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Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches are often biased and manually curated. Here we harness an existing stemness model for assessing oncogenic states to transform its application to single cell and spatial omic datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic or proteomic features from non-transformed stem cells to identify dedifferentiated cell states. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. Finally these stemness indices are applicable across a variety of spatial transcriptomic and proteomic technologies for the identification of oncogenic cell types in the tumor microenvironment.Graphical Abstract

Black women have 42% higher mortality rate from estrogen receptor positive (ER+) breast cancer than white women. Molecular mechanisms underlying worse outcome in black women are understudied. Recently, downregulation of specific DNA damage repair (DDR) genes was shown to causally induce resistance to standard care endocrine therapy by dysregulating cell cycle regulation, and to associate with poor outcome in white women with ER+ breast cancer. However, frequency and patterns of DDR dysregulation in Black women with ER+ breast cancer and impact on survival outcomes remains untested. By assessing RNA expression of 104 DDR genes across three tumor, and two normal breast, datasets, here, we map for the first time, global patterns of DDR gene expression regulation specific to Black women, both in tumors and in the normal breast. We identify a specific subset of 8 candidate DDR genes that are dysregulated at the RNA level in tumors from Black women. Of note, a novel DDR regulation signature where genes from the homologous recombination pathway are upregulated and genes from SSBR pathways (mainly base excision repair) are coincidently downregulated is almost uniquely detectable in tumors from Black women (8% incidence relative to 1% in tumors from white women, p=0.01). Moreover, this coincident DDR signature associates with dysregulated cell cycle gene expression (p Citation Format: Aloran Mazumder, Athena Jimenez, Rachel E Ellsworth, Sophia George, Stephen J Freedland, Matthew N Bainbridge, Svasti Haricharan. The DNA damage repair landscape in Black women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-03.

Objective Mutations in the MAP kinase pathway (KRAS, NRAS, BRAF) are common in low grade serous ovarian carcinoma (LGSOC). The effect of these and other mutations on RNA transcription in this disease is poorly understood. Our objective was to describe patterns of somatic mutations and gene transcription in a racially diverse population with LGSOC. Methods Utilizing an institutional tumor registry, patients with LGSOC were identified and charts were reviewed. RNA was extracted from available tumor tissue. Commercial tumor profiling results were analyzed with PanCancer pathway nanoString mRNA expression data. Along with nanoString n-Solver software, Chi-squared, Fishers Exact, and Cox proportional hazards models were used for statistical analysis, with significance set at p Results 39 patients were identified—20% Black, 43% Hispanic, and 36% non-Hispanic White. 18 patients had commercial somatic DNA test results, and 23 had available tumor tissue for RNA extraction and nanoString analysis. The most common somatic alterations identified was KRAS (11 patients, 61%), followed by ERCC1 and TUBB3 (9 each, 50%). KRAS mutations were less common in smokers (14.3% vs 90.9%, p = 0.002). RNA expression analysis demonstrated a greater than two-fold decrease in expression of HRAS in tumors from older patients (p = 0.04), and a greater than two-fold decrease in the expression of HRAS in recurrent tumors (p = 0.007). No significant differences were seen in somatic testing results, RNA expression analysis, or progression free survival between different racial and ethnic cohorts. Conclusions Somatic deficiencies in ERCC1, TUBB3, and KRAS are common in LGSOC in a population of minority patients. HRAS demonstrates decreased expression in tumors from older patients and recurrent tumors.

The Moore Criteria is a prognostic index for recurrent or metastatic cervical cancer based on five factors. The criteria were developed retrospectively and validated prospectively in clinical trial populations receiving systemic chemotherapy (C). Our objective was to evaluate the prognostic value of the Moore Criteria in a largely minority, non-trial population at first recurrence.Patients treated for recurrent cervical cancer diagnosed between 2012 and 2017 were analyzed retrospectively. Progression free survival (PFS) was defined from the date of recurrence to date of second recurrence. Overall survival (OS) was defined from the date of recurrence to date of death.Of 274 patients identified, 78 were treated in the second line. 48 (61.5%) were Hispanic, 22 (28.2%) were black, and 7 (9%) were white non-Hispanic. By Moore criteria, 9 patients (11.5%) were classified as low-risk, 48 (61.5%) as moderate risk, and 21 (26.9%) as high-risk. 53 patients (67.9%) received C, and 25 (32.1%) received other treatment modalities without C. The high-risk category carried a significantly higher hazard ratio for both PFS (5.24, p .001) and OS (3.15, p = .002) compared with the low- and intermediate-risk combined group. The low- and intermediate-risk groups demonstrated 78.9% response rate, compared with 33.3% in the high-risk category (p = .001). Black race did not affect survival or response rate.The Moore Criteria carries prognostic value across a diverse recurrent cervical cancer population outside of the clinical trial setting. Our data suggest that in a non-trial population, black race is not predictive of worse OS or PFS.

