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Background: Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women. Methods: We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases [307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown] and 1,563 controls in the Ghana Breast Health Study (GBHS), and estimated lifetime risk for carriers. We compared results with those for European, Asian, and African American ancestry women. Results: The frequency of PV in GBHS for nine breast cancer genes was 8.38% in cases and 1.22% in controls. Relative risk estimates for overall breast cancer were: (OR, 13.70; 95% confidence interval (CI), 4.03–46.51) for BRCA1, (OR, 7.02; 95% CI, 3.17–15.54) for BRCA2, (OR, 17.25; 95% CI, 2.15–138.13) for PALB2, 5 cases and no controls carried TP53 PVs, and 2.10, (0.72–6.14) for moderate-risk genes combined (ATM, BARD1, CHEK2, RAD51C, RAD52D). These estimates were similar to those previously reported in other populations and were modified by ER status. No other genes evaluated had mutations associated at P < 0.05 with overall risk. The estimated lifetime risks for mutation carriers in BRCA1, BRCA2, and PALB2 and moderate-risk genes were 18.4%, 9.8%, 22.4%, and 3.1%, respectively, markedly lower than in Western populations with higher baseline risks. Conclusions: We confirmed associations between PV and breast cancer risk in Ghanaian women and provide absolute risk estimates that could inform counseling in Ghana and other West African countries. Impact: These findings have direct relevance for breast cancer genetic counseling for women in West Africa.

Hair relaxers and skin lighteners have been commonly used by African women, with suggestions that they may have hormonal activity.To investigate the relationship of hair relaxer and skin lightener use to serum estrogen/estrogen metabolite levels.We utilized the postmenopausal population-based controls of the Ghana Breast Health Study to estimate adjusted geometric means (GM) and 95% confidence intervals of individual circulating estrogen levels by hair relaxer/skin lightener exposure categories.Of the 585 postmenopausal women included in our analysis, 80.2% reported hair relaxer use and 29.4% skin lightener use. Ever hair relaxer use was positively associated with estriol (adjusted GM 95.4 pmol/L vs. never 74.5, p value = 0.02) and 16-epiestriol (20.4 vs. 16.8, p value = 0.05) particularly among users of lye-based hair relaxers. Positive associations between scalp burns and unconjugated estrogens were observed (e.g., unconjugated estrone: 5+ scalp burns 76.9 [59.6-99.2] vs. no burns 64.0 [53.7-76.3], p-trend = 0.03). No association was observed between use of skin lighteners and circulating estrogens.This study presents evidence that circulating 16-pathway estrogens (i.e., estriol and 16-epiestriol) may be increased in users of lye-based hair relaxer products. Among hair relaxer users, unconjugated estrogen levels were elevated in women with a greater number of scalp burns.In this population-based study of hair relaxer and skin lightener use among postmenopausal women in Ghana, altered estrogen metabolism was observed with hair relaxer use, particularly among women using lye-based products or with a greater number of scalp burns. In contrast, skin lightener use was not associated with differences in estrogen metabolism in this population. Continued investigation of the potential biological impact on breast cancer risk of hair relaxer use is warranted.

