bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploratory analysis of the effect of maintenance rucaparib on postprogression outcomes in patients (pts) with platinum-sensitive recurrent ovarian carcinoma (OC) and updated safety data from the phase 3 study ARIEL3.
Authors: Coleman Robert L. , Oza Amit M. , Lorusso Domenica , Aghajanian Carol , Oaknin Ana , Dean Andrew Peter , Colombo Nicoletta , Weberpals Johanne I , Clamp Andrew R. , Scambia Giovanni , Leary Alexandra , Holloway Robert W. , Amenedo Margarita , Fong Peter C.C. , Goh Jeffrey C. , O'Malley David M. , Cameron Teresa , Maloney Lara , Goble Sandra , Ledermann Jonathan A. 
Published: May 2019

5522 Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-type BRCA/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Exploratory endpoints of time to first subsequent therapy (TFST), time to investigator-assessed PFS on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the predefined cohorts. Results: Exploratory efficacy endpoint data are given in the Table. As of Dec 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs 0.0%). Conclusions: Rucaparib significantly improved the clinically meaningful endpoints TFST, PFS2, and TSST vs placebo in all predefined cohorts of pts with platinum-sensitive, recurrent OC. The updated safety profile was consistent with prior reports. Clinical trial information: NCT01968213. [Table: see text]
A phase I study of veliparib incorporated into front-line platinum based cheotherpy and bevacizumab in epithelial ovarian cancer (NCT00989651): A GOG/nrg trial.
Authors: Armstrong Deborah Kay , Moore Kathleen N. , Miller Austin , Bell-McGuinn Katherine M. , Schilder Russell J. , Fracasso Paula M. , Walker Joan L. , Duska Linda R. , Mathews Cara Amanda , Chen Alice P. , O'Malley David M. , Gray Heidi J. , O'Cearbhaill Roisin Eilish , Guntupalli Saketh R , Hagemann Andrea R. , Aghajanian Carol 
Published: May 2019

5523 Background: Veliparib, a poly-(ADP-ribose)-polymerase inhibitor, increases anti-tumor activity when combined with platinum chemotherapy and has monotherapy activity in BRCA deficient tumors. This study was done to determine the recommended phase II dose (RP2D) of veliparib in combination with front line treatment for epithelial ovarian cancer (EOC). Methods: Eligible patients had newly diagnosed, stage II-IV EOC. Six regimens were evaluated, 3 variations of chemo delivery with either continuous (D1-21) or intermittent (days-2-5) veliparib BID. Chemo included 1: IV q3week carboplatin (C) (AUC 6) and paclitaxel(T) (175mg/m2); 2, IV q3week C (AUC 6) and weekly T(80mg/m2); and 3, IV T (135mg/m2, day 1), IP cisplatin (75mg/m2, day 1 or 2) and IP T (60mg/m2, day 8). Bevacizumab 15mg/kg started cycle 2 and continued as monotherapy cycles 7-22. A 3+3 dose escalation design evaluated dose-limiting toxicities (DLTs) in cycles 1 and 2. Once < 2/6 patients experienced a DLT, that dose level was expanded to evaluate feasibility over 4 cycles. Results: The study accrued 424 treated patients. For regimen 1, continuous (Reg1c) the maximum tolerated dose (MTD) was 250mg veliparib BID but the feasible dose was found to be 150mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250mg BID respectively. For Reg2c the MTD and feasible dose were the same at 150mg BID. For Reg2i the MTD and feasible dose were 250 and 150mg BID respectively. For Reg3c the MTD and feasible dose are both 150mg BID and for Reg3i, the MTD was 400mg BID and the feasible dose felt to be 300mg BID. Median PFS by residual disease and BRCA status is: (Positive residual disease) 14.6, 19.1 and 16.9 months for BRCA+, BRCAwt and BRCA ukn respectively. For no gross residual disease the PFS is NR, 34.2 and 24.5 months respectively. Conclusions: Given the difficulty with toxicity not defined as a DLT, the RP2D for all regimens is veliparib 150mg BID. This data informed the dose that moved into the phase III trial GOG 3005/Velia: NCT02470585. Velia also incorporated maintenance veliparib instead of maintenance bevacizumab among all high grade serous patients (BRCA+ and wt). These results will determine utilization of veliparib in this space. Clinical trial information: NCT00989651.
Human papillomavirus genotype and prognosis of invasive cervical cancer: A nationwide cohort study.
Authors: Lei Jiayao , Ploner Alexander , Lagheden Camilla , Eklund Carina , Nordqvist Kleppe Sara , Andrae Bengt , Elfström Klara Miriam , Dillner Joakim , Sparén Pär , Sundström Karin 
Published: May 2019