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

BackgroundThe vaginal microbiome is an underexplored environment which may yield insights about endometrial cancer (EC) pathophysiology and serve as an early marker of disease. Our objective was to evaluate the preoperative vaginal microbiome in women undergoing hysterectomy for benign conditions and EC to identify patterns which could segregate benign disease from EC, and to assess if the microbiome distinguishes low-grade (LG) from high-grade (HG) histologies.MethodsVaginal microbiome samples were prospectively collected at the time of hysterectomy, and clinicopathologic data collected. Extracted DNA underwent shotgun metagenomics sequencing. Microbial diversity was calculated using the Shannon Index (α-diversity) and PERMANOVA (β-diversity). Hierarchical clustering was used to describe community state types (CST), which were then compared by microbial diversity and grade. Machine learning was utilized to assess the predictive value of grade and histology based on relative bacterial abundance.Results61 patients participated: 1) benign gynecologic disease (n=11), 2) LG EC (n=30), and 3) HG EC (n=20). 40 (62.5%) were White, 22 (34.3%) were Black, and 37 (57.8%) were Hispanic. Both α- and β-diversity were associated with tumor grade (p□=□0.026 and p□=□0.035, respectively). Four CST were identified that associated with grade of disease (p=0.036). Different histologies demonstrated variation in CST even within tumor grades (p=0.017). Markers at the species level informed models that predicted benign vs cancer (AUC 0.878), HG versus benign (AUC=0.803), and HG versus LG (AUC=0.771) with high accuracy.ConclusionsThe vaginal microbiome segregates benign disease from EC, and is predictive of histology and grade, suggesting it may be an effective tool for screening.

Introduction Variability in endometrial cancer (EC) risk and outcomes exist, with Black women disproportionately negatively affected related to White women. The biologic etiologies of these observations are poorly understood. Our objective was to describe the somatic mutations of the tumor genome and compare them to RNA expression in self-identified Black and White women diagnosed with EC. Methods Women with newly diagnosed EC and undergoing hysterectomy were recruited prospectively. Fresh tumors obtained at the time of surgery were flash-frozen, underwent DNA and RNA extraction and were submitted for whole exome sequencing (WES) analysis (DNA) or bulk RNA sequencing analysis. Differentially expressed genes between racial groups and tumor grade were calculated using Deseq2. Genomic ancestry was determined using ADMIXTURE. Chi-square and Mann Whitney U tests were used for analyses, with a threshold for significance of p14% African ancestry. The remaining 13 (26.5%) patients had admixed European and Native American ancestry, with Citation Format: Alex P. Sanchez-Covarrubias, Ramlogan Sowamber, Leah Dodds, Andre Pinto, Sophia George, Matthew Schlumbrecht. Endometrial cancer genomics varies by race [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C052.

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BACKGROUND Black women are known to have a higher risk of aggressive endometrial cancers. Little data exist about the role of nativity as a determinant of survival outcomes in women with this disease. AIM Our objective was to evaluate a population of Haitian immigrants with endometrial cancer in an urban setting using the Florida Cancer Data System (FCDS). METHODS A search of FCDS identified 107 women born in Haiti and who received treatment for invasive endometrial cancer in Miami-Dade County between 1989 and 2013. Clinicopathologic data were extracted to describe the cohort and assess associations with overall survival. Statistical analyses were performed using Cox proportional hazards models, the log-rank test, and the Kaplan-Meier method, with significance set at P ≤ 0.05. RESULTS Median age at diagnosis was 65 years. 63.9% of the patients had a type II, high-grade, histology, and 52.6% presented with extrauterine metastatic disease. Nearly three quarters had health insurance. Within the entire cohort, only presence of extrauterine disease was associated with worse overall survival [Hazard ratio (HR) = 2.70, 95% confidence interval (CI): 1.31-5.57, P = 0.007]. However, after stratification by histologic grade, both age (HR = 0.88, 95%CI: 0.81-0.96, P = 0.002) and extrauterine disease (HR = 2.49, 95%CI: 1.01-6.21, P = 0.049) were independently associated with worse survival, but only in women with type II malignancies. CONCLUSION Urban Haitian women with endometrial cancer have a high burden of aggressive histologies. Additional investigation to explain the etiology of these findings is needed.

