bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumoral genetic variations of the homologous recombination (HR) reparation system in brain metastases in women with epithelial ovarian cancer (EOC).
Authors: Fontanilles Maxime , Castera Laurent , Gouardon Nicolas , Jeanne Corinne , Vaur Dominique , Brachet pierre-Emmanuel , Joly Florence 
Published: September 2018

e17048 Background: Brain metastases (BM) EOC are rare and late events. We explored tumoral genetic variations of HR system. We identify genomic alterations with NGS in both primary tumor and BM EOC Methods: Seven patients suffering from histologically proven EOC and BM, which underwent neurosurgery, were included in the study. Seven matched samples (primary tumor and BM) were analyzed by high throughput sequencing after enrichment by capture of the whole exome. After bioinformatics procedures (BWA, HaplotypeCaller, Varscan2, Outlyzer) the analysis was restricted firstly to a in silico panel of 69 genes involved in HR system. Results: Mean age was 56 years (47 to 71). Five had serous and 2 endometrioid carcinomas. All the patients had an initial FIGO stage ≥IIIA, were platine-sensitive. Median time from diagnosis of EOC to BM was 29 months (24 to 76). BM occurred after first line treatment in 5 cases and after at least 2 relapses in the 2 other cases. Median Overall survival (OS) from diagnosis of BM was 17 months (1 to 45). Five primary tumor showed a variation of at least one HR gene: pathogenic variants inactivating in BRCA2 (n = 2), CDK12 (n = 1) and probably pathogenic missenses in BRIP1 (n = 1) and TOPB1 (n = 1). These 5 variations have been also found in the BM tissues. Among the 2 patients without variations in the primary tumor, 2 probably pathogenic missenses were detected in the BM tumor (1 FANCD2 and 1 FANCM). Time to BM relapse and OS were longer among these 2 last patients compared to the remaining 5 patients (median 68 vs 29 months and 90 vs 56 months, respectively). Conclusions: Patients with BM presented HR somatic mutations and are susceptible to have high response to Parp inhibitors.
Inhibition of Wnt signaling as therapeutic option in platinum-resistant ovarian cancer.
Authors: Trillsch Fabian , Preinfalk Valentina , Rahmeh Martina , Vogel Marianne , Czogalla Bastian , Burges Alexander , Jeschke Udo , Mahner Sven 
Published: September 2018

e17050 Background: New therapeutic approaches for platinum-resistant ovarian cancer patients are urgently needed. In this context, Wnt signaling appears to be a promising target so that inhibition of this pathway in platinum-resistant cell lines was aim of the present study. Methods: The ovarian cancer cell line A2780 and its platinum-resistant clone A2780cis were treated with different concentrations of Wnt singaling inhibitors SB216761, XAV939, and triptolides. Metabolic activity and cell viability was estimated by MTT cell proliferation assays. Immunohistochemistry for ß-Catenin visualized activity of the Wnt pathway. Results: MTT proliferation tests revealed an impaired proliferation following treatment with all three agents. While triptolides already led to significantly reduced metabolic activity after 48h, this effect was seen for SB216761 and XAV939 not before 72h. Immunohistochemistry for ß-Catenin confirmed inhibition of Wnt signaling. Following XAV939 treatment of A2780cis, ß-Catenin signals shifted from the nucleus towards the cell membrane. Conclusions: Re-sensitizing platinum-resistant ovarian cancer cells for platinum-based chemotherapy by inhibition of Wnt signaling seems to be mechanism visualized by the translocation of ß-Catenin from the nucleus towards the cell membrane. In this context, a dose-dependent response was noted for XAV939. Inhibition of Wnt Signaling appears to be a prospective therapeutic approach for platinum-resistant ovarian cancer patients.
Clinical characterization of long term survivors (LTS) in ovarian cancer (OC): Results of a propensity score matched (PSM) analysis of the international prospective tumor bank for ovarian cancer (TOC Network).
Authors: Braicu Elena Ioana , Woopen Hannah , Glajzer Joanna , Hunsicker Oliver , Woelber Linn , Feldheiser Aarne , van Nieuwenhuysen Els , Mueller Michael D , Concin Nicole , Achimas Patrick , Ruscito Ilary , Mahner Sven , Benedetti Panici Pierluigi , Gasparri Maria Luisa , Papadia Andrea , Birrer Michael J. , Vergote Ignace , Darb-Esfahani Silvia , Sehouli Jalid 
Published: September 2018

