bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of early tumor shrinkage as a response to VEGF inhibitors as a predictor of progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Gruenwald Viktor , Seidel Christoph , Fenner Martin , Woike Michael , Kalanovic Daniel
Published: March 2020

4631

Background: Several novel targeted agents significantly prolong overall survival (OS) in metastatic renal cell cancer (mRCC) patients (pts.). Translational research, however, has not identified any prospectively validated prognostic or predictive biomarkers. Recently, progression free survival (PFS), overall response rate (ORR) and early tumor shrinkage were proposed as putative predictors for clinical outcome. In this study we aim to explore the potential role of treatment induced tumor remission as a prognostic or predictive parameter in mRCC. Methods: In our analyses we investigated the putative prognostic role of best response according to RECIST 1.1 criteria (complete remission (CR), partial remission (PR), stable disease (SD), progressive disease (PD)) in first line Tyrosine-kinase inhibitor (TKI) treatment in n=83 pts. Responders were defined by achieving CR, PR or SD at any time during the course of treatment. Furthermore, we tested whether tumor shrinkage of 10% or more within 12 weeks of treatment qualifies as a potential cut-off-parameter to predict PFS or OS. Uni- and multivariate analyses were performed using Log-rang test, Kaplan-Meier-, and Cox-regression analysis. Results: Univariate analyses revealed that first-line treatment non-responders had a significantly shorter OS than responders (p <0.0001). Tumor shrinkage of <10% or ≥10% also correlated with an OS of 14.5 vs. 29.1 mo. (p=0.001) and a PFS of 3.0 vs. 11.5 mo. (p <0.001). In multivariate analyses tumor shrinkage of ≥10% was tested with other common variables such as ECOG, MSKCC-score, histology, and metastatic sites and proved to be a significant independent prognostic (HR 0.361; 95% CI 0.156-0.833) and predictive (HR 0.306; 95% CI 0.152-0.612) parameter. Conclusions: Our results outline that sensitivity to first line treatment of mRCC is an important prognostic factor in mRCC. Hereby tumor shrinkage of ≥10% within 12 weeks of treatment reveals a novel cut-off-parameter, which showed to be a promising prognostic and predictive marker in mRCC. Further investigations are needed to validate this parameter.
Use of miRNA profiling in metastatic renal cell carcinoma to reveal a tumor suppressor effect for mir-215.
Authors: Yousef George M. , Chan Susanne M. , White Nicole MA , Khella Heba WZ , Grigull Joerg , Adzovic Sonja , Youssef Youssef M. , Honey R. John , Stewart Robert , Pace Kenneth T , Jewett Michael A. S. , Evans Andrew , Gabril Manal Y. , Bjarnason Georg A.
Published: March 2020

4633

Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The five-year survival rate for metastatic RCC is <10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. Methods: We performed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared to primary RCC. Results were validated by quantitative real time PCR. Target prediction analysis and gene expression profiling identified many of the dysregulated miRNAs could target genes involved in tumor metastasis. The effect of miR-215 on cellular migration and invasion was shown in a RCC cell line model. Results: We identified 65 miRNAs that were significantly altered in metastatic when compared to primary RCC. Nine (14%) miRNAs had increased expression while 56 (86%) miRNAs showed decreased expression. miR-10b, miR-196a, and miR-27b were the most downregulated while miR-638, miR-1915, and miR-149* were the most upregulated. A non-supervised 2D-cluster analysis showed that a sub-group of the primary tumors clustered under the metastatic arm with a group of miRNAs that follow the same pattern of expression suggesting they have an inherited aggressive signature. We validated our results by examining the expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in two independent cohorts of patients. We also showed that overexpression of miR-215 decreased cellular migration and invasion in a RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumor metastasis. Conclusions: Our analysis showed that miRNAs are altered in metastatic RCC and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.
Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role for EN2?
Authors: Killick Emma , Morgan Richard , Launchbury Francesca , Annels Nicola E. , Bancroft Elizabeth , Page Elizabeth , Castro Elena , Kote-Jarai Zsofia , Eeles Ros A. , Pandha Hardev S. ,   IMPACT Steering Committee and IMPACT Collaborators
Published: March 2020

4653

Background: EN2 is part of the HOX gene family and plays a role in foetal development. More recently a potential oncogenic role for the protein has been postulated and its utility as a cancer biomarker has been explored in prostate cancer (PrCa) and breast cancer. Carriers of mutations in the BRCA1 and BRCA2 genes have an increased risk of PrCa (1.8-fold and 5-fold respectively) and their tumours tend to be more aggressive and advanced than sporadic cases. Currently there is no national screening program for BRCA mutation carriers in the UK, and the IMPACT study was set up to evaluate PSA screening in this particular group. Here we analyse the efficacy of the urinary EN2 protein as a marker of early cancer detection within this higher risk group. Methods: First pass urine (without preceding digital rectal examination) was collected as part of the IMPACT screening study which enrolled individuals aged between 40 and 69 who were unaffected by PrCa at time of enrolment into the study (n= 418). All participants were from families harbouring a BRCA1 or BRCA2 mutation and were either BRCA mutation carriers themselves or controls with a negative predictive BRCA genetic test. They underwent annual PSA test with a PSA of > 3.0 ng/ml triggering a diagnostic biopsy. EN2 protein was measured in the urine using an ELISA; (positive = > 42.5ng/ml). Results: Our initial results demonstrated urinary EN2 had a sensitivity of 66.67% and a specificity of 89.29% when discriminating which men had been diagnosed with PrCa; the ROC AUC was 0.816. The difference in EN2 level between those diagnosed with cancer and those who were not was significant (p = <0.001). There was trend towards higher EN2 levels in those with more aggressive tumours (median EN2 84.5ng/mL in Gleason ≤3+4 vs 111ng/mL in Gleason ≥4+3), however this was not statistically significant. In one PrCa case EN2 rise preceded PSA rise by 2 years. Further samples are in the process of being analysed, results from these will be included. Conclusions: Urinary EN2 protein measurement warrants further investigation as a PrCa biomarker in this higher risk group with genetic predisposition to PrCa.
Phase I results from a phase I/II study of orteronel, an oral, investigational, nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Petrylak Daniel Peter , Gandhi Jitendra G. , Clark William R. , Heath Elisabeth I. , Lin Jianqing , Oh William K. , Agus David B. , Kucuk Omer , Moran Susan , Wang Jingyuan , Bargfrede Michael , Liu Glenn
Published: March 2020