BACKGROUND: There are few studies that directly investigate disparities in outcome within the African diaspora in the US. We investigated the association between nativity of Black women diagnosed with breast cancer (Caribbean or USA place of birth) and ethnicity, age at diagnosis, treatment, tumor characteristics and outcome. METHODS: The data were obtained from the University of Miami Health System, and Jackson Health System. Individual-level data from 1132 cases was used to estimate hazard rations (HRs) of women born in the Caribbean (Caribbean Blacks, CB) or in the USA (US Black, USB) using Cox proportional hazards regression analysis for overall survival. RESULTS: The cohort contains data from 624 (54.9%) USB women and 507 (45%) CB women diagnosed with breast cancer between 2006 and 2017. Compared to CB patients, USB patients had more Estrogen Receptor negative (31.4% vs. 39.1%, P = 0.018) and triple negative breast cancers (19.6% vs. 27.9%, P = 0.003). CB women presented at more advanced stages III/IV (44.2% vs. 35.2%; P = 0.016). CB patients showed a better overall survival (hazard ratio, HR = 0.75; 95% CI 0.59–0.96; P = 0.024). Overall Black Hispanic patients had a better overall survival (HR = 0.51; 95% CI 0.28–0.93; P = 0.028) compared to non-Hispanic Black patients. CONCLUSION: In conclusion the study found that CB immigrants diagnosed with breast cancer have an improved overall survival when compared with USB patients. This finding suggests that within the African diaspora in the USA, additional factors beyond race contribute to worse outcomes in African Americans.

The objective of this review is to summarize recent research advances in the detection and prevention of ovarian cancer and discuss the experts’ opinions of future directions. The 12th Biennial Ovarian Cancer Research Symposium was held in Seattle, Washington, in September 2018. At this meeting, experts in ovarian cancer research gathered to present and discuss recent breakthroughs and their visions of future ovarian cancer research. Session 1 of the symposium focused on the detection and prevention of ovarian cancer. It included two invited oral presentations from Ranjit Manchanda, MD, PhD (Barts Cancer Institute) and Rosana Risques, PhD (University of Washington). Another eight oral presentations were selected from abstract submissions. Fifteen abstracts were presented in poster format. These presentations covered topics including cellular origin of high-grade serous cancer, risk factors for ovarian cancer, new methods for early detection of ovarian cancer, mechanisms underlying ovarian cancer development, and new therapeutic approaches for preventing ovarian cancer from forming or progressing. In conclusion, a clear understanding of the cellular origin and molecular mechanisms underlying the initiation of high-grade serous cancer is essential for developing effective means for early detection and prevention of this most devastating type of ovarian cancer. Recognizing the complexity of ovarian cancer and appreciating that ovarian cancer is not a single disease will help us to generate proper models, design rational experiments, and collect and analyze patient data in a meaningful way. A concerted effort in the field will help to bridge the basic science and clinical applications and lead to more precise and effective detection and treatment.

Background CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBPδ in different tumours, such as glioblastoma and breast cancer either promotes tumour progression or inhibits growth and has low expression in normal tissue until activated by cytotoxic stressors. Methods Higher overall expression of C/EBPδ in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBPδ in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBPδ in proliferation, migration, and the epithelial to mesenchymal transition. Findings Expression of C/EBPδ induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBPδ in epithelial cancer cell lines did not have significant effects on proliferation, yet overexpression demonstrated downregulation of growth, similar to normal fallopian tube cells. C/EBPδ promoted a partial mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating Vimentin and N-cadherin in FTE cells and increased migratory activity, which suggests a regulatory role in the epithelial-mesenchymal plasticity of these cells. Interpretation Our findings suggest that C/EBPδ regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis. Fund This study was funded by the CDMRP Ovarian Cancer program (W81WH-0701-0371, W81XWH-18-1-0072), the Princess Margaret Cancer Centre Foundation, Foundation for Women's Cancer – The Belinda-Sue/Mary-Jane Walker Fund, Colleen's Dream Foundation and Sylvester Comprehensive Cancer Center.

PurposeData on endometrial cancer outcomes among immigrant women in the USA are lacking. The objective was to determine the effect of Caribbean nativity on outcomes in black women with endometrial cancer compared with women born in the USA, with attention paid to the effects of tumor grade, sociodemographic factors, and treatment approaches.MethodsA review of the institutional cancer registry was performed to identify black, non-Hispanic women with known nativity and treated for endometrial cancer between 2001 and 2017. Sociodemographic, treatment, and outcomes data were collected. Analyses were done using the χ2 test, Cox proportional hazards models, and the Kaplan–Meier method, with significance set at PResults195 women were included in the analysis. High grade histologies were present in a large proportion of both US born (64.5%) and Caribbean born (72.2%) patients. Compared with US born women, those of Caribbean nativity were more likely to be non-smokers (P=0.01) and be uninsured (P=0.03). Caribbean born women had more cases of stage III disease (27.8% versus 12.5%, PConclusionsThe prevalence of high grade endometrial cancer histologies among black women of Caribbean nativity is higher than previously reported. Caribbean nativity may be associated with improved overall survival although additional study is warranted.