5525 Background: The role of human papillomavirus (HPV) in development from oncogenic infection to invasive cervical cancer (ICC) has been well established. However, the association of HPV genotypes and prognosis of ICC is controversial. Methods: We identified all ICC diagnosed in Sweden during the years 2002-2011 (4254 confirmed cases after clinical and histo-pathological review), requested all archival formalin-fixed, paraffin-embedded blocks and subjected them to comprehensive HPV genotyping. Twenty out of twenty-five archives agreed to the study, contributing a total of 2845 confirmed cases with valid HPV results. Cases were followed up from date of cancer diagnosis to 31 December, 2015, migration from Sweden, or death; whichever occurred first. Five-year relative survival ratios (RSRs) were calculated and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression. Results: HPV was detected in 2365 tumors (83.1% of all cases). The five-year RSR by tumor HPV status was 0.54 (HPV negative), 0.76 (HPV16 positive), 0.73 (HPV18 positive), 0.72 (other high-risk HPV positive) and 0.56 (low-risk HPV positive) compared to the age-matched general female population. Compared to cases with HPV-negative tumor, a significantly lower excess mortality was seen if the tumor was positive for HPV16 (EHR:0.54, 95% CI 0.44-0.65), other high-risk HPV (EHR:0.47, 95% CI 0.37-0.60), and low-risk HPV (EHR:0.48, 95% CI 0.32-0.74), after adjustment for age, time since cancer diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, educational level and histology. However, the mortality among women with HPV18 positive tumors were not statistically significantly different from cases with HPV-negative tumors. In women with a single HPV infection of either HPV16 or HPV18, those with HPV18-positive tumors had 56% (EHR:1.56, 95% CI: 1.13-1.97) higher excess mortality compared to women with HPV16-positive tumors. Conclusions: HPV genotype in cervical cancer tumor is associated with prognosis of ICC. Single HPV18 positivity indicated a poorer prognosis than single HPV16 positivity. This could add information of value beyond the established clinical prognostic factors for women diagnosed with ICC.
Prognostic significance of the number of pelvic lymph-nodes resection in patients with cervical adenocarcinoma: An analysis from JGOG 1070S study.
Authors: Ikeda Yuji , Kita Tsunekazu , Furusawa Akiko , Takekuma Munetaka , Mikami Mikio 
Published: May 2019

5529 Background: Although resection of more than 20 lymph-nodes is considered to be adequate in pelvic lymphadenectomy for cervical cancer patients, prognostic significance of the number of resected lymph-nodes (PLN-num) is clinically still unknown. Methods: This nationwide multicenter retrospective study (JGOG 1070S) examined consecutive 693 patients with clinical stage IB-IIB cervical cancer who underwent radical hysterectomy including pelvic and/or para-aortic lymphadenectomy between 2008-2009 at 87 institutions of the Japanese Gynecologic Oncology Group. Maximum number of enrollments from one institution was limited 10 or less to minimize the inter-institutional bias. Correlation between PLN-num and prognosis was analyzed using Cox hazard model with considering histological subtypes. Results: Of 473 eligible cases in this study, the average PLN-num per a case in each institution was positively correlated with the number of total cases treated in each institution per year. (R = 0.42, P = 0.012). Patients with high PLN-num showed favorable progression free survival (PFS) (P = 0.12). Focusing on adeno and adeno-squamous carcinomas, significantly improved PFS was shown in high PLN-num cases (P = 0.012), although no significance was found in squamous cell carcinoma (P = 0.754). Multivariate analysis in adeno and adeno-squamous cases showed PLN-num as an independent prognostic factor (HR; 0.46, 95%CI; 0.24–0.84, P = 0.026) along with disease stage and adjuvant therapeutics. Subset analysis of adeno and adeno-squamous cases without adjuvant therapeutics showed significant improvement of survival in high PLN-num group (P = 0.019). Conclusions: In our study, PLN-num in lymphadenectomy for patients with cervical adeno or adeno-squamous carcinoma was clarified to be a significant prognostic factor. Systematic total lymphadenectomy is recommended for these patients to obtain a favorable prognosis.
Cervical cancer harboring a Rb1 mutation may sensitize to cisplatin via PI3K/AKT pathway by regulating apoptosis.
Authors: Luo Peng , Zou Jingwen , Bu Junguo , Meng Hui , Chen Jie , Zhang Jian 
Published: May 2019