4656

Background: The investigational agent orteronel (ortl, TAK-700) is a selective 17,20-lyase inhibitor that blocks androgen production. Since DP is standard chemotherapy in mCRPC, this phase 1/2 study examined ortl + DP in men with mCRPC. Methods: The primary phase I objective was to determine the maximum dose of ortl 200–400 mg BID that can be administered safely with DP in castrate men (testosterone [T] <50 ng/dL) with mCRPC, ≤1 prior chemotherapy and no ketoconazole/abiraterone ≤30 d prior. A 3+3 dose escalation was used with ortl 200 then 400 mg BID. Ortl dosed daily and D (75 mg/m2 q3w) + P (5 mg BID) was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d. Results: 14 men, median age 68 yrs (range 53–81), ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL (5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable disease, were treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men received ortl 200 and 400 mg BID + DP, in cohorts 1 and 2, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3 pts); in cohort 2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no DLTs occurred in group 2. 3 pts discontinued due to AEs (2 D infusion reactions, 1 at each dose; 1 unrelated cardiorespiratory death at 200 mg). All men had at least 1 AE Gr ≥3 which were treatment-related in 11 men. The most common Gr ≥3 AEs were seen at both doses and included neutropenia 50% (n = 7), hyperglycemia 21% (n = 3), febrile neutropenia, infusion reaction, hyponatremia, decreased neutrophil count (2 each); at 400 mg only: fatigue, hypophosphatemia, and decreased WBC count (2 each). 7 men had serious AEs (SAEs), which were drug-related in 5. The most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and PSA90 rates were 86% and 36%, respectively; 12/14 men had a median PSA decline ≥70%; and median T declined to ≤0.2 ng/dL (0–10.7). The Cmax of D + ortl was similar to D alone. Conclusions: Ortl 200 mg and 400 mg BID + DP appears safe and tolerable with androgen-lowering activity at the maximum planned dose in mCRPC. There is no evidence of AE potentiation when ortl is administered with DP. The phase II portion of the study will use ortl 400 mg BID + DP.
Regional variation in survival after metastatic prostate cancer diagnosis.
Authors: Lakdawalla Darius , Gupta Charu , Luna Yesenia L , Thompson Stephen F , Tangirala Muralikrishna , Ng Daniel B , Nicacio Leonardo , Perlroth Daniella
Published: March 2020

4666

Background: Survival after diagnosis of metastatic prostate cancer (mPC) averages 2-3 years. Substantial regional differences in survival have been documented for PC prior to 2000. We investigated the extent to which regional variation exists in survival for mPC patients during 2000-2007. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims, we identified men (mean age, 77.6 years) continuously enrolled in Medicare Parts A/B who were diagnosed with mPC between 2000 and 2007 and not diagnosed with another malignancy. The base-case model was limited to hospital service areas with >50 patients. A Cox proportional hazards model was used to estimate hazard ratios (HR) for overall survival (OS), adjusting for year of diagnosis, age, marital status, poverty and education covariates, Gleason score, comorbidities, and region covariates. Sensitivity of results was tested by limiting the analysis to patients surviving at least 6 months after diagnosis and by removing regional sample size limits. We report HRs for covariates, results of a Wald test of joint significance for region effects, and percentage difference from the mean for each region’s HR for death. Results: A total of 2696 patients with mPC met the inclusion criteria. OS was 37% at 3 years and mean HR for death was 4.8 (sd 2.1). HRs for death were positively correlated with age (HR=1.96, 95% CI: 1.6-2.3 for >80 years), PC-specific comorbidity index (HR=1.2, 95% CI: 1.1-1.3), and Gleason score (HR=6.6, 95% CI: 2.4-17.8 for poorly differentiated). Year of diagnosis, race, and socioeconomic status were not significantly associated with mortality. Wald test of joint significance for survival across regions of P=.019 indicated significant differences in survival across regions and was robust in sensitivity analyses. Patients living in regions with the worst survival rates had HRs for death that were 20% higher than the mean (HR=5.8) and those living in regions with the best survival rates had HRs 30% lower than the mean (HR=3.4). Conclusions: There are significant regional differences in survival for mPC patients in the 2000s. Further research is needed to determine if treatment differences play a role in this disparity.
Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): A randomized, open-label phase II study.
Authors: Oza Amit M. , Cibula David , Oaknin Ana , Poole Christopher John , Mathijssen Ron H.J. , Sonke Gabe S. , Colombo Nicoletta , Špacek Jirí , Vuylsteke Peter , Hirte Hal W. , Mahner Sven , Plante Marie , Schmalfeldt Barbara , Mackay Helen , Rowbottom Jacqui , Tchakov Ilian , Friedlander Michael
Published: March 2020