Objective Polypharmacy has been associated with morbidity and mortality in patients with cancer. Data about polypharmacy among patients with ovarian cancer are limited. The primary objective of this study was to evaluate polypharmacy in a cohort of patients with ovarian cancer and to assess the evolution of polypharmacy from initial presentation to 2 years posttreatment. A secondary objective was to evaluate differences in polypharmacy between a subset of patients primarily treated in our comprehensive cancer center (CCC) and our safety net hospital (SNH). Methods Women treated for ovarian cancer between January 1, 2011, and December 31, 2016, were included. Data were abstracted from the electronic medical record. Medication safety was assessed using the established Anticholinergic Burden (ACB) scale and the Beers criteria. Statistical analyses were performed using paired t tests and Cox proportional hazards models, with significance set at p < .05. Results The study included 152 patients. The majority of patients had high-grade serous carcinoma. Hypertension was the most common medical problem. The mean number of medications at the time of diagnosis was 3.72. Paired testing demonstrated significant patient-level increases in the number medications at 2 years following initial diagnosis (4.16 vs. 7.01, p < .001). At the CCC, 47.4% of patients met criteria for polypharmacy at diagnosis compared with 19.4% at the SNH (p < .001). By 2 years postdiagnosis, 77.6% of patients at the CCC met criteria for polypharmacy compared with 43.3% at the SNH (p = .001). The use of any medications on the ACB scale (p < .001) increased significantly between initial diagnosis and 2 years for the entire population. Polypharmacy was not a significant predictor of overall survival. Conclusion Polypharmacy worsens as women go through ovarian cancer treatment. Both at initial presentation and at 2 years postdiagnosis, rates of polypharmacy were higher at the CCC. Polypharmacy did not have an effect on survival in this cohort. Implications for Practice Awareness of escalating numbers of medications and potentially adverse interactions is crucial among women with ovarian cancer, who are at high risk for polypharmacy.

Objectives: To characterize socioeconomic and clinical factors associated with refusal of gynecologic cancer surgery. Methods: The National Cancer DataBase (NCDB) was surveyed for patients with uterine, cervical, or ovarian cancer treated at participating Commission on Cancer sites between 2004 and 2017. Demographic and clinical data were abstracted, descriptive statistics and Pearson's chi squared tests performed. Univariate and multivariate logistic regression were performed to examine the association between variables and refusal of surgery, with the threshold for two-sided significance set at p Results: Of the 938 773 patients with gynecologic cancer included in the NCDB, 5875 patients (0.6%) did not undergo surgery and had documented refusal. On univariate analysis, age, race, Hispanic ethnicity, rural residence, lower median household income, regional high school graduation rate, facility type (academic vs community), geographic location and distance to treating hospital, disease site, stage, and increasing Charlson comorbidity index were all associated with refusal of surgery (p 3 (OR 1.34 95% CI 1.16-1.56). Clinical trial enrollment was not associated with refusal. Conclusions: Multiple social, racial, economic, and systematic factors that impact marginalized members of society are independently associated with refusal of NCCN guideline-indicated surgery. Refusal of surgery is more common in underserved patients and may represent another aspect of healthcare disparity that deserves closer attention.

IMPORTANCEAfrican American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers.OBJECTIVETo characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome.DESIGN SETTINGS AND PARTICIPANTSThree independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939.MAIN OUTCOME AND MEASURESUp/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets.RESULTSOverall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival.CONCLUSION AND RELEVANCEOverall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations.

Thrombocytosis (platelets &ge, 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&ndash, 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 &lt, 0.01). This finding was most pronounced in uterine serous carcinoma (16.4 months with thrombocytosis vs. 34.4 months without, p &lt, 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 &lt, 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.

Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.