5531 Background: Cervical cancer is one of the most common malignant tumors in women and major causes of cancer death in women. Although concurrent chemoradiotherapy has improved the treatment of cervical cancer, due to the heterogeneity of the tumor to chemotherapy or radiation therapy, especially the varied response to chemotherapy, the patients respond differently to the same therapeutic regimen, furthermore some patients get rapid progression. Therefore, we attempted to analyze the potential relationship between genomic mutation and chemotherapy response and survival in cervical cancer patients. Methods: Clinical information and sequencing data of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) in Genomic Data Commons (GDC) data portal were obtained through TCGAbiolinks. Only patients with stage IIB-IV CESC who received cisplatin only and were included. Cisplatin sensitivity data and sequencing data of CESC cell lines were obtained from the Genomics of Drug Sensitivity in Cancer (GDSC). Cox regression analysis, Kaplan-Meier survival analysis, differential analysis of gene expression and functional enrichment were used to explore the role of different mutations in survival and cisplatin sensitivity. Results: A total of 48 patients with stage IIB-IV CESC were enrolled. 77 genes with mutation frequency > 10% were included in final analysis . Multivariate analysis showed that the mutation of Rb1 was an independent predictor of overall survival (OS) (HR = 0.07, 95%CI 0.01-0.73, P = 0.026). Patients with mutant Rb1 had better overall survival (134.2 versus 86.8 months) compared with patients with wild-type Rb1. The half maximal inhibitory concentration (IC50) of the mutant Rb1 cell line to cisplatin was significantly lower than that of the wild-type cell line (3.49 versus 10.15μM, P = 0.038). A total of 332 differently expressed genes (DEGs) were identified and the KEGG pathway enrichment analysis showed that most DEGs were enriched in the PI3K/AKT pathway (P = 0.015). Conclusions: We found that Rb1 mutation was an independent survival predictor in stage IIB-IV CESC, and CESC patients with Rb1 mutation may be more sensitive to cisplatin.
Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.
Authors: Swetzig Wendy M , Lurain John Robert , Berry Emily , Pineda Mario Javier , Shahabi Shohreh , Perry LaToya , Neubauer Nikki Lynn , Nieves-Neira Wilberto , Schink Julian C. , Schiller Alissa , Novak Karen , Anderson Nancy Jean , Burdett Kirsten Bell , Strohl Anna Everett , Kocherginsky Masha , Matei Daniela 
Published: May 2019