5001

Background: The oral PARP inhibitor olaparib has shown antitumor activity in pts with SOC. Our multicenter study compared the efficacy of (Arm A) olaparib capsules plus P/C for 6 cycles then maintenance olaparib monotherapy vs (Arm B) P/C alone for 6 cycles and no further therapy in pts with PSR SOC (NCT01081951). Methods: Pts received 6 x 21-day(d) cycles of olaparib (200 mg bid, d1–10/21) + P (175 mg/m2 iv, d1) + C (AUC4 iv, d1), then olaparib monotherapy as maintenance (400 mg bid, continuous) (Arm A), or 6 x 21d cycles of P (175 mg/m2 iv, d1) + C (AUC6 iv, d1) then no further therapy (Arm B), until progression. Randomization (1:1) was stratified by number of platinum treatments and platinum-free interval. Primary endpoint: progression-free survival (PFS) by central review (RECIST 1.1). Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Archival tissue was collected where available for analysis of biomarker correlation. Results: Of 162 pts randomized (n=81 per arm), 156 received treatment (Arm A, n=81; Arm B, n=75) and 121 began the maintenance/no further therapy phase (Arm A, n=66; Arm B, n=55). Olaparib + P/C (AUC4) followed by maintenance olaparib showed a significant improvement in PFS vs P/C (AUC6) alone (HR = 0.51, 95% CI 0.34, 0.77; P=0.0012; median = 12.2 vs 9.6 months). OS data are immature (total events: 14%). ORR was similar for Arm A and Arm B (64 vs 58%). Most common AEs during the combination phase were alopecia (74 vs 59%), nausea (69 vs 57%) and fatigue (64 vs 57%) for Arm A vs Arm B, respectively. Pts with grade ≥3 AEs (65 vs 57%), serious AEs (SAEs: 15 vs 21%) and AEs leading to treatment discontinuation (19 vs 16%) were similar for Arm A vs Arm B. Most common AEs during maintenance/no further therapy were nausea (50 vs 6%) and vomiting (29 vs 7%). 29 vs 16% of pts had grade ≥3 AEs, 9 vs 7% had SAEs and 8% vs N/A discontinued due to AEs in the olaparib vs no treatment arms, respectively. There were no fatal AEs. Conclusions: In pts with PSR SOC, olaparib plus P/C (AUC4) followed by olaparib 400 mg bid monotherapy maintenance treatment resulted in a significant improvement in PFS vs P/C (AUC6) alone.
Outcome of patients with borderline ovarian tumors: Results of the multicenter AGO ROBOT study.
Authors: De Gregorio Nikolaus , Baumann Klaus H. , Keyver-Paik Mignon-Denise , Reuss Alexander , Canzler Ulrich , Wollschlaeger Kerstin , Kommoss Friedrich , Forner Dirk , Peters Martin , Schroeder Willibald , Münstedt Karsten , Richter Barbara , Ewald-Riegler Nina , Mahner Sven , Fotopoulou Christina , Schmalfeldt Barbara , Hilpert Felix , Kommoss Stefan , Hauptmann Steffen , Du Bois Andreas
Published: March 2020

5005

Background: Borderline ovarian tumors (BOT) are a rare entity; current standard of care is based on the available data of predominantly small retrospective trials. Therefore we performed a pattern of care study including central pathology review. Methods: All consecutive patients diagnosed with BOT between 1998 and 2008 in 24 German institutions were included. Tumor samples were prospectively sent for central histopathological review to specialized gynecopathologists, clinical data were collected and patient follow-up was prospectively updated. Results: Pathological review was obtained in 1,042 of 1,236 pts resulting in 950 confirmed BOT cases analyzed here. Under- and overdiagnosis occurred in 3.8% and 5.0% of cases, respectively. Median age was 49 years; 84% of patients had FIGO stage I disease; serous type (S-BOT) was diagnosed in 64% and mucinous type (M-BOT) in 31%. Primary/re-staging surgery led to complete debulking in 92.3% of pts (residual disease 1.3%, unknown 6.4%). Adjuvant chemotherapy was given to 33 (3.5%) pts only. 165 (17%) underwent fertility preserving surgery and 31 (19%) of these patients had documented pregnancies thereafter. Overall, 74 (7.8%) pts experienced relapse and 43 (4.5%) died. Disease progression in the form of invasive carcinoma occurred in 30% of the relapses. Inadequate surgical staging, residual tumor, fertility sparing surgery and higher FIGO stage were associated with shorter progression-free survival (PFS). M-BOT showed a non-significant trend to longer PFS compared to S-BOT (p = 0.07). No differences were observed for laparatomy vs. laparoscopy as initial surgical approach or application of adjuvant chemotherapy. Conclusions: To this day, this is the largest data set available for BOT. Prognosis is favorable even without adjuvant therapy if correct surgical staging is performed. Both tumor characteristics and treatment variables had a significant impact on relapse rate and outcome. In contrast to previous studies, disease progression in the form of invasive carcinoma occurred in a significant amount of patients with relapsed disease.
Randomized phase II study of docetaxel plus vandetanib (D+V) versus docetaxel followed by vandetanib (D-V) in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (OC): SWOG S0904.
Authors: Coleman Robert L. , Moon James , Sood Anil , Branham Donna , Delmore James Edwin , Bonebrake Albert J. , Anderson Garnet L , Alberts David Samuel , Markman Maurie
Published: March 2020