Breast cancer (BC) is the leading cause of cancer death in Caribbean women. Across the Caribbean islands, the prevalence of hereditary breast cancer among unselected breast cancer patients ranges from 5 to 25%. Moreover, the prevalence of BC among younger women and the high mortality in the Caribbean region are notable. This BC burden presents an opportunity for cancer prevention and control that begins with genetic testing among high-risk women. Measured response to positive genetic test results includes the number of preventive procedures and cascade testing in family members. We previously reported data on an active approach to promote cascade testing in the Bahamas and report on preventive procedures showing moderate uptake. Here, we describe a clinically structured and community-partnered approach to the dissemination and follow-up of genetic test results including family counseling for the promotion of risk mitigation strategies and cascade testing in our Trinidadian cohort of patients tested positive for BC predisposition genes. As a part of our initial study of BC genetic testing in Trinidad and Tobago, all participants received pre-test counseling including three-generation pedigree and genetic testing for BRCA1/2, PALB2, and RAD51C. The study was approved by the University of Miami IRB and the Ethics Committee of the Ministry of Health, Trinidad and Tobago. We prospectively evaluated a clinically structured approach to genetic counseling and follow-up of BC mutation carriers in Trinidad and Tobago in 2015. The intervention consisted of (1) engaging twenty-nine BC patients with a deleterious gene mutation (probands), and (2) invitation of their at-risk relatives to attend to a family counseling session. The session included information on the meaning of their results, risk of inheritance, risk of cancer, risk-reduction options, offering of cascade testing to family members, and follow-up of proband decision-making over two years. Twenty-four of twenty-nine mutation carriers (82.8%) consented to enroll in the study. At initial pedigree review, we identified 125 at-risk relatives (ARR). Seventy-seven ARR (62%) attended the family counseling sessions; of these, 76 ARR (99%) consented to be tested for their family gene mutation. Genetic sequencing revealed that of the 76 tested, 35 (46%) ARR were carriers of their family mutation. The ARR received their results and were urged to take preventative measures at post-test counseling. At 2-year follow-up, 6 of 21 probands with intact breasts elected to pursue preventive mastectomy (28.5%) and 4 of 20 women with intact ovaries underwent RRSO (20%). In Trinidad and Tobago, a clinically structured and partnered approach to our testing program led to a significant rate of proband response by completing the intervention counseling session, executing risk-reducing procedures as well as informing and motivating at-risk relatives, thereby demonstrating the utility and efficacy of this BC control program.

The development of the Papanicolaou smear test by Dr. George Nicholas Papanicolaou (1883-1962) is one of the most significant achievements in screening for disease and cancer prevention in history. The Papanicolaou smear has been used for screening of cervical cancer since the 1950s. The test is technically straightforward and practical and based on a simple scientific observation: malignant cells have an aberrant nuclear morphology that can be distinguished from benign cells. Here, we review the scientific understanding that has been achieved and continues to be made on the causes and consequences of abnormal nuclear morphology, the basis of Dr. Papanicolaou's invention. The deformed nuclear shape is caused by the loss of lamina and nuclear envelope structural proteins. The consequences of a nuclear envelope defect include chromosomal numerical instability, altered chromatin organization and gene expression, and increased cell mobility because of a malleable nuclear envelope. HPV (Human Papilloma Virus) infection is recognized as the key etiology in the development of cervical cancer. Persistent HPV infection causes disruption of the nuclear lamina, which presents as a change in nuclear morphology detectable by a Papanicolaou smear. Thus, the causes and consequences of nuclear deformation are now linked to the mechanisms of viral carcinogenesis, and are still undergoing active investigation to reveal the details. Recently a statue was installed in front of the Papanicolaou's Cancer Research Building to honor the inventor. Remarkably, the invention nearly 60 years ago by Dr. Papanicolaou still exerts clinical impacts and inspires scientific inquiries.

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). Citation Format: George SH, Bravo GL, Sandoval AC, Palacio S, Ali J, Donenberg TR, Akbari MR, Narod S, Hurley J. An active approach to genetic counseling in Trinidadian women with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-11.

