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The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K–Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

PURPOSE: This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women. METHODS: Appalachian women’s survey data and blood samples from the Community Awareness, Resources, And Education (CARE) CARE I and CARE II studies (N=163 invasive cervical cancer cases, 842 controls) were used to assess gene-environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t-tests and chi-square tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics. RESULTS: Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between “Appalachian self-identity” variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18. CONCLUSIONS: This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represents an emerging avenue of scientific exploration.

Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog (MUTYH) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian cancer by the failure of its well-known base excision repair mechanism or by failure to induce cell death. Biallelic germline MUTYH mutations confer a 14% risk of ovarian cancer by age 70. A monoallelic germline mutation in conjunction with a somatic MUTYH mutation may also contribute to the development of ovarian cancer. Resistance to platinum-based chemotherapeutic agents may be seen in tumors with monoallelic mutations, but platinum sensitivity in the biallelic setting. As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH-driven ovarian cancers.

Background: Chemotherapy-induced cognitive impairment (CICI), ‘chemo-brain,’ involves concentration and executive functioning difficulty and slowed processing speed and memory. Although cognitive changes in CICI can be subtle and difficult to quantify, CICI affects up to 75% of cancer survivors and impacts quality of life. Objectives: The objective of our study was to add to the definition of CICI by quantifying changes in specific cognitive domains before and after administration of platinum/taxane-based chemotherapy in gynecologic cancer patients using a tailored battery of neurocognitive tests. Methods: Following institutional review board approval, chemotherapy-naive gynecologic cancer patients scheduled to receive six cycles of intravenous platinum/taxane-based chemotherapy were identified. Baseline demographic, social, and clinical characteristics were obtained. Eleven neurocognitive assessments measured cognitive domains of interest (Table 1), including a brief cognitive screen, evaluation of fine motor skills, verbal fluency, working memory, information processing speed, visuospatial learning and memory, attention, mental flexibility, and abstract problem-solving skills. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and Psychiatric Diagnostic Screening Questionnaire assessed emotional functioning. The Functional Assessment of Cancer Therapy - Cognitive Function assessed self-perceived cognitive functioning. Testing was performed prior to the first and three to four weeks after the last cycle of chemotherapy. Descriptive statistics identified trends in individual indices of cognitive dysfunction and quality of life. Results: Fourteen patients enrolled and nine were eligible for complete analyses. The mean age was 60.6 years. The mean full scale intelligence quotient prior to therapy was 103.5. Most patients were White (8/9, 89%), had obtained at least a Bachelor's degree (5/9, 55.6%), and were diagnosed with high grade (6/9, 66.7%) stage III or IV disease (5/9, 55.6%). The majority of patients declined on cognitive screening performance (5/9, 55.6%) as well as worse scores on indices of attention (7/9, 77.8%), mental flexibility (5/8, 62.5%) verbal learning (5/9, 55.6%), and fine motor skills (5/9, 55.6%) after completion of chemotherapy. Most patients improved on indices of verbal memory (7/9, 77.8%), visuospatial learning (6/8, 75%), and verbal fluency (5/9, 55.6%). Despite changes in indices of cognitive function, most patients’ perceived quality of life improved (5/9, 55.6%) after chemotherapy. Download : Download high-res image (219KB) Download : Download full-size image Conclusions: Although gynecologic cancer patients complain of CICI, there is discrepancy regarding its incidence and affected cognitive domains. This pilot study highlights attention and mental flexibility as indices of cognitive dysfunction that may be at risk following receipt of chemotherapy in gynecologic cancer patients. Future research may focus on targeted assessment strategies.

Epithelial ovarian cancers (EOC) consist of several sub-types based on histology, clinical, molecular and epidemiological features that are termed "histo-types", which can be categorized into less aggressive Type I and more aggressive Type II malignancies. This investigation evaluated the disease-specific survival (DSS) of women with Type I and II EOC using histo-type, grade, and stage. A total of 200,658 EOC cases were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. Kaplan-Meier survival analyses, one-factor ANOVA and Chi-square analyses were performed on 10-year DSS survivals. DSS strongly supported a 2-tiered classification (grade 1 vs. grade 2 & 3) for serous EOC. DSS of early stage serous EOC for grade 2 was significantly different from grade 3 indicating that a 2-tier classification for serous EOC applied only to late stage. DSS of Type I EOC was much better than Type II. However, DSS was 46-58% lower with late stage Type I than with early stage Type I indicating that Type I ovarian cancers should not be considered indolent. Early stage Type II EOC had much better DSS than late stage Type II stressing that stage has a large role in survival of both Type I and II EOC.