5015

Background: Antiangiogenesis therapy has led to antitumor effects both preclinically and clinically. Vandetanib (V) is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET. These targets are of interest in OC care, as targeting has shown anti-tumor efficacy, particularly in combination with taxanes. We explored the efficacy, safety, and toxicity of docetaxel (D) and V in women with recurrent OC. Methods: Women with resistant, refractory, or progressive/persistent OC were eligible for this randomized phase II study provided they had not received D or V for recurrent disease. Patients were allowed to receive other anti-VEGF targeted agents for primary therapy (stratification variable). Up to 3 additional cytotoxic regimens for recurrence were allowed. Patients were allocated 1:1 to D(75 mg/m2, I.V.)+V (100 mg daily, p.o.) or D(75 mg/m2). Patients receiving single agent D were allowed to crossover to V upon progression (D-V). The primary endpoint was PFS. Other objectives were: OS, objective response (ORR), and frequency/severity of adverse events. The study was designed with 84% power to detect a 1.55 PFS hazard ratio using a one-sided P of 0.1. Results: 131 patients were enrolled; 5 were excluded (1 ineligible, 4 eligible but untreated). 9% had received prior anti-angiogenic therapy. 61 patients on D+V were assessable for toxicity; 19 (31%) had treatment-related G4 events, primarily hematologic. Similarly, 17 (26%) of 65 patients receiving D alone had G4 events, primarily hematologic. 34 (52%) patients crossed over to V; no G4 events were recorded among 32 evaluable patients. G3 diarrhea was observed in 14% of D+V patients; 5% D-V patients. G3 acneiform rash occurred in 2% and 0%, respectively. The median PFS estimates were 3.0 mos (D+V) vs 3.5 (D-V); HR (PFS): 0.98 (80% CI:0.75-1.27). For OS, the median estimates were 14 mos (D+V) vs 12 mos (D-V); HR (OS):0.84 (80% CI:0.56-1.28). ORR was 14% and 17%, respectively. Crossover V response was 4% (1/27 measurable patients). Conclusions: D+V was well tolerated in this population however, did not prolong PFS with respect to D.
A novel autologous oxidized whole-tumor antigen vaccine therapy for recurrent ovarian cancer.
Authors: Kandalaft Lana
Published: March 2020

5023

Background: Despite surgical and chemotherapeutic advances, the death rate from ovarian cancer has not changed. We report here an enhanced dendritic cell vaccine platform developed for clinical testing. Furthermore we report the application of this novel platform comprising of dendritic cell (DC)-based autologous whole tumor antigen vaccination in a pilot study of patients with recurrent ovarian cancer. Methods: To determine the optimal tumor lysate preparation for loading DCs, ovarian tumor lines were prepared by HOCl-oxidation, UVB-irradiation or freeze and thaw. Normal donor DCs were evaluated for tumor lysate uptake, cytokine and chemokine productions and phenotype. The optimal lysate preparation, was used in a phase I study where five patients with recurrent ovarian cancer with available tumor lysate from secondary debulking surgery underwent intranodal vaccination with OC-DC, an autologous DC preparation pulsed with HOCL oxidized autologous tumor cells. Feasibility, safety, and biological and clinical efficacy were evaluated. Results: Normal donor DCs pulsed with HOCl-oxidized tumor lines demonstrated the highest tumor lysate uptake, matured efficiently after LPS and IFN-gamma stimulation, and produced higher levels of proinflammatory cytokines and chemokines. In vitro, these lysates loaded DCs primed T cell responses against ovarian tumor associated antigens and effectively expanded against tumor specific T cells from donors and patients. Therapy was feasible and well tolerated in all subjects. Vaccination with OC-DC produced limited grade 1 toxicities and elicited tumor-specific T cell responses. Moreover specific HLA-A2-restricted responses were documented following vaccination and HER-2/neu specific T cells were expanded following 10 days of in vitro culture. Patients exhibiting immune response demonstrated clinical benefit including two patients who demonstrated remission inversion on vaccine maintenance. Conclusions: We developed a DC-HOCl oxidized whole tumor lysate vaccine which was safe and well-tolerated by patients. The vaccine was highly proinflammatory and elicited cellular and humoral anti-tumor responses establishing a platform for immune-combinatorial therapy.
A comprehensive analysis of BRAF and KRAS mutation status in low-grade serous (LGS) and serous borderline (SB) ovarian cancer (OC).
Authors: Grisham Rachel Nicole , Garg Karuna , Zhou Qin , Iasonos Alexia , Berger Michael F. , Dao Fanny , Hyman David Michael , Levine Douglas A. , Solit David B. , Aghajanian Carol , Iyer Gopa
Published: March 2020