Objectives: Standard of care treatment for advanced stage EOC is a combination of chemotherapy and surgery. Despite this approach, the majority of women remain incurable, underscoring the need for novel therapeutics. This study assessed the pathologic objective response rate (pORR), historically reported as 6-10% and tumor transcriptomic changes in women with advanced stage EOC treated with neoadjuvant pembrolizumab, paclitaxel, and carboplatin. Methods: This was an open-label, single-arm, phase II trial for women with newly diagnosed biopsy proven EOC dispositioned to receive carboplatin, paclitaxel and pembrolizumab 200mg/m2 every 21 days. Patients received 3-4 cycles prior to interval debulking surgery followed by another 3-4 cycles of adjuvant therapy. A planned interim analysis to assess futility (based on reported historic response with NACT, required 1 pORR) was completed after enrollment of 20 of planned 40 evaluable patients. Transcriptomic analyses of bulk RNA to identify functional genes and significant pathways from matched specimens from treatment naive tumor, and tumor after 3-4 cycles of NACT plus immune checkpoint inhibitor, (ICI) were completed. Strand-specific RNA libraries were sequenced using single-end reads (50 bp, average 40 million reads per sample) on the DNBSeq platform. Differentially expressed genes (DEG) with a false discovery rate q 1.5 were used. Results: Interim data for the first 20 patients evaluable for pORR are reported. Most women were White (95%) and had high grade serous histology (100%). In 11 cases (55%), R0 (complete) cytoreduction was achieved. There have been no surgical complications related to combination treatment. Treatment was generally well tolerated, with mostly grade 1/2 toxicity: 30% pruritic rash, 10% thyroid abnormalities. One patient had grade 3 nephritis that recovered with treatment. A total of 6 patients achieved a pathologic complete response (pCR, 30%) and another 4 (25%) pathologic partial response (pPR) for a 55% pORR. There were 4 pts with deleterious genetic mutation in the homologous recombination pathway (20%) and 2 patients with Fanconi anemia somatic mutations (10%). There were 863 DEGs between the chemonaive and ICI+NACT matched tumors. ICI+NACT induced activation of PI3K-Akt pathway, myeloid differentiation, AGE-RAGE signaling, and focal adhesion kinase pathways which included upregulation of FXR, NLRP11 and FOXL2 expression, known regulators of inflammation and immune responses. Conclusions: Interim analysis demonstrates an increase in pORR compared to previously reported in literature (6-10%) and is generally well tolerated. Transcriptomic analyses revealed specific ICI induced gene signatures when combined with NACT. Further characterization of complete and partial responders are needed to improve patient selection for ICI therapies.

Objectives: Ovarian Germ Cell Tumors (GCT) are rare, and understudied, subtypes of ovarian cancer. Our objective was to evaluate the effects of race, ethnicity, and clinicopathologic characteristics on treatment selection, treatment delays, and overall survival in this disease. Methods: Data from the National Cancer Database between 2004 and 2015 were evaluated for adult women with invasive ovarian GCT. Mann-Whitney U-test and Chi Square analysis were used to identify differences in sociodemographic factors based on race and ethnicity. Logistic regression and Poisson regression were used to evaluate associations between treatment receipt and treatment delays, respectively. Time to treatment initiation (TTI) was defined as the duration between date of diagnosis and the first treatment received, and overall survival (OS) was defined as the time from date of diagnosis to either date of death from any cause or date of last contact. Cox proportional hazards regression model was used to calculate hazard ratios for OS. Statistical significance was set at p Results: There were 3,049 evaluable women with GCT. 74.1% of patients were White and 15.6% were Black. 15.6% were Hispanic and 78.2% were non-Hispanic. The median age of the overall cohort was 27 (range 18-90). There was no difference in mean age at diagnosis between Blacks and Whites, while Hispanics were diagnosed significantly younger than Non-Hispanics (28.0 vs 30.8 years, p Conclusions: Multiple clinical, socioeconomic, and systematic factors are associated with increasing time to treatment and adjuvant therapy selection after primary surgical resection in GCT. Of these factors, type of insurance, and accreditation status of the treating institution are associated with worse overall survival, reflecting the possible need for centralization of care for this rare tumor.

African American (AA) estrogen receptor positive (ER+) breast cancer patients have worse outcomes than Caucasian Americans (CA) being 42 % more likely to die from the disease. However, AAs are severely underrepresented in currently available datasets of patient tumors, which precludes comprehensive approaches to identify race-specific molecular drivers of these poor outcomes. Endocrine therapy (ET) is the first line standard of care for ER+ breast cancer. Nevertheless, 1 in 4 patients develop ET resistance. Specific DNA damage/repair (DDR) defects have been shown to associate with poor outcome in CA patients, and to induce ET resistance. Whether these or other DDR defects contribute to poor outcomes observed in AA patients remains unknown. For the purpose of this investigation, we assessed the DDR dysregulation landscape of AA ER+ tumors using three independent tumor datasets (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA) and two normal breast datasets (1) GSE43973 (2) GSE50939. This analysis identified a distinct set of AA ER+ tumors with simultaneous dysregulation of genes from multiple DDR pathways, rarely seen in CA tumors. This simultaneous dysregulation also associated with worse patient outcomes in all three datasets analyzed. This work constitutes the first systematic analysis of race-specific DDR dysregulation in ER+ breast cancer, and identifies DDR as a potential predictive biomarker for worse outcome seen in AA patients. Citation Format: Aloran Mazumder, Athena Jimenez, Rachel Ellsworth, Stephen Freedland, Sophia George, Matthew Bainbridge, Svasti Haricharan. Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2521.