e17063 Background: OC has the highest mortality rate amongst gynecological malignancies. Nevertheless a small fraction of OC patients will survive longer than 8 years. Aim of our study was to analyze differences in the clinical appearance and management of LTS versus “classical” OC patients. Methods: OC patients living longer than 8 years were identified within the TOC Network between 1998 and 2008, representing the LTS subgroup. PSM analysis was used to select comparable groups of LTS and OC patients who died within first 5 years (control group - CG). PSM was conducted using nearest neighbor caliper matching without replacement to match LTS and CG for age, FIGO and residual tumor mass. All calculations were performed with the R project for Statistical Computing (R-packages used: “MatchIt”). Results: A total of 347 OC patients with different histological subtypes were included in the current analysis, i.e. 173 LTS and 174 in the CG. After PSM 114 patients remained in each group. Patients had similar age, FIGO stage and residual mass (p = 0.99, p = 0.35 and p = 0.88, respectively). Tumor spread in middle and upper abdomen (p = 0.002 and 0.013, respectively) was higher and diaphragm, mesentery and peritoneum (p = 0.009, 0.037 and 0.002, respectively) were significantly more often involved in CG than in the LTS. When only considering the HGSOC patients, 95 patients remained in each group. All patients received surgery and platinum based chemotherapy. The PSM analysis showed significant higher involvement of upper abdomen (p = 0.028), higher peritoneal spread (p = 0.002), higher ascites volume (p = 0.0007) and higher bowel resection rates (p = 0.002) in the CG compared to LTS. Neoadjuvant chemotherapy rate was similar in the LTS and CG (p = 0.5). Conclusions: Based on this PSM analysis, HGSOC-LTS seem to have mainly similar clinical pattern as the control group, however with lower rates of ascites and involvement of upper abdomen. Molecular characterization including analysis of clonal diversity might help elucidate mechanisms of tumor spread and good prognosis.
Performance of preoperative plasma HE4 and CA-125 levels in predicting ovarian cancer mortality in women with epithelial ovarian cancer (EOC).
Authors: Bairati Isabelle , Gregoire Jean , Plante Marie , Douville Pierre 
Published: September 2018

e17076 Background: Additional prognostic biomarkers are needed to better manage women with EOC, especially dichotomized indicators for decision making. The objective of this external validation study was to assess the performance of preoperative plasma HE4 and CA-125 levels in predicting mortality by EOC. Methods: Eligible EOC women were newly diagnosed cases treated by upfront debulking surgery in a gynecology oncology center (CHU de Québec, L’Hôtel-Dieu, Canada) in 1988-2006 (cohort 1, n=136) and in 2007-2013 (cohort 2, n=177). All FIGO stages were included. Preoperative plasma HE4 and CA-125 levels were measured by Elecsys® automated immunoassay (Roche Diagnostics). Dates and causes of death were obtained by record linkage with the Quebec mortality files. In cohort 1, time-dependent receiver operating characteristic (ROC) curves were performed and optimal thresholds for HE4 and CA-125 were generated using the Youden index J. In cohort 2, crude and standardized Cox proportional models were done to validate the usefulness of these biomarkers according to their optimal thresholds. Standardized models included standard prognostic factors. The Likelihood Ratio (LR) tests were done to compare the standardized models with and without each biomarker. Results: In cohorts 1 and 2, medians of follow-up were respectively 5.3 and 3.2 years. Five-year disease free survival rates were 53% in cohort 1 and 54% in cohort 2. In cohort 1, the AUC for HE4 and CA-125 were respectively 64.2 (95% CI: 54.7-73.6) and 63.1 (95%CI: 53.6-72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA-125. In cohort 2, higher levels of plasma HE4 (≥277 pmol/L) were significantly associated with death by EOC (adjusted hazard ratio (aHR): 1.80; 95% CI: 1.03-3.15; p-value for LR test: 0.03), while higher levels of CA-125 (≥282 U/ml) were not associated with death by EOC (aHR: 1.50; 95% CI: 0.88-2.55; p-value for LR-test: 0.12). In serous EOC, the associations with mortality were respectively 2.46 (95% CI: 1.26-4.80) for HE4 and 1.56 (0.87-2.80) for CA-125. Conclusions: Preoperative plasma HE4 is a promising prognostic biomarker in women with EOC and performs better than CA-125 to predict mortality.
Molecular-based classification algorithm for endometrial carcinoma to categorize ovarian endometrioid carcinoma into prognostically significant groups.
Authors: Parra-Herran Carlos , Lerner-Ellis Jordan , Xu Bin , Bassiouny Dina , Cesari Matthew , Ismiil Nadia , Nofech-Mozes Sharon 
Published: September 2018