5030

Background: LGS OC develops in a step-wise pattern from serous cystadenoma to SB tumor to invasive LGSOC. LGSOC accounts for 6-22% of serous OC and is a chemoresistant disease. Prior studies have reported that LGS/SB ovarian tumors harbor BRAF mutations in 28-35% of cases, suggesting that LGS/SB OC may respond to mutant BRAF inhibitors. Methods: We genotyped 75 LGS and SB ovarian tumors for BRAF and KRAS hotspot mutations using a mass spectrometry based Sequenom assay. All samples were collected at MSKCC between 2000-2010. All specimens underwent two independent pathologic reviews for diagnostic confirmation and macrodissection to ensure 80% cellularity. The incidence and identity of BRAF and KRAS mutations were defined and results were correlated with stage, response to treatment, and outcome. Exon capture sequencing is underway to sequence all coding exons of 230 cancer associated genes to identify additional targetable alterations in LGS/SB OC. Results: Of 75 samples examined, 56(75%) were SB and 19(25%) LGS histology. 57% of samples showed KRAS mutation (KRAS+) (n=17, 23%) or BRAF mutation (BRAF+) (n=26, 35%). Mutation status was mutually exclusive. All BRAF + were V600E, KRAS+ were G12D (n=9) or G12V (n=8). BRAF+ was associated with early stage (I-II) at presentation and SB histology. 22 (29%) patients were treated with chemotherapy, 2 (9%) with KRAS + and 0 with BRAF+. 4(15%) BRAF+ patients underwent resection of recurrent disease. All BRAF+ patients are alive without evidence of disease at a median follow-up of 43.3 months (range 1.9- 129.3 months). Conclusions: V600E BRAF mutations are present in 35% of cases of SB/LGS ovarian cancer. Presence of BRAF + in SB/LGS OC is associated with good prognosis and surgical cure of disease. Patients with SB/LGS OC who require systemic therapy are unlikely to have BRAF+. Our group is performing a detailed search for additional targetable alterations in multiple signal transduction pathways through next generation sequencing technology. [Table: see text]
Use of HE4 and CA125 to predict surgical outcome and for prognostic value for progression-free survival (PFS) and overall survival (OS) in primary epithelial ovarian cancer (EOC) patients (pts).
Authors: Braicu Ioana , Chekerov Radoslav , Richter Rolf , Vergote Ignace B. , Mahner Sven , Zeimet Alain G , Ganapathi Ram N. , Woelber Linn Lena , Castillo-Tong Dan Cacsire , Cadron Isabelle , Zeillinger Robert , Fotopoulou Christina , Sehouli Jalid
Published: March 2020

5034

Background: Optimal surgical cytoreduction and response to platinum (P) based chemotherapy (ChTh) remain the cornerstones of therapeutic management of primary EOC. Aim of this study was to analyze the predictive role of HE4 and CA125 as biomarkers (BM) for clinical outcome in primary EOC pts at diagnosis and during subsequent follow-up. Methods: In the European OVCAD project 275 pts with primary EOC were enrolled. Pts were eligible if radical cytoreductive surgery and P-based ChTh were applied. Plasma collected at first diagnosis and 6 months after 1st line ChTh in P-sensitive pts was analyzed for HE4 and CA125 levels using ELISA and Luminex technique, respectively. Results: Complete cytoreduction with no residual tumor disease (RTD) was obtained in 69.9% pts. HE4 and CA125 expression in plasma at first diagnosis correlated with RTD, p = 0.002 and p=0.002, respectively. The sensitivity (SE) and specificity (SP) of the combinative use of both BM in predicting RTD was 64.8% and 73.5%, respectively. Pts having over-expression of both BM in plasma had a 6.1 greater risk for RTD (p<0.001, OR: 6.107, 95% CI 2.41-15.46). P-resistance occurred more frequently when both BM were over-expressed (p=0.028, OR= 3.1, 95%CI 1.13-8.46). Elevated BM levels during follow-up predicted recurrence (SE 90% and SP 71% for CA125 ≥55U/ml; SE 72.7% and SP 81.4% for HE4 ≥150pM) and when HE4 or CA125 were positive, a SE of 86.4% and SP of 72.9% were achieved. Elevated CA125 and HE4 at 6 months following adjuvant therapy was associated with significantly poorer PFS (p<0.001, HR 9.6, 95%CI 3.93-23.44 with elevated HE4 or CA125, and HR=50.52, 95%CI 14.44-176.78, with elevated HE4 and CA125) and OS (p<0.001, HR=7.42 95%CI 1.43-38.42 with elevated HE4 or CA125 and HR=28.38 95%CI 6.50-123.97 with elevated HE4 and CA125). Conclusions: The combinative use of HE4 and CA125 appears to have a significant value in predicting optimal surgical outcome and development of P resistance disease in EOC pts. Elevated plasma levels 6 months after 1st line ChTh significantly correlate with OS and PFS in P-sensitive pts.
Functional profiling of clear cell ovarian cancer.
Authors: Miller Rowan , Brough Rachel , Bajrami Ilirjana , Kaye Stanley B. , Lord Christopher J. , Ashworth Alan
Published: March 2020

5035

Background: Clear cell ovarian cancer represents up to 15% of epithelial ovarian cancers. In comparison to other subtypes, clear cell ovarian carcinomas have a poorer prognosis and are relatively resistant to standard platinum based chemotherapy. Recently, loss of function mutations in the tumour suppressor gene ARID1A were identified in up to 50% of ovarian clear cell carcinomas. We have adopted an integral functional and molecular profiling approach as a route to identify new genetic dependencies and therapeutic targets for this disease. Methods: Clear cell ovarian cancer cell lines were functionally profiled using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and transcriptome sequencing to aid the discovery of novel targets. Results: Using functional screens we have now identified critical gene dependencies and potential therapeutics in a series of clear cell ovarian cancer models. The comparison of functional viability profiles for models characterized by ARID1A loss of function mutations is now enabling an analysis of synthetic lethal effects that could be used to target clear cell ovarian cancers carrying these mutations. Conclusions: The work undertaken so far provides the framework for the discovery of therapeutic targets for clear cell ovarian cancer using an integrated approach. Revalidation of these preliminary results is now underway to characterize new genetic dependencies for this disease.
Phase Ib study of AMG 386 in combination with paclitaxel (P) and carboplatin (C) in high-risk stage I and stages II-IV epithelial ovarian, primary peritoneal, or fallopian tube cancers.
Authors: Casado Antonio , Oaknin Ana , Baurain Jean-Francois , Wong Shirley S. , Yang Xinqun , Wu Benjamin , Zhong Zhandong Don , Puhlmann Markus , Vergote Ignace B.
Published: March 2020