Introduction: The luteal phase of BRCA mutation carrier tissues has distinct profiles of differentially expressed genes compared to wild-type fimbria. High Grade Serous Ovarian Carcinoma (HGSOC) is one of the most lethal gynecological diseases and presents at late tumor stage. Studies focusing on the early events of the disease have implicated the fimbriated end of the fallopian tube as the high-risk zone for cancer development. In this study, we aim to identify BRCA transcriptomic signatures in the fimbria of patients with a BRCA mutation and compare the luteal and follicular phases to capture the effect of the extrinsic milieu in response to stressors. Experimental Procedures: Laser capture microdissection (LCM) was performed on 68 formalin fixed paraffin embedded (FFPE) fallopian tube samples based on BRCA mutation status and ovulatory cycle: Normal-Follicular, Normal-Luteal, BRCA-Follicular, BRCA-Luteal. Nine HGSC samples were derived from patients with a mutation in BRCA1. 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 and were processed using Illumina Tru-Seq Stranded Total RNA Kit with RiboGold ready and sequenced on the Illumina Hi-seq 2000 V3. Bioinformatic analysis performed on multiple comparisons highlighted differentially expressed genes. Gene Set Enrichment Analysis (GSEA) performed on subgroups highlighted pathways of interest for each comparison. Genes highly expressed or strongly suppressed were shortlisted for further analysis. Western blot analysis performed on wildtype patients (WT), BRCA1 mutation and BRCA2 mutation showed protein expression of selected genes. Results: The fimbriae compared to ampullae have more stem-like features, have up-regulated antioxidant/xenobiotic genes, and have more inflammatory cells intercalated within the epithelia. The fimbria of FTE-BRCA have distinctly up-regulated genes involved in DDR (DNA damage response) which are exacerbated in the luteal phase of the ovulatory cycle. BRCA1/2 luteal versus follicular phases are involved in endoplasmic reticulum stress, migration, MAPKK. Whereas decreased differentially expressed genes are involved with G2/M checkpoint, DNA replication and ER-associated degradation pathway. Post-ovulatory phase of the ovarian cycle drives inflammation, differentiation and DNA damage-repair in FTE cells. Furthermore, GSEA analysis of the luteal and follicular phases showed positive enrichment of the inflammatory response pathway and negative enrichment of oxidative phosphorylation in the luteal phase. Conclusions: Our results highlight distinct pathways related to repair and inflammation for the BRCA1 mutation carriers and luteal phase of the fimbria. These results are consistent with previous examination of the fallopian tube and provide insight into targetable genes associated with the development of HGSC. Citation Format: Ramlogan Sowamber, Iru Paudel, Alex Sanchez, Alexandra Diaz, Patricia Shaw, Matthew Schlumbrecht, Sophia George. BRCAness in HGSC cancer initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2155.

Purpose We compared a cohort of Haitian immigrants with residents in Haiti with breast cancer (BC) to evaluate the effects of location on presentation, treatment, and outcomes. Patients and Methods Participants were Haitian women with BC living in Miami who presented to the University of Miami/Jackson Memorial Hospital and women with BC living in Haiti who presented to the Innovating Health International Women’s Cancer Center. The primary outcome was the relationship between location, cancer characteristics, and survival. The secondary objective was to compare our results with data extracted from the SEER database. Cox regression was used to compare survival. Results One hundred two patients from University of Miami/Jackson Memorial Hospital and 94 patients from Innovating Health International were included. The patients in Haiti, compared with the patients in Miami, were younger (mean age, 50.2 v 53.7 years, respectively; P = .042), presented after a longer duration of symptoms (median, 20 v 3 months, respectively; P < .001), had more advanced stage (44.7% v 25.5% with stage III and 27.6% v 18.6% with stage IV BC, respectively), and had more estrogen receptor (ER) –negative tumors (44.9% v 26.5%, respectively; P = .024). The percentage of women who died was 31.9% in Haiti died compared with 17.6% in Miami. Median survival time was 53.7 months for women in Haiti and was not reached in Miami. The risk of death was higher for women in Haiti versus women in Miami (adjusted hazard ratio, 3.09; P = .0024). Conclusion Women with BC in Haiti experience a significantly worse outcome than immigrants in Miami, which seems to be related to a more advanced stage and younger age at diagnosis, more ER-negative tumors, and lack of timely effective treatments. The differences in age and ER status are not a result of access to care and are unexplained.

