A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed.

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II-versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II-versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p \ 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N=2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N=522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR=0.87, 95% CI 0.81-0.92, p<0.0001, N=1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR=0.52, 95% CI 0.36-0.74, p=0.0003, N=392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

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Background Breast cancer outcomes among patients who use safety-net hospitals in the highly populated Harris County, Texas and Southeast Brazil are poor. It is unknown whether treatment delay contributes to these outcomes. Methods We conducted a retrospective cohort analysis of patients with non-metastatic breast cancer diagnosed between January 1, 2009 and December 31, 2011 at Harris Health Texas and Unicamp’s Women’s Hospital, Barretos Hospital, and Brazilian National Institute of Cancer, Brazil. We used Cox proportional hazards regression to evaluate association of time to treatment and risk of recurrence (ROR) or death. Results One thousand one hundred ninety-one patients were included. Women in Brazil were more frequently diagnosed with stage III disease (32.3% vs. 21.1% Texas; P = .002). Majority of patients in both populations had symptom-detected disease (63% in Brazil vs. 59% in Texas). Recurrence within 5 years from diagnosis was similar 21% versus 23%. Median time from diagnosis to first treatment defined as either systemic therapy (chemotherapy or endocrine therapy) or surgery, were comparable, 9.9 weeks versus 9.4 weeks. Treatment delay was not associated with increased ROR or death. Higher stage at diagnosis was associated with both increased ROR and death. Conclusion Time from symptoms to treatment was considerably long in both populations. Treatment delay did not affect outcomes. Impact Access to timely screening and diagnosis of breast cancer are priorities in these populations.

Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mortality. Initially most women respond to platinum chemotherapy, but rapidly many become resistant to the drug and progress to relapse and death. Better knowledge of the pathways responsible for the mechanisms of invasion and metastasis in women with HGSOC may help in the identification of prognostic biomarkers and in the development of new target therapies. The epithelial-mesenchymal transition (EMT) is an important cellular process related to invasion and metastasis. Some protein components such as the receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), acting on the signal-regulated kinase 1/2 (ERK1/2) extracellular pathway, and the transcriptional co-activator yes-associated protein (YAP), acting in Hippo, are associated with EMT. In such pathways, microRNAs, such as miR-182, miR-96, and miR-9 are described as post-transcriptional regulators. Objective: To evaluate the expression of DDR2, YAP and miR-182, miR-96 and miR-9 in formalin-fixed, paraffin-embedded blocks with HGSOC, and its association with clinical, tumor, platinum response, and survival characteristics. Methods: 63 women with HGSOC stages III and IV, who underwent platinum chemotherapy from 1996 until 2013, followed up until 2016 at the Women's Hospital Prof. Dr. José Aristodemo Pinotti, Brazil, were included. All women had paraffin blocks and complete clinical data on the chart. DDR2 and YAP expression were assessed by immunohistochemistry on tissue microarray (TMA) slides and the microRNAs were evaluated by real-time polymerase chain reaction (rtPCR). For the comparison of DDR2 and YAP expression with age, CA125 serum level, post-surgery residual stage disease, and platinum response, Mann-Whitney and Fisher tests were used. Progression-free survival (PFS) and overall survival (OS) were calculated by Cox regression. The PFS and OS curves were estimated by the Kaplan-Meier method and compared by the Log-Rank test. Expression of miR and DDR2 and YAP levels were compared by the t-test. Results: DDR2 expression was high in 8 (13.7%) women. There was no association between DDR2 expression and age, stage, CA125, residual post-surgery disease, and response to platinum-based chemotherapy. PFS was significantly worse in women whose tumors had high DDR2 expression (p=0.03), but not OS (p=0.49). MiR-182 level expression was lower in the group with high DDR2 expression (p&lt;0.001), but not the expression level of miR-96 (p=0.067). High nuclear expression of YAP with low cytoplasmic expression was found in 15 (24.5%) women. There was no association between the expression of YAP and the characteristics of the disease or evolution of the women. MiR-9 level expression was not associated with YAP expression. Conclusions: Low levels of miR-182 expression were associated with high expression of DDR2, which was associated with poorer DFS. These findings suggest that the ERK1/2 signaling pathway was relevant to the EMT of these HGSOCs. The role of Hippo remained indeterminate. Citation Format: Susana Oliveira Ramalho, Luis Otávio Sarian, Rodrigo Natal, Liliana Andrade, Amanda Ferracini, Marina Pavanello, Cassio Cardoso Filho, Sophie Derchain. Prognostic evaluation of components associated with epithelium-mesenchymal transition in women with serous carcinoma of high ovary grade [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B16.

IntroductionOverall survival of women with high‐grade serous ovarian cancer (HGSOC) is highly related with platinum resistance. Parameters of collagen can be used as potential new prognostic biomarkers, since their relation with tumor growth, invasion and metastasis has been demonstrated. These parameters are (1) quantity which is the amount of fibers deposited, (2) uniformity which refers to how collagen fibers are closely deposited side by side and (3) organization refers to how the fibers are arranged.AimTo evaluate the association of intratumoral collagen fiber parameters with platinum resistance in HGSOC patients.Methods35 women with HGSOC, 14 platinum resistant and 21 platinum sensitive were included. Their samples of paraffin embedded human were sectioned (4 μm) and stained with hematoxylin and eosin. Three intratumoral regions of interest were analyzed by second harmonic generation microscopy, in a Zeiss LSM 780‐NLO confocal (Carl Zeiss AG, Germany). The images were captured (1024×1024 format; 40×/1.3 NA oil) with an excitation wavelength of 890 nm, a pulse length of approximately 100 fs, and emission filter centered at 445 nm with a 20 nm bandwidth (Semrock, Rochester, New York) (Figure 1). Each image was divided in 16 regions (256 × 256) and analyzed in an independently way, using the ImageJ (NIH, Bethesda, USA). Intratumoral collagen fiber parameters were compared considering platinum resistance status using t‐tests. Sensitivity and specificity were analyzed using receiver operator characteristics (ROC) curves.ResultsThere was a significant association between platinum resistance and thick collagen fiber quantity (p=0.04) and a trend of association with thin collagen fiber quantity (p=0.06). Further, intratumoral thick and thin collagen fiber uniformity also were associated with platinum resistance (p=0.02 and p=0.02, respectively). There was no association between intratumoral thick and thin collagen fiber organization with platinum resistance (p=0.29 and p=0.27, respectively). ROC curves demonstrated the highest area under the curve using thin collagen fiber uniformity as parameters, in this case it was found 47.6% of sensibility and 92.9% of specificity to determine platinum resistance (Figure 2).ConclusionOur preliminary results are encouraging since there was an association between intratumoral thick and thin collagen fiber quantity and uniformity with platinum resistance status in women with HGSOC.Support or Funding InformationPartially financed by Cnpq number 306583/2014‐3.

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