5538 Background: Tivozanib is a potent, selective pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian cancer (OC), fallopian tube cancer (FTC) or primary peritoneal cancer (PPC). Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients had recurrent, platinum-resistant OC, FTC or PPC; ECOG PS of 0-1; normal end organ function; and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily (3 weeks on/1 week off). The primary endpoint was response rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. If 1 partial response (PR) was observed in stage I [n = 12], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 4 responses in 30 patients. Results: Thirty-one patients were enrolled, and 30 were treated. Twenty-three had OC [76.67%], 5 FTC [16.67%] and 2 PPC [6.67%]. Twenty-six had measurable [86.67%] and 4 detectable disease [13.37%]. The median age was 60, and median number of prior regimens was 4 [range 1-9]. Four PRs [13.33%] were recorded. Twelve patients had stable disease (SD) [40%]. The clinical benefit rate (PR + SD) was 53%. Seven patients [23.33%] survived progression-free for > 6 mos. One patient continued treatment for > 2 yrs. The median PFS was 4 mos [range 1-25] and median OS was 8 mos [range 1-39]. There were no treatment-related deaths. Grade 3-4 related toxicities were hypertension [8], fatigue [3], fistula [2], hyponatremia [2], intestinal perforation, obstruction, stroke, proteinuria, hypomagnesemia, hypoalbuminemia, portal hypertension, nausea and anemia [1 each]. Frequent grade 1-2 related toxicities included fatigue [19], hypertension [13], anorexia [12], arthralgia [11], diarrhea [11], weight loss [10], hoarseness [8], headache [8] and nausea [7]. Exploratory analyses in tumor samples are ongoing. Conclusions: Tivozanib is active in patients with recurrent OC, FTC or PPC, without substantial toxicity, supporting its further development. Clinical trial information: NCT01853644.
Genomics of HER2+ breast cancer in young women before and after exposure to chemotherapy (chemo) plus trastuzumab (H).
Authors: Waks Adrienne Gropper , Jain Esha , Collins Laura C. , Rosenberg Shoshana M. , Ruddy Kathryn Jean , Tamimi Rulla M , Schapira Lidia , Come Steven E. , Peppercorn Jeffrey M. , Borges Virginia F. , Warner Ellen , Snow Craig , Partridge Ann H. , Wagle Nikhil 
Published: May 2019

554 Background: HER2+ breast cancer (BC) is particularly common in young women. Genomic features of HER2+ tumors before and after H-based therapy have not been described in a population of young women and may point to clinically targetable mechanisms of resistance. Methods: From a large prospective cohort of women diagnosed with BC age ≤40 years, we identified those with HER2+ BC and tumor tissue available for sequencing before and after chemo+H. Whole exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. Evolutionary analysis was performed for patients with both pre- and post-treatment (tx) samples. Results: 22 women had successful WES samples from at least one timepoint; 13 of these had paired sequencing results both before and after chemo+H. For the majority of women, post-tx sample was following neoadjuvant chemo + H, though post-tx timepoint for other women represented locoregional or distant metastasis (Table). TP53 was the only gene that was significantly recurrently mutated in both pre- and post-tx samples. Comparison of matched pre-tx and post-tx samples demonstrated that large changes in HER2 CN over the course of tx were uncommon, only 2/13 pts had > 2-fold change in HER2 CN. Other clonal and subclonal genomic alterations were found to be acquired in the post-tx sample compared to the pre-tx sample. One patient acquired a putative activating mutation in ERBB2. Another patient acquired a clonal hotpsot mutation in TP53. MYC gene amplification was observed in 4 post-tx tumors. NOTCH2 alterations were found in post-tx biopsies from 2 different patients, and mutations in STIL were also found in post-tx biopsies from 2 patients, though the function of these mutations is not known. Conclusions: HER2+ breast tumors in young women display genomic evolution following tx with chemo+H. HER2 CN changes are uncommon, but we identified several genes that warrant exploration as potential mechanisms of resistance to therapy in this population.[Table: see text]
Results of the VENUS study: Bevacizumab efficacy and safety in platinum-sensitive recurrent ovarian cancer (OC)—A real-life ambispective study.
Authors: Ray-Coquard Isabelle Laure , Alexandre Jerome , Goldwasser Francois , Spano Jean-Philippe , Berton-Rigaud Dominique , Savoye Aude-Marie , Fabbro Michel , Bazan Fernando , Kalbacher Elsa , Raban Nadia , Giraud Claire , Pottier Virginie , Selle Frédéric , Patsouris Anne , Garnier-Tixidre Claire , Mercier Blas Anne , Provencal Jocelyne , Brocard Fabien , Berdougo-Tritz Jessica , Launay-Vacher Vincent ,   VENUS Study Group
Published: May 2019