Jamaica is an island nation with one of the highest breast cancer incidence rates in the Caribbean (40/100,000 per year). The contribution of cancer susceptibility gene mutations to the burden of breast cancer in Jamaica has not yet been explored. We sought to determine the prevalence of germline mutations in BRCA1, BRCA2, and PALB2 in 179 unselected Jamaican women with breast cancer. We sequenced the entire coding regions of BRCA1, BRCA2, and PALB2 for all the study subjects. Overall, 8 of 179 patients (4.5%) had a mutation in one of the three genes: one in BRCA1, two in BRCA2, and five in PALB2. These data suggest that in addition to BRCA1 and BRCA2, PALB2 should be included in genetic testing for breast cancer patients in Jamaica.

The sixth International African–Caribbean Cancer Consortium (AC3) Conference was held 6–9 October 2017 in Miami, Florida, U.S.A. The conference was open to all researchers, trainees, clinical and public health professionals, and community members, and served as an international hub for the United States, the Caribbean, and Africa. Sessions included AC3 collaboration meetings, cancer surveillance and research skills training workshops, and a community cancer prevention conference.

Objectives In a previous cohort of predominantly breast cancer patients, ∼25% of cases had 7 recurrent mutations in BRCA1 and BRCA2.The rate of hereditary ovarian cancer in the Bahamas was sought using an Oncology-led point of genetic testing at the Princes Margaret Hospital (PMH) in the Bahamas. Methods Women were counseled and consented for genetic testing in the Gynecology Oncology clinic at our facility. Saliva samples underwent next generation sequencing (NGS) in a CLIA approved external laboratory. A 30 gene panel linked to breast, ovarian and/or uterine cancer risks was used to identify: BRCA1, BRCA2, Lynch genes, MLH1, MSH2, MSH6, PMS2, EPCAM, MUTYH, APC, STK11, PALB2, MITF, BAP1, CDKN2A, TP53, BMPR1A, SMAD4, POLD1, POLE1, CHEK2, PTEN, CDH1, BRIP1, CDK4, GREM1, RAD51C, RAD51D, PMS2, NBNand BARD1. Reportsincluded presence or absence of deleterious mutations and variants of unknown significance (VUS). Results Between 03/2018–03/2019, 28 women were tested, 17 women had ovarian cancer, 7 endometrial cancer, 2 breast cancer, and 2 women with a strong family history of ovarian cancer. The mean age at testing was 60 years. 21.4% had a deleterious mutation in BRCA: 5 in BRCA1 and 1 in BRCA2. Of the patients with BRCA mutation 5/6 women were diagnosed with ovarian cancer (29.5%) and 1/6 had ductal carcinoma of the breast. Conclusions Genetic testing at point of care in the Bahamas is feasible and acceptable. Results highlight need for universal hereditary screening for women in the Bahamas with ovarian cancer as this can allow for better treatment options.

Key Points Question What proportion of patients in the Caribbean who develop breast or ovarian cancer carry deleterious variants? Findings This genetic association study included 1018 adult women and men with breast and ovarian cancer, of which 144 individuals had a pathogenic variant in a moderate- to high-risk gene. This finding was consistent with high rates of premenopausal breast cancer in Black women with Caribbean ancestry. Meaning Results of this study suggest that in people with Caribbean ancestry diagnosed with breast or ovarian cancer, 1 in 7 will have an actionable pathogenic variant, which may lead to use of targeted therapies and precision prevention approaches., 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, This genetic association study assesses the prevalence of pathogenic gene variants among adults with breast and ovarian cancer in 7 Caribbean nations.

Highlights • Expeditious germline testing is a vital component of epithelial ovarian cancer treatment. • Uninsured and minority patients are at risk for lower germline testing rates. • Physician performed germline testing shortens the interval to results reporting in a safety net clinic population. • The majority of patients tested were uninsured or underinsured at the time of testing., Germline genetic mutations occur in approximately 25% of women with epithelial ovarian cancers (EOC). We sought to determine whether newly initiated in-office oncologist-led germline testing improved time to testing and dissemination of results compared with historical controls. Patients with epithelial ovarian cancer seen between 4/1/2018 and 12/31/2019 were identified. Patients treated before genetic testing kits were made available in the gynecologic oncology clinics were compared to those treated after. Categorical variables were compared using Chi Squared and Fisher’s Exact test. Cox proportional hazards model was used to compare elapsed time from testing to results. 73 patients were identified, and 502 clinic visits were analyzed. 56 (76.7%) patients were White Hispanic, 15 (20.5%) were Black, and 2 (2.7%) were White non-Hispanic. 55 (75.7%) underwent germline testing. Median time to genetic testing in the intervention group was shorter than in the control group (5, vs 24.3 weeks, 95% CI = 0–10.8 vs 14.9–33.7, p