Purpose: Analysis of cell free DNA could provide a rapid and non-invasive approach to detect cancer and provide new molecular insights in many African countries where expert pathology is lacking. Hence, we tested whether whole-genome sequencing of cfDNA (WGS-cfDNA) could identify somatic alterations that drive breast cancer. Methods: We conducted a pilot on 15 Ghanaian women (median age 49.5 years) recruited as part of the Ghana Breast Health Study. cfDNA was extracted and subjected to WGS at 30x and 0.1x. ichorCNA software was used to predict copy number alterations and ctDNA fractions. Results: We found extensive amplification and deletion of multiple chromosomal regions including those with oncogenes and tumor suppressor genes associated with breast cancer. Similar copy number alterations for selected breast cancer genes were observed with 0.1x and 30x cfDNA-WGS with increasing concordance between the two instruments as the ctDNA fraction increases. We observed a high frequency (>50%) of copy number gain in 3/5 regions and potential target genes for the amplification (chr8p11-12 [ZNF703] n=8, 53.3%; chr8q24.2 [MYC] n=9, 60%; chr19q12 [CCNE1] n=9, 60%), which were in agreement to previous observations among African-American (AA) ancestry compared to European-American (EA) ancestry in TCGA datasets. Conclusion: Our data provided evidence that ctDNA-based genomic studies are possible and ctDNA analysis could be a tool for future molecular oncology studies in Africa for cancer etiology, surveillance and clinical trials. Citation Format: Samuel Ahuno, Anna-Lisa Doebley, Thomas Ahearn, Joel Yarney, Nicholas Titiloye, Nancy Hamel, Ernest Adjei, Joe-Nat Clegg-Lamptey, Lawrence Edusei, Baffour Awuah, Xiaoyu Song, Verne Vanderpuye, Mustapha Abubakar, Maire Duggan, Daniel Stover, Kofi Nyarko, John Bartlet, Francis Aitpillah, Daniel Ansong, Kevin Gardner, Anne Bowcock, Carlos Caldas, William Foulkes, Seth Wiafe, Wiafe-Addai, Montserrat Garcia-Closas, Alexander Kwarteng, Gavin Ha, Jonine Figueroa, Paz Polak, On Behalf Of Ghana Breast Health Study Team. Studying Ghanian Cancer Genomes Using Cell-free DNA [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 81.

Cancer incidence is rising and mortality rates are high in Africa, where access to molecular pathology is limited. Analysis of cancer-related mutations in circulating tumor DNA (ctDNA) from cell-free DNA (cfDNA) that is shed into the bloodstream by tumor cells could be transformative to the African continent and provide new molecular insights. Using samples collected from the Ghana Breast Health Study we tested whether whole-genome sequencing (WGS) of cfDNA could detect ctDNA and identify somatic alterations that drive breast cancer. We selected 15 breast cancer patients (median age 49.5 years) with duplicated plasma samples. Pathologic grade, age, and immunohistochemical (IHC) stains for estrogen receptor (ER), progesterone receptor (PR) and HER2 were available for the majority of patients (>80%). cfDNA extraction and WGS at 30x and 0.1x was performed. ichorCNA software was used on Next Generation Sequencing (NGS) read counts to estimate the ctDNA fraction and predict copy number alteration profiles. High depth 30x cfDNA-WGS analysis showed that all 15 breast cancer patients had 1% ctDNA or greater (median[IQR] 3.96%[2.22%-8.13%]). There was high concordance between estimated ctDNA fraction using 0.1x and 30x WGS (Pearson r = 0.9). Copy number profiling showed extensive amplification and deletion of multiple chromosomal regions containing important cancer genes (such as MYC, PIK3CA, TERT, and GATA3). Of the four patients classified as HER2 positive based on IHC, two had increased ERBB2 copy number (50 and 3 copies, respectively). Our data provide evidence that ctDNA-based genomic studies are possible and ctDNA analysis could be a tool for future molecular oncology studies in Africa for cancer etiology, surveillance and clinical trials. Citation Format: Samuel T. Ahuno, Lawrence Edusei, Nicolas Titiloye, Ernest Adjei, Joe-Nat Clegg-Lamptey, Joel Yarney, Beatrice Wiafe-Addai, Baffour Awuah, Verne Vanderpuye, Maire Duggan, Seth Wiafe, Kofi Nyarko, Francis Aitpillah, Daniel Ansong, Thomas Ahearn, Alexander Kwarteng, Mustapha Abubakar, Montserrat Garcia-Closas, Gavin Ha, Jonine D. Figueroa, Paz Polak, on behalf of the Ghana Breast Health Study Team. Circulating tumor DNA (ctDNA) from peripheral blood is detectable among Ghanaian breast cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-093.