5038

Background: AMG 386 is a first-in-class investigational peptibody that inhibits angiopoietin-1/-2 binding to Tie2. We report on an ongoing, 2-part, open-label phase 1b study of AMG 386 + PC as first-line treatment of high-risk ovarian cancer. Methods: Part 1 enrolled women, GOG performance status 0/1, with newly diagnosed, FIGO high-risk stage I or stages II, IIIA-B (primary debulking surgery; PDS) or IIIC & IV (PDS or interval debulking surgery; IDS) ovarian cancer. Patients (pts) received AMG 386 at 15 mg/kg QW IV + P at 175 mg/m2 Q3W + C at AUC 6 Q3W for 6 cycles (or until disease progression or unacceptable toxicity); AMG 386 was withheld 4 weeks pre-/post-debulking. Pts completing 6 cycles continued AMG 386 QW as maintenance for up to 18 months. Part 1: incidence of dose-limiting toxicities (DLTs) dictated expansion to 25 pts (part 2). Primary endpoint: DLT incidence; secondary: adverse events (AEs), PK and efficacy measures. Results: At the time of analysis, 16 pts had received ≥1 dose of AMG 386 + PC and completed ≥2 cycles of therapy (PDS, n=8; IDS, n=8). No DLTs occurred in part 1. 15 pts continue on-study; 6 pts have received a median of 6 doses of maintenance AMG 386. One pt discontinued due to progression. AEs are tabulated below. One serious AE (decreased appetite; maintenance phase) required hospitalization. AE incidence and type were similar for PDS or IDS. Combination therapy did not affect the PK of AMG 386 or PC. Non-neutralizing antibodies against AMG 386 were detected in 2 pts. Conclusions: AMG 386 at 15 mg/kg QW + PC is tolerable in pts with high-risk ovarian cancer. AMG 386 maintenance was tolerated and associated with few AEs. Updated toxicity and efficacy data will be presented. [Table: see text]
The combination of intravenous bevacizumab and metronomic oral cyclophosphamide for recurrent platinum-resistant ovarian cancer.
Authors: Barber Emma L. , Neubauer Nikki Lynn , Zsiros Emese , Schink Julian C.
Published: March 2020

5039

Background: This study was undertaken to determine the progression free survival and overall survival in heavily pre-treated patients with recurrent ovarian carcinoma treated with bevacizumab and metronomic oral cyclophosphamide. Methods: An IRB-approved retrospective review was performed for all patients with recurrent ovarian, fallopian tube or primary peritoneal carcinomas treated with intravenous bevacizumab 10mg/kg every 14 days and oral cyclophosphamide 50mg daily between January 2006 and December 2010. Response to treatment was determined by change in disease status according to RECIST criteria and/or CA-125 levels. Results: Sixty-six eligible patients were identified with a median age of 58 years. Fifty-five patients (83%) originally had optimal cytoreduction and all were platinum resistant. Median time from diagnosis to beginning bevacizumab and cyclophosphamide was 36 months. Median number of prior chemotherapy treatments was 7.5 (range 3-16). Eight patients (12.1%) had side effects which required discontinuing bevacizumab and cyclophosphamide, most common were hypertension, proteinuria, and fatigue. There was one bowel perforation (1.5%). A complete response was noted in 7 patients (10.6%), partial response was seen in 21 patients (31.8%) with an overall response rate of 42.4%. Fifteen patients (22.7%) had stable disease and 23 (34.8%) had disease progression. Median progression free survival (PFS) for responders was 5 months (range 2-14) and 11 months (range 4-14) for those with a complete response. Median overall survival (OS) from start of bevacizumab and cyclophosphamide for responders was 20 months (range 2-56) and 9 months (range 1-51) for nonresponders. Conclusions: Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pre-treated patients with recurrent ovarian carcinoma which significantly improves PFS and OS in responders. Response rates were significantly better than the rates we have reported in this same group of patients receiving topotecan (22%) or liposomal doxorubicin (25%) and were superior to reported rates for single agent bevacizumab (18%) in patients with only 2-3 prior regimens.
Changes of serum glycome in patients suffering from ovarian cancer.
Authors: Blanchard Veronique , Biskup Karina , Braicu Elena Ioana , Sehouli Jalid , Tauber Rudolf , Berger Markus
Published: March 2020

