates of breast and ovarian cancer diagnosis. In this article, we propose to examine the changing factors that affect the development of breast and ovarian cancer in women with breast and ovarian cancer of Afro-Caribbean origin. Methods: This prospective study was approved by the University of Miami IRB and the Ministry of Health in the Bahamas. We recruited breast and ovarian cancer patients from public and private clinics in the Bahamas between September 2008 and January 2010. Women were eligible if they had been diagnosed with breast or ovarian cancer, and if at least one parent was born in the Bahamas. Data were analyzed from 250 women from 229 families. The cohort was divided into four groups depending on the year that they were born: 1970. Data analysis was conducted using the c2 test or ANOVA with adjustment for clustered data. Results: Data analysis was conducted on the 250 patients, and the groups were broken down as follows: fifty-six patients were born before 1950, ninety-one were born between 1950-1959, seventy-one between 1960-1969, and thirty-two in or after 1970. The mean age of diagnosis of their first cancer decreased from 57 years (born before 1950) to 31 years (born in or after 1970, p<0.0001). Patients born before 1950 had more siblings (p=0.045), more pregnancies (p<0.0001), and more children (p<0.0001). They had their menarche at an older age (13.8 years vs to 12.7 years, p=0.028) and their first pregnancy at a younger age (21.6 years vs 24.8 years, p=0.021) when compared to the patients born in or after 1970. There was no difference in their body mass index or family history of breast and ovarian cancer. 3.6% of the women were diagnosed with ovarian cancer. At the time of enrollment to study, 21% of the cohort had a TAH-BSO. 59.4% of women born in the 1950s underwent a TAH-BSO. Multivariate analysis of women diagnosed with breast or ovarian cancer, born in the 1960s or 1970s, had a significant odds ratio of having a BRCA mutation, OR 2.88 (1.26, 6.57), p=0.012 and OR 4.06 (1.62, 10.36), p=0.003, respectively. Conclusions: The Bahamas has undergone a rapid change from a developing country fertility pattern in the 1950s and by 1970 to a developed country's fertility pattern, in one generation. These changes influence breast and ovarian cancer risk and are associated with younger age of onset of breast cancer. We documented that 2.8% of Bahamian women without breast or ovarian cancer who had a family history of breast cancer had a deleterious mutation in BRCA 1 or 2. 40% of the 1,857 unaffected women who were offered genetic testing had a family history; thus, the prevalence of these mutations in the population is approximately 1% overall. However, the incidence of ovarian cancer is low. The unintended consequence of TAH-BSO for birth control and menorrhagia is a decrease in expected rates of both breast cancer and ovarian cancer. Citation Format: Sophia HL George, Ana Sandoval Leon, Talia Donenberg, Raleigh Bulter, Darron Halliday, DuVaughn Curling, Theodore Turnquest, John Lunn, Mohammad R. Akbari, Steven Narod, Judith Hurley. Changing fertility factors affecting breast cancer in the Bahamas [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B81

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

Abstract 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. Citation Format: Sophia H.L. George, Talia Donenberg, Cheryl Alexis, Vincent DeGennaro, Hedda Dyer, Sook Yin, Priscila Barreto-Coelho, Simonnette Thompson, Raleigh Butler, Gillian Wharfe, Jameel Ali, Theodore Turnquest, DuVaughn Curling, Mohammad Akbari, Steven Narod, Judith Hurley. The spectrum of germline mutation carriers in a cohort of breast and ovarian cancer patients in the Caribbean [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C060

Reproductive risk factor patterns in the Caribbean affecting breast cancer age of onset

e13632 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 ( 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 1970, there was a statistically significant difference between means for the variables: Age at Breast cancer diagnosis (60.7 vs 35, p 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