Background: Women of African ancestry have a higher proportion of early-onset and oestrogen receptor (ER) negative cancers compared to women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status might explain this disparity. Methods: We analysed data from 1,126 women with invasive breast cancer and 2,106 population controls aged 18-74 years recruited from three hospitals in Ghana from 2013-2015. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for menstrual and reproductive factors using polytomous logistic regression models adjusted for potential confounders. Findings: Among controls, the medians for age at menarche, parity, age at first birth and breastfeeding/pregnancy were 15 years, 4 births, 20 years, and 18 months, respectively. For women >50 years, parity and extended breastfeeding were associated with decreased risks: >5 births vs. nulliparous, OR 0·40 (95% CI 0·20-0·83), and 0·71 (95% CI 0·51-0·98) for >19 vs.

Late diagnoses and poor prognoses of breast cancer are common throughout Africa. To identify responsible factors, we utilized data from a population-based case–control study involving 1184 women with breast malignancies conducted in three hospitals in Accra and Kumasi, Ghana. Interviews focused on potential breast cancer risk factors as well as factors that might contribute to presentation delays. We calculated odds ratios (OR) and 95% confidence intervals (CI) comparing malignances with biopsy masses larger than 5 cm. (62.4% of the 1027 cases with measurable lesions) to smaller lesions. In multivariate analyses, strong predictors of larger masses were limited education (OR 1.96, 95% CI 1.32–2.90

Background: Breast cancer is a heterogeneous disease with clinically, molecularly and pathologically defined subtypes that have different etiologies, clinical presentations and outcomes. African women reportedly have especially high rates of breast cancers that are estrogen receptor (ER) or progesterone receptor (PR) negative, or triple negative [ER, PR and human epidermal growth factor receptor-2 (HER-2) negative], with the proportion reported for triple negative breast cancers ranging from 28-82%, compared to 11-20% among Caucasian populations. However, it is unclear to what extent pathology and specimen handling affect receptor measurements in Africa. Here we sought to determine pathology specimen quality of breast tumor tissues from three hospitals in Ghana where we are conducting a molecular epidemiologic study of breast cancer. Methods: We acquired 15 formalin-fixed paraffin-embedded (FFPE) archived breast cancer tissue blocks with specimens obtained at biopsy (N=5) or surgery (N=10) from three hospitals in Ghana. Blocks were re-embedded and four 0.5um whole sections were cut for hematoxylin and eosin stains, and immunohistochemistry (IHC) using previously validated protocols for ER (clone 1D5), PR (clone PgR1294) and HER2 (polyclonal), all obtained from Dako (Carpinteria CA). Specimens were considered ER or PR positive if 10% or more cells stained positive, while HER2 was considered positive if intensity of staining was 3+. Results: Specimens were noted to be embedded in high-melting temperature paraffin. To perform ER, PR, and HER2 IHC staining, deparaffinization procedures were optimized for hard paraffin. Zonal and gradient staining patterns were noted in surgical specimens, features that are likely due to delayed/prolonged fixation. Zonal/gradient staining issues were not identified in the needle biopsies, which were smaller compared to specimens collected at surgery and generally placed in buffered formalin immediately after collection. IHC assays of the tumor specimens revealed that 67% were ER-positive, 20% PR-positive, and 66% HER2 positive. The proportion negative for all three markers was 13%. Conclusion: In contrast to previous reports for African breast cancer patients, within our sample of FFPE breast cancers from Ghana we found a higher prevalence of ER positive tumors and a lower prevalence of tumors negative for all three markers. These results suggest that the high rates of hormone receptor negativity previously reported in African populations may be inaccurate due to various sources of error, particularly fixation time and IHC staining protocols. Future studies focusing on proper documentation of sample collection procedures and optimization of IHC methods are required to determine the true prevalence of molecular subtypes of breast cancer among African women. Such efforts are essential for breast cancer surveillance, identifying etiologic factors for prevention efforts and developing more effective treatment programs. Citation Format: Jonine D. Figueroa, Lawrence Edusei, Ernest Adjei, Nicholas Titiloye, Kris Ylaya, Beatrice Addai, Joe Nat Clegg-Lamptey, Baffour Awuah, Kofi Nyarko, Daniel Ansong, Seth Wiafe, Louise A. Brinton, Stephen Hewitt. Impact of pathologic specimen quality on classifying molecular subtypes of breast cancer: A pilot study from three hospitals in Ghana, Africa. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C11. doi:10.1158/1538-7755.DISP13-C11