5047

Background: Protein glycosylation plays an important role in many biological processes. Most human serum proteins, with the exception of albumin, are glycosylated. Glycosylation is known to be altered with development of diseases such as cancer. In the case of ovarian cancer, tumor markers among them CA-125 that are clinically used are known to have poor specificity. In addition, they fail to detect the disease at an early stage. Therefore, better biomarkers are needed. The aim of the present research work is to identify new potential glycan biomarkers by analyzing the serum N-glycome of patients suffering from ovarian cancer Methods: Serum was collected from 67 patients as well as from 33 healthy age-matching women. N-glycans were released from 10 ul serum by PNGase F digestion, permethylated and subsequently analyzed by means of MALDI-TOF mass spectrometry. The SPSS software was used for the statistical analysis. Results: The N-glycome of patients was found to have more fucosylated structures, especially in tri- and tetraantennary sialylated glycans. The PCA analysis indicates that there are significant differences between the glycome of ovarian cancer patients in all stages of the disease and the glycome of healthy controls. We identified 14 potential structures that were divided in two categories, one of monofucosylated structures with high antennarity (sensitivity 94%, specificity 97%) and one containing high-mannose structures and an asialylated structures (sensitivity 97%, specificity 97%). Conclusions: Our study is the first trial to identify major differences between ovarian cancer sera and control sera, which could potentially be used in the future as biomarkers.
NGR-hTNF and doxorubicin in relapsed ovarian cancer (OC).
Authors: Lorusso Domenica , Scambia Giovanni , Amadio Giulia , di Legge Alessia , Pietragalla Antonella , De Vincenzo Rosa , Masciullo Valeria , Di Stefano Mirella , Mangili Giorgia , Lambiase Antonio , Bordignon Claudio
Published: March 2020

5059

Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is able to promote antitumor immune responses and to improve the intratumoral doxorubicin (D) uptake by selectively damaging tumor vessels. Methods: OC patients (pts) with progressive disease (PD) after ≥ 1 platinum/taxane regimen and with a platinum free interval lower than 6 months (PFI <6) or ranging from 6 to 12 months (PFI 6-12) received NGR-hTNF (N) 0.8 µg/m2 and D 60 mg/m2 on day 1 every 3 weeks. Primary endpoint of this phase 2 trial was response rate by RECIST criteria with a target of ≥ 6/37 responding pts. Secondary aims were progression free survival (PFS) and overall survival (OS). Results: 37 pts (median age 57 years; PS 0/1 32/5; PFI < 6/6-12 25/12; prior regimens 1-5) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6/mL (interquartile range 1.2-2.1). In all, 177 cycles were given, with 18 pts (49%) receiving ≥ 6 cycles and 12 pts (32%) 8 cycles. Neither grade 3/4 adverse events (AEs) related to N nor increase of D-related AEs were noted. Common grade 1/2 AEs included chills (65%). Eight pts (23%; 95% CI 12-39) had partial response (PR; 2 with PFI < 6 and 6 with PFI 6-12; median duration: 8.2 months). Fifteen pts had stable disease (SD, 43%; 10 with PFI < 6 and 5 with PFI 6-12; median duration: 4.9 months) for an overall disease control (DC, PR+SD) rate of 66%. Mean changes from baseline in target tumor size after 2, 4, 6, and 8 cycles were 2%, -54%, -69%, and -77%, respectively. Median PFS was 5.0 months (95% CI 3.1-6.9) and median OS was 17.0 months (10.4-23.6). In pts with PFI < 6 or 6-12, median PFS were 3.8 and 7.8 months (p=.03) and median OS were 14.3 and 20.1 months (p=.14), respectively. Pts with DC had longer median OS than those with early PD (24.0 and 4.9 months, respectively, p=.02). Longer PFI (p=.03) and higher PBLC (p=.01) were associated with better PFS, while OS correlated only with PBLC (p=.001). In the subset with PFI < 6, pts with PBLC ≥ or < 1.2/mL (1st quartile) had median PFS of 4.9 and 2.6 months (p=.02) and median OS of 15.8 and 4.3 months (p=.0001), respectivel Conclusions: A randomized phase II trial is currently testing D ± NGR-hTNF in pts with PFI < 6 (refractory/resistant). The role of PBLC as blood-based biomarker deserves further investigation.
Application of an ointment with high radical protection factor as a prevention strategy against PPE.
Authors: Kluschke Franziska , Martschick Anja , Darvin Maxim E. , Zastrow Leonhard , Chekerov Radoslav , Lademann Juergen , Sehouli Jalid
Published: March 2020

5064

Background: Pegylated liposomal doxorubicin has proved to be highly efficient in the treatment of various tumors. Depending on the application protocol, up to 80% of patients develop palmar-plantar erythrodysesthesia (PPE). So far, a prevention strategy is still unknown. Recently, it was shown that parts of the chemotherapeutics were excreted with the sweat onto the skin surface, spreading there homogeneously and penetrating into the stratum corneum. The formation of free radicals in the tissue results in PPE. The aim of the study was to investigate if a topically applied ointment containing antioxidants with high radical protection factor (RPF) can be a PPE prevention strategy. Methods: 20 patients with ovarian carcinoma, who had been treated with pegylated liposomal doxorubicin (40 mg/m2), were investigated. They applied the ointment at least twice daily, 2 days before and during 3 cycles of chemotherapy. Their skin condition was examined by a trained dermatologist. Results: From 20 patients enrolled in the study, only 12 (60%) met the conditions by applying the cream at least twice daily in the palmar and plantar regions. These patients did not develop PPE. One patient died in the 2nd cycle of therapy. 7 patients (35%) did not follow the ointment application protocol for various reasons; 6 of them developed PPE and resumed ointment application thereafter. As a result, PPE disappeared or was strongly reduced in these patients so that chemotherapy could be continued. Due to the small group of patients, the fact that PPE was not induced in patients who had applied the ointment regularly can be generalized only restrictedly. Far more interesting are the findings in those patients, who had stopped ointment application during chemotherapy and developed PPE, which disappeared after they resumed applying the ointment. The regression or distinct reduction of PPE after re-application of the ointment clearly proves the efficacy of this strategy. Conclusions: The topical application of an ointment containing antioxidants with high radical protection factor (RPF) could be an efficient strategy against the development of PPE during chemotherapy.
Targeting therapy based on preclinical analysis of clinical, molecular, and functional characteristics of individual high-grade serous ovarian cancers.
Authors: Topp Monique , Hartley Lynne , Cook Michele , Etemadmoghadam Dariush , Galleta Laura , Pyman Jan , McNally Orla , Haluska Paul , Swisher Elizabeth M. , Kaufmann Scott H , Wakefield Matthew , Bowtell David , Scott Clare L.
Published: March 2020