e17081 Background: The Cancer Genome Atlas classification divides endometrial carcinoma in biologically distinct groups, and testing for p53, mismatch repair proteins (MMR) and polymerase ɛ (POLE) exonuclease domain mutations has been shown to predict the molecular subgroup and clinical outcome. While abnormalities in these markers have been described in ovarian endometrioid carcinoma (OEC), their role in predicting its molecular profile and prognosis is still not fully explored. Methods: OECs resected in a 14 year period were retrieved. Only tumors with confirmed endometrioid histology and negative WT1 were included. POLE mutational analysis and immunohistochemistry for p53, MLH1, MSH2, MSH6 and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. Following the molecular classifier proposed for endometrial carcinoma ( B J Cancer 2015;113:299-310), cases were classified as: POLE mutated, MMR abnormal, p53 abnormal and p53 wild type. Clinicopathologic information was recorded including patient outcome. Results: 73 tumors were successfully reviewed and tested. Of these, 8 (11%) were POLE mutated, 6 (8%) were MMR abnormal and 17 (23%) were p53 abnormal; the remaining 42 cases (58%) were p53 wild type (no POLE, p53 or MMR abnormalities). Mean follow-up period was 69 months (median 62, range 1-179). The molecular classification was an independent predictor for disease free and overall survival on multivariate analysis (p = 0.005 and 0.045 respectively, Cox proportional hazard model). POLE mutated and MMR abnormal groups had 100% 5 year DFS and OS. p53 wild type cases had intermediate survival rates (86% DFS and OS). Conversely, the p53 abnormal group had worse outcomes with 42% DFS and 76% OS at 5 years. Conclusions: OEC can be classified into prognostically distinct subgroups by testing for molecular surrogates, akin to endometrial cancer. MMR and POLE alterations seem to identify a subset of ovarian endometrioid carcinomas with excellent outcome; conversely, abnormal p53 expression carries a worse prognosis. In the era of personalized medicine, the use of these markers in the routine evaluation of ovarian endometrioid tumors should be considered.
Comprehensive molecular profiling of advanced gynecologic malignancies.
Authors: Rojas Luis , Williams Casey B. , Starks David , Williams Kirstin Anne , Leyland-Jones Brian 
Published: September 2018

e17082 Background: Precision medicine has been studied in patients with advanced, heavily-treated cancers by administering molecularly targeted monotherapies. Rational combination approaches that are selected based upon molecular analysis, tailored for each patient based upon their past medical history, performance status and unique molecular profile, and curated to prevent the development of resistance represent a possible solution that warrants further exploration. Methods: The primary aim of this proposal, Identifying Molecular Drivers of Cancer (NCT02470715), is to recognize genetic drivers of cancer by performing comprehensive genomic profiling (CGP) and/or proteomic characterization, and further translational research of patient samples. A molecular tumor board discussed results upon receipt and recommended customized combinations. Final decisions of implementation were the choice of the treating physician. Results: CGP was evaluable in 46/64 (72%) advanced gynecologic malignancies (GYN). The remaining 18 are either awaiting therapy or too early for evaluation. Thirty three/45 (73%) patients received combination therapy matched to the CGP. Fourteen/34 (41%) matched patients achieved CR, 12/34 (35%) achieved a PR, 6/34 (18%) achieved SD, and 2/34 (6%) had progression after 3 cycles. Clinical benefit rate was 94%. For ovarian cancer (25 pts), the response rate was 75% and the median progression-free survival (PFS) is 8.5 months and ongoing in 4 patients. Twelve/46 (26%) patients received CGP, but were treated with standard treatments because of insurance denial or inability to get drugs. Two/12 (17%) achieved a CR, 3/12 (25%) achieved SD, and 7/12 (58%) had progression. The PFS for patients that received standard therapies was 1 month. Median number of prior therapies in all patients was 4. Conclusions: Management of advanced gynecologic malignancies with customized combinations of approved agents based on the patient’s tumor CGP was feasible, resulted in superior therapeutic outcomes and improved PFS compared to standard therapies in heavily pretreated controls within this cohort. This precision oncology therapeutic model for gynecologic malignancies deserves prospective large scale evaluation. Clinical trial information: NCT02470715.
Adjuvant carboplatin and paclitaxel chemotherapy followed by radiotherapy in high-risk endometrial cancer: A retrospective analysis.
Authors: Colombo Bonadio Renata RC , Azevedo Renata Gondim Meira Velame , Harada Guilherme , Miranda Vanessa Costa , Ferreira Patricia Alves de Oliveira , Freitas Daniela , Filho Elias Abdo , Gabrielli Flavia , Estevez-Diz Maria Del Pilar , Costa Samantha Cabral Severino da 
Published: September 2018