e24051 Background: Chemotherapy-induced cognitive impairment (CICI) is a common side effect of cancer therapy, affecting up to 75% of cancer patients. Oxidative stress is thought to play a key role in CICI and patients who have been treated with chemotherapy have demonstrated biochemical brain changes on magnetic resonance spectroscopy (MRS). Methods: Following institutional review board approval, chemotherapy-naïve gynecologic cancer patients scheduled to receive intravenous platinum/taxane-based chemotherapy were identified. The primary objective of this study was identification of chemotherapy-induced cognitive function changes using the Montreal Cognitive Assessment (MoCA) tool. This exploratory analysis evaluates correlations between changes in MoCA scores, oxidative analytes TNF-a, protein carbonyls (PC), and 4-hydroxynonenal (HNE) protein adducts, and MRS metabolic signals. Testing was performed at baseline and three weeks post-treatment. Simple linear regression was performed to evaluate the correlation between changes in MoCA scores and oxidative metabolites. Results: Fourteen patients were enrolled. Six patients had complete pre/post oxidative stress data, and four patients had complete pre/post MRS data. Five of six had decreased PC values (mean net change -15.17%, SD 0.15), half had increased HNE levels (mean net change +16.38%, SD 0.38), and four of six had decreased TNF-a values (mean net change -15.10%, SD 0.27) (Table). MoCA scores were positively correlated with serum PC levels ( r = 0.86, p = 0.03) and not significantly correlated with TNF-a or HNE levels. Of those with complete pre/post MRS data, all patients had a decrease in glycerophosphocholine + phosphocholine/creatinine ratio signals. MoCA raw score prior to and after completion of chemotherapy. A higher score indicates improved test performance. Positive percentage of oxidative stress markers (PC, HNE, TNF-a) indicates increased post-therapy levels compared to pre-therapy. Conclusions: In this study, we evaluated candidate oxidative stress serum markers and changes in MRS metabolite signals for CICI. Serum PC levels correlate with cognitive screening scores. For patients undergoing brain imaging, MRS evaluation for individual choline components, glycerophosphocholine and phosphocholine, may serve as an additional marker of oxidative damage. This pilot study highlights the potential value of serum PC levels and dedicated brain imaging for signs of oxidative stress, including MRS, to guide future CICI identification studies. Clinical trial information: NCT03324945. [Table: see text]

• HVO focuses on the education, surgical training and development of research skills of surgical oncology residents.

Introduction: Invasive cancer of the uterine cervix (ICC) is a leading cause of cancer death in women worldwide. ICC incidence and mortality rates are especially high among women from Appalachia. In addition to lifestyle and social-behavioral factors and HPV infections, hereditary predispositions may mediate cervical cancer risk. Polymorphic alleles within the Transforming Growth Factor Beta (TGFB) signaling cascade, an important regulator of epithelial cell growth, have been implicated in modifying cancer susceptibility. The contributions of these factors within a gene-environment model have not been well characterized in Appalachian ICC patients. Hypothesis: High-risk genomic variants of TGFB signaling pathway components will be overrepresented in Appalachian women diagnosed with ICC compared to their healthy Appalachian counterparts. Methods: A case-control study was conducted with 163 cases, women diagnosed with ICC, and 842 controls, women with normal Pap tests from Appalachia Ohio, West Virginia, and Kentucky. Inclusion criteria were (i) women residing in Appalachian counties who were ≥18 years, (ii) spoke English, (ii) not cognitively impaired, (iii) able to provide informed consent. Three distinct groups were considered, representing (i) prevalent invasive cervical cancer cases, (ii) newly diagnosed invasive cervical cancer cases, and (iii) healthy controls. Targeted genomic variance analysis of 9 SNPs (rs1800469, rs1800470, rs3917200, rs7034462, rs11568785, rs868, rs1042522, rs750749, rs1800566) and a polymorphic repeat variant was conducted on blood DNA. Behavioral and environmental factors were collected using a comprehensive, self-administered questionnaire completed at the time of enrollment. Characteristics between cases and controls were compared by a two sample t-test, assuming unequal variance for continuous variables and by Fisher's exact test for categorical variables. Associations between disease status, polymorphism and behavioral or environmental characteristics were estimated via multivariable logistic regression. Results: Never smokers with TGFB1 rs1800469 overdominant allele types A/A-G/G had 0.4 (95% CI: 0.22-0.73, p=0.003) times the odds of cervical cancer compared to never smokers with A/G genotype. This effect was not observed in ever smokers (interaction p=0.02). While there was a suggestion of an increased risk of cervical cancer for never smokers with TGFB1 rs1800469 recessive A/G-A/A genotypes compared to G/G non9A genotype CD83 dominant T/T compared to C/C-C/T, or overdominant C/C -T/T compared to C/T alleles, there were no strong interaction effects identified. The effect of dominant TP53 rs1042522 allele type (C/C C/G versus G/G) differed by smoking status. There was a significant 3-fold increase in the odds of cervical cancer (aOR: 3.1, 95% CI: 1.1-8.5, p=0.03) for never smokers with TP53 rs1042522 G/G compared to never smokers with C/C-C/G genotypes. A similar increase was not observed in ever-smokers (smoking status by genotype interaction effect p=0.02). In codominant types, there was a similar increased adjusted odds (aOR: 3.65, 95% CI: 1.21-11.0, p=0.021) of cervical cancer for never smokers with G/G genotypes compared to never smokers with C/G genotypes. This effect was not observed in ever smokers (interaction effect p=0.06). Conclusions: Genetic susceptibility may contribute to the overall cervical cancer risk associated with the Appalachian population, especially among non-smokers. Inclusion of additional demographic and social-behavioral features, as well as other genetic events, may further define this evolving cervical cancer risk model. Citation Format: Thomas J. Knobloch, Steve Oghumu, Marta Sears, Zhaoxia Zhang, Blessing Ogbemudia, Joe Perrault, David Cohn, Cecilia R. DeGraffinreid, Bo Lu, Juan Peng, Erinn M. Hade, Michael A. Schiano, Byron C. Calhoun, William McBee, Jr., Jamie Lesnock, Holly Gallion, Jondavid Pollock, Mack T. Ruffin, IV, Christopher M. Weghorst, Electra D. Paskett. Inherited alterations of Transforming Growth Factor Beta signaling components in Appalachian Cervical Cancers. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B57.