5073

Background: Recent molecular exploration of high-grade epithelial ovarian cancer (OC) has revealed potential targets for novel therapy based on altered DNA repair function, deregulated pathways and recurrent amplifications (Cancer Genome Atlas Research Network. 2011. Nature 474). Improved pre-clinical models allowing analysis of specific molecular subsets of ovarian cancer are urgently required to test novel treatment strategies. Methods: We have generated a novel xenograft model of human high-grade serous OC (HG-SOC). Histologic, functional and molecular analysis of the novel xenograft cohort (at baseline and following xenotransplantation) allows stratification of individual HG-SOC for testing with appropriate targeted therapy. We perform functional analysis of in vitro Homologous Recombination (HR) DNA repair and drug response capabilities on fresh human HG-SOC immediately following surgical resection. Molecular classification (similar to Tothill [Clin Canc Res. 2008;14]); analysis of NHEJ pathway (Proc Natl Acad Sci. 2011;108) and other DNA repair genes (Proc Natl Acad Sci USA 2011;108) is performed. In vivo drug response is studied in murine xenografts. Results: Sixteen chemotherapy-naive potentially HG-SOC samples and associated clinical data have been collected. Functional evidence of DNA repair (HR) capability and response to DNA damaging agents will be presented, including IHC for markers of DNA damage (gH2AX), DNA repair (RAD51AP1) and apoptosis (capsase 3 cleavage). Molecular classification, DNA repair gene and DNA repair pathway analyses are underway. Twelve HG-SOC have been transplanted and 6 of the first 8 have successfully xenografted, with serial transplantation and phenotyping of xenograft derivatives underway. In vivo drug response will be presented. Conclusions: This xenograft model will enable us to address hypotheses generated by recent molecular analyses of human HG-SOC (Cancer Genome Atlas Research Network. 2011. Nature 474; Clin Canc Res. 2008;14). Clinical, functional and molecular annotation will allow pre-clinical drug testing based on the plausible hypothesis approach.
Association of smoking with pulmonary recurrences among women with intermediate- to high-risk early-stage endometrial adenocarcinoma.
Authors: Weinberg Lori Elizabeth , Zanotti Kristine M. , Kunos Charles
Published: March 2020

5089

Background: While a number of histologic risk factors have been identified in endometrial carcinoma, host factors are less well studied. Our aim was to examine the influence of smoking on the risk of pulmonary recurrences in women with early stage intermediate to high-risk endometrioid uterine cancer (EC). Methods: Women with surgically treated stage I or II EC from 1994 to 2010 were included in this study if they had lymphovascular space invasion (LVSI), FIGO grade 2 or 3 histology (G2/3), or outer half myometrial invasion (OI). All demographic, medical and oncologic data were obtained from chart review. Patients were excluded if their follow-up period was less than six months or if they had a diagnosis of a second primary invasive cancer. We performed univariate and multivariate logistic regression analyses and Fisher’s Exact test for two-way analyses of categorical variables to identify prognostic factors of pulmonary recurrences. Significance was determined by two-sided tests with α=0.05. Results: 349 patients were identified to meet histologic criteria, 3% were excluded. The remaining 337 patients had a median follow-up of 60 months (range 6 to 194). The median age of this cohort was 68 years and median BMI was 30.7 kg/m2. 81 patients (24%) had a past or present history of smoking. There were 14 pulmonary recurrences (4.1%), 36 (10.7%) distant recurrences and 58 (17.2%) total recurrences in the cohort. Smoking (present or past) was significantly associated with pulmonary recurrences, with an odds ratio of 1.09 (95% CI 1.04-1.15; P=0.0002). In a multivariate analysis adjusting for age, BMI, grade, LVSI, OI, cervical invasion, and adjuvant therapy, smoking was still a predictor of pulmonary recurrences. Conclusions: Smoking is a significant and independent predictor of pulmonary recurrences among women with early stage EC. Refining our understanding of host factors that influence risk may further allow us to identify those who may benefit most from adjuvant therapies as well as intensive surveillance.
PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).
Authors: Oliveira Mafalda , Navarro Alejandro , De Mattos-Arruda Leticia , Sánchez-Ollé Gessamí , Bellet Meritxell , Balmaña Judith , Gómez-Pardo Patricia , Perez-Garcia Jose Manuel , Muñoz-Couselo Eva , Vidal Maria , Ortega Vanessa , Dienstmann Rodrigo , Aura Claudia , Prudkin Ludmilla , Vivancos Ana , Rodon Ahnert Jordi , Baselga José , Tabernero Josep , Cortes Javier , Saura Cristina
Published: March 2020

509

Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]