Article Database

48 Variations in Endometrial Cancer Risk and Histologic Distribution by Caribbean Nativity

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Endometrial Cancer Among a Cohort of Urban Haitian Immigrants

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EP482 Associations Between Thrombocytosis, Predictive Biomarkers, and Survival Outcomes in Uterine Serous Carcinoma

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EP483 Biomarker Prediction of Outcome Varies by Race in Uterine Serous Carcinoma

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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.

BIOMARKER PREDICTION OF OUTCOME VARIES BY RACE IN UTERINE SEROUS CARCINOMA: EP483

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Introduction/Background Minority women are known to have higher risk for uterine serous carcinoma (USC). Limited data exist to establish reliability of prognostic biomarkers by race in these patients. Our objective was to evaluate patterns of clinical and pathologic biomarkers and their effects on outcome between white and non-white patients. Methodology A retrospective review was completed on all women diagnosed with USC between 2005 and 2017. Hematologic parameters and CA125 were ascertained at time of diagnosis, and pathology reports assessed for tumor size, lymphovascular space invasion (LVSI), and immunohistochemical (IHC) staining (>1% tumor cells) for estrogen receptor (ER) and progesterone receptor (PR). Statistics were done using chi-square, Cox proportional hazards, and the Kaplan-Meier method, with significance set at p<0.05. Results 59 patients were non-white (35.5%), 57 of whom were black; 107 were white (64.5%). At diagnosis, no differences were seen in mean CA125 levels (745 white vs. 630 non-white, p=0.83) or mean platelet levels (320K white vs. 354K non-white). There were no differences in proportion of women with LVSI or positive staining for ER or PR by race (all p>0.05). Primary tumors were larger in non-white patients, though this was not significant (55 mm vs 43 mm, p=0.06). Thrombocytosis (platelets ≥450K) was associated with worse overall survival (OS) in whites (HR 4.38 [CI 1.55–12.34], p=0.005) but not in non-whites (HR 2.05 [CI 0.73–5.74], p=0.17). For both races, tumor size and higher stage were negatively associated with OS (p<0.05), while ER and PR had no effect. Median OS was worse for non-whites without thrombocytosis (30.1 vs 38.4 months), but was better for non-whites when thrombocytosis was present (22.1 vs 16.4 months) (p=0.01) (figure 1). Conclusion Biomarker variation is minimal by race in USC, while the effect of thrombocytosis on OS varies significantly by race. Further investigation is warranted to elucidate the mechanism behind this observation. Disclosure Nothing to disclose.

African–Caribbean Cancer Consortium Scientific and Training Conference 2017

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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.

Pressing Need to Dig Deeper Into Female Cancer Health Disparities

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The rates of endometrial cancer globally have been increasing for years.¹ Although much of this has been attributed to more Westernized diets, which predispose to obesity, such patient-level factors ignore the more aggressive subtypes of endometrial cancers (collectively referred to as type II tumors, and inclusive of serous, clear cell, high-grade endometrioid, and carcinosarcoma histologies) whose driver mutations are independent of the hyperestrogenized pathway. Clarke et al² recently reported on incidence trends and differences in survival in endometrial cancer using the Behavioral Risk Factor Surveillance System. The authors found that hysterectomy-corrected rates of endometrial cancer are increasing among all minority races and ethnicities, and that aggressive, nonendometrioid malignancies disproportionately affect non-Hispanic black (NHB) women, who also have worse overall survival from this disease. Though the approach to this investigation and the adjustment for hysterectomy rates are novel, the findings are not. In 2015, Cote et al³ reported an increase in age-adjusted incidence of endometrial cancer among all racial groups, with NHB women demonstrating the highest risk of aggressive endometrial cancers. In addition, the proportion of NHB women having high-grade histologies was approximately 36%, significantly higher than the 21% seen in non-Hispanic whites.

What these and other authors have done in their analyses, however, is to assume that black women are a homogeneous group. In so doing, these studies miss the nuances of the many subpopulations who identify as black and whose nativities range from Africa, throughout the African diaspora into the Caribbean and South America, and into the United States. Investigating subpopulations of minority patients is crucial to identify risks that may further explain not just etiology of disease but offer opportunities for improved risk stratification and assessment of treatment responses. Our group recently published an evaluation of black women with high-grade endometrial cancers in South Florida.⁴ In contrast to the prevalence of disease seen in the study by Cote et al², our cohort had a prevalence of type II histologies ranging from 64.5% in US-born blacks to 72.2% in Caribbean-born blacks. Such findings were mirrored in a population of African and Afro-Caribbean immigrants in Brooklyn, New York, in which nearly 60% had high-grade tumors.⁵ The SEER program, used by Clarke et al², is a useful research tool for population-based studies, but it does not include areas of high African and Afro-Caribbean immigration, thus potentially underestimating the true risks of disease among NHB. That the results of Clarke et al² show differences in uterine cancer rates by geography further underscores the need to explore population nativity as a potential mediator of risk.

Studies investigating minority subpopulations have demonstrated that even within racial groups, differences in cancer risk and outcomes exist. In a population-based study investigating subpopulations of Hispanic women with type II endometrial cancer, we noted marked variation in risk among women of Cuban, Dominican, and South Central American nativity.⁶ In fact, differences in risk varied considerably when specific histologies were examined. Pinheiro et al⁷ reported on differences in cancer mortality by nativity, showing that US-born blacks have a higher overall cancer mortality rate than do black Caribbean people.⁷ In our cohort of patients with endometrial cancer, we saw a similar trend toward improved survival among Caribbean-born black women with high-grade endometrial cancer, despite presenting at higher stages of disease.⁴

Variations in cancer risk and survival outcomes among subpopulations of black women go beyond just endometrial cancer and have been observed in other malignancies of women. A recent evaluation of breast cancer subtypes among NHB women born in the United States, East Africa, West Africa, and the Caribbean demonstrated that the prevalence ratio of triple-negative breast cancer differed significantly by birthplace.⁸ Intravaginal use of an herbal substance unique among Haitian women increases uptake of high-risk human papillomavirus and thus predisposes to cervical cancer.⁹ Among a cohort of women with ovarian cancer from Trinidad and Tobago, African ancestry was significantly associated with worse survival.¹⁰ These observations truly highlight the need for further understanding of genetics, population admixture, and cultural practices within subgroups of minorities as they relate to cancer etiology and outcomes.

As we pursue personalization of cancer care, we need to look beyond the differences between minority groups and explore the differences within them. Although endometrial cancer may represent the gynecologic cancer in which some of the greatest racial disparities are observed, we owe it to all women to increase the depth and granularity by which we are assessing cancer risks and outcomes in an attempt to reduce burden of disease.

The Moore Criteria: Applicability in a Diverse, Non-Trial, Recurrent Cervical Cancer Population

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Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla—Site of Origin of Serous Carcinoma of the Ovary

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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.