e17115 Background: It remains unclear which is the best chemotherapy (CT) regimen and what is the role of adding radiotherapy (RT) to adjuvant CT in high-risk endometrial cancer. Methods: We performed a retrospective analysis of the patients (pts) with high-risk endometrial cancer (endometrioid histology stages III-IVA or carcinossarcoma/ clear cells/ serous histology stages I-IVA) treated with adjuvant carboplatin (AUC 5) and paclitaxel (175 mg/m2), every 3 weeks, for 6 cycles, followed by RT (conformal external beam radiotherapy to pelvic or pelvic and paraortic fields with 45Gy-54Gy plus weekly vaginal brachytherapy with 20Gy in 4 fractions). Pts were treated from 2010 to 2016 at a Brazilian public cancer center. Medical records were reviewed for demographic, clinicopathologic and outcome information. Data was analyzed for overall survival (OS), disease-free survival (DFS), prognostic factors and toxicity. The Kaplan-Meier method was used for survival analysis and Cox proportional hazard model for prognostic factors. Results: 146 consecutive pts were evaluated. Median age was 62 years (range 35-81). Most patients had ECOG 0-1 (98%), endometrioid (53%) or serous histology (26%), grade 3 tumor (57%) and FIGO stage III (77%). Median follow-up was 26.5 months. The OS rates were 85% (95% CI 75 – 91%) in 3 years and 73% (95% CI 58 – 84%) in 5 years. Factors that significantly affected OS in a multivariate analysis were FIGO stage (p = .009), pelvic lymphadenectomy (yes vs no, p = .023) and positive peritoneal cytology (yes vs no, p = .002). 3-year and 5-year DFS rates were 79% (95% CI 70 – 86%) and 68% (95% CI 52 – 80%), respectively. The initial site of recurrence was limited to the pelvis in 3% of the pts, within the abdomen in 1% and extra-abdominal in 11%. Grade 3/4 AEs occurred in 47% of the pts and were mainly hematologic toxicity (43%). There were only 3 cases of febrile neutropenia and 4 cases of hospitalization due to toxicity. Conclusions: Our data suggests that adjuvant carboplatin and paclitaxel, followed by RT, in high-risk endometrial cancer is safe and effective. Low rates of pelvic recurrence were observed, which might be explained by the addition of RT to adjuvant CT.
Somatic tumor profiling of DNA mismatch repair (MMR) deficient endometrial cancers (EC).
Authors: Cadoo Karen Anne , DeLair Deborah , Mandelker Diana , Trottier Magan , Stewart Carolyn , Tran Christina , Kemel Yelena , Walsh Michael Francis , Scharf Felicia , Hyman David Michael , Joseph Vijai , Robson Mark E. , Abu-Rustum Nadeem , Offit Kenneth , Solit David B. , Berger Michael F. , Aghajanian Carol , Stadler Zsofia Kinga 
Published: September 2018