5540 Background: The VENUS study reports on the efficacy/safety of bevacizumab (Bev) in patients (pts) treated in the real-life setting. Methods: In this multicentric observational ambispective VENUS study, all Pts were naive of any antiVEGF and received Bev +/- chemotherapy. Pts were followed until progression or death, for a maximum of 3 years since Bev initiation. De novo side effects were defined as symptoms for which patients were naïve at baseline. Results: 148 OC pts were included (27 centres), 10 excluded and 8 were lost of follow-up. 52 were retrospective. Median age 64 years (55-70). 84.1% were advanced. Median duration of Bev was 8.6 months, min 1 max 36 months. Initial Bev dose was 15 mg/kg Q3W for 65.3%, 10.0 for 22.5%, 7.5 for 10.2% and 5.0 for 2%. 2 pts presented with thrombotic micro-angiopathy (1.4%). Before Bev, hypertension (HTN) was present in 28.9%; proteinuria in 11.3%. Incidence of de novo HTN was 25%. 43 pts (31.2%) experienced de novo Grade 1-2 Pu, for a total of 56 events, no grade 3-4 was observed. A total of 12 Grade 4 events occurred: 9 neutropenia and 3 thrombopenia. Mean overall survival (OS) and progression free survival (PFS) were 30.0 and 13.3 months, respectively. Conclusions: 1) 1/3 of pts were treated at low doses in this real-life study; 2) safety of Bev in real-life was manageable and as expected, 3) OS and PFS were consistent with those reported in the OCEANS study: PFS 12.4 and OS 33.6 months but lower than in the GOG-0213 study: PFS 13.8 and OS 42.6 months. De novo events recorded during follow-up. [Table: see text]
SOLO1 versus SOLO2: Cost-effectiveness of olaparib as maintenance therapy for newly diagnosed and platinum-sensitive recurrent ovarian carcinoma among women with germline BRCA mutations (gBRCAmut).
Authors: Wolford Juliet Elizabeth , Tewari Krishnansu Sujata , Liang Su-Ying , Bai Jiaru , Mann Amandeep Kaur , Moore Kathleen N. , Pujade-Lauraine Eric , Ledermann Jonathan A. , Monk Bradley J. , Chan John K. 
Published: May 2019

5545 Background: With the December 19, 2018 regulatory approval by the US FDA of olaparib tablets as maintenance therapy for women with deleterious or suspected deleterious germline or somatic BRCAmut advanced ovarian carcinoma, it becomes important to clarify the role of PARP inhibitors in this disease. We evaluated cost-effectiveness of olaparib in the upfront (SOLO1) versus the recurrent maintenance setting (SOLO2). Methods: Data were obtained from SOLO1, the phase 3 placebo-controlled randomized upfront maintenance study among gBRCAmut patients [median PFS greater than 49.8 vs 13.8m: HR 0.30; 95% CI, 0.23-0.41; p < 0.001, NCT01844986] and SOLO2, the phase 3 placebo-controlled randomized maintenance study among gBRCAmut patients with platinum-sensitive recurrence and at least two prior lines of therapy [median PFS 19.1 vs 5.5m: HR 0.30; 95% CI, 0.22-0.41; p < 0.0001, NCT01874353]. Investigator-assessed median PFS and toxicity data from the trials were incorporated in a Markov model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2015, the costs of pre-treatment testing (eg. gBRCAmut), medications, and management of adverse effects were analyzed. Incremental cost-effectiveness ratios (ICERs) per month of life gained and individual PFS-life year saved (PFS-LYS) were also calculated and compared. Results: In SOLO1, cost prior to progression was 1.7x that of SOLO2 ($937,440 vs $564,451). With the extended, estimated median PFS of at least 49.8m for SOLO1 and 19.1m for SOLO2, upfront maintenance therapy was more cost-effective. SOLO 1 was associated with $312,480 PF-LYS per individual patient, while SOLO2 demonstrated $498,045 PF-LYS. Maintenance olaparib was found to be more cost-effective in the 1st-line setting, with an ICER of $12,149 per month of life gained when compared directly to SOLO2. Conclusions: Although the higher cost associated with olaparib in SOLO1 reflects the longer time patients stay on drug due to extended PFS, the ICER supports early use in the disease course as first-line maintenance therapy among women with gBRCAmut advanced ovarian carcinoma.