e17121 Background: Approximately 20% of EC have loss of MMR ( MSH2, MSH6, MLH1, PMS2) protein expression by immunohistochemistry (IHC). The majority have somatic MLH1/PMS2 loss, driven by MLH1 promoter hypermethylation. For the remaining patients (pts), germline testing for Lynch Syndrome (LS) is recommended. However, half do not have a corresponding germline mut. This is considered “Lynch-like syndrome” (LLS) & clinical management is challenging. We sought to determine if tumor profiling could identify somatic mut potentially underpinning loss of protein expression. Methods: Per institutional standard, all EC, regardless of age or family history undergo reflex LS screening with IHC for MMR protein expression. Pts consented to IRB approved protocols. Tumor-normal sequencing was performed via custom next-generation sequencing panel (MSK-IMPACT). Electronic medical records were reviewed. Results: 16 pt have completed tumor sequencing, median age 53 (35-83), 6 (38%) < 50 yrs at diagnosis. 2 had personal history of additional cancer (DCIS, ovary), none had first degree relative with colon or EC. A mix of EC histologies was represented: 10 endometrioid (all grades), 2 clear cell, 4 mixed. There were no serous cancers. There were median 58 mut (9-546), 14 (88%) had hyper or ultra mutated EC. 5 EC were driven by somatic POLE mut (3 known hotspot, 1 likely pathogenic), all ultra-mutated phenotype, resulting in multiple somatic MSH6 muts with isolated IHC MSH6 loss. 4 EC had MSH2/MSH6 IHC loss with corresponding double somatic mut in MSH2. 5 had one somatic mut corresponding to the MMR protein loss, assessment of LOH in these cases is pending. Two cases are unexplained: 40 yo with IHC MLH1 loss, 47mut; 69 yo, IHC MSH6 loss, 12 mut. In this cohort of LLS, somatic muts were frequently observed in ARID1A (13,81%), PTEN (10,63%) & PIK3CA(9,56%), in keeping with non serous histologies. Conclusions: In line with our prior report that pt with LLS had benign personal & family cancer histories compared with LS pts, we have identified that in 56% of LLS EC either POLE mut or double somatic MMR mut likely underpins the MMR IHC loss. As such, in these LLS EC cases, somatic tumor profiling may help to rule out LS. Further testing is ongoing to increase cohort size.
Tumor volume as a prognostic factor in patients (pts) with locoregionally advanced head and neck squamous cell carcinoma (LAHNSCC) treated with induction chemotherapy (IC).
Authors: Palhares Daniel Moore Freitas , Batista Fernando Coutinho , Veneziani Ana Lima , Mattos Marcos Duarte , Mamere Augusto Elias , Capuzzo Renato Castro , Santos Carlos Roberto , Carvalho Andre Lopes , Viana Luciano De Souza , Jacinto Alexandre Arthur 
Published: September 2018

e17507 Background: Tumor volume and the ratio of volumetric change have been demonstrated to have a prognostic role in head and neck cancers during definitive treatment in LAHNSCC. The aim of this study was to evaluate the prognostic value of tumor volume assessment during IC. Methods: We retrospectively assessed the tumor volume of 58 pts with LAHNSCC included in a prospective phase II trial which evaluated the safety of a non–5-fluorouracil-based IC (paclitaxel; cisplatin) followed by chemoradiotherapy (cisplatin; 70Gy/35fx) during 2009-2012. The volume of primary tumor (PrimV), all suspicious lymph nodes (LNV) and their sum (SumV) were determined on tomography before (CT1) and after (CT2) IC using a radiotherapy treatment planning system and the ratio of volumetric change was calculated for each variable (PrimV%, LNV% and SumV%). Results: The median follow-up time, the progression free survival (PFS) and the overall survival (OS) was 78,1, 19,3 and 22,5 months, respectively. Fifty-four pts were men, mean age 55,3±8,3y. Most had oropharynx (53%) and stage IV (72%) cancer. The median volume (cm3) was PrimV1= 25,5, LNV1= 7,5, SumV1= 40,7, PrimV2= 10,9, LNV2= 3,0, SumV2= 18,8 and median ratio of change (%) was PrimV% = 55, LNV% = 51 and SumV% = 54. Volume wa s associated with resectability (PrimV1, AUC ROC curve = 0,66, p = 0,04; LNV1, AUC = 0,85, p < 0,001; SumV1, AUC = 0,86, p < 0,001). Pts with SumV% reduction > 35% had better PFS (median 84,0 vs 10,1 months, 3y 52% vs 29%; HR = 0,39, p = 0,01) and OS (median 45,5 vs 17,0 months, 48% vs 21%; HR = 0,49, p = 0,04). On univariate analysis the PFS was correlated with T (p = 0,004), N (p = 0,01), stage (p = 0,03), primary site (p = 0,01), resectability (HR = 0,32, p = 0,001), PrimV1 (p = 0,002), SumV1 (p = 0,001), PrimV2 (p = 0,02), LNV2 (p = 0,04), SumV2 (p = 0,004), PrimV% (p = 0,04), LNV% (p = 0,003) and SumV% (p = 0,04) and OS was associated with T (p = 0,04), N (p = 0,02), stage (p = 0,04), primary site (p = 0,01), resectability (HR = 0,29, p < 0,001) PrimV1 (p = 0,003), LNV1 (p = 0,002) and SumV1 (p < 0,001). Conclusions: Tumor volume and the volumetric response during IC were associated with prognosis in LAHNSCC in the present study. Clinical trial information: NCT00959387.