bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of volasertib (BI 6727) versus chemotherapy (CT) in platinum-resistant/refractory ovarian cancer (OC).
Authors: Pujade-Lauraine Eric , Weber Beatrice E. , Ray-Coquard Isabelle , Vergote Ignace , Selle Frédéric , Del Campo Jose Maria , Sufliarsky Jozef , Tschöpe Inga , Garin Chesa Pilar , Nazabadioko Serge , Pilz Korinna , Joly Florence
Published: March 2020

5504

Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study investigated V vs CT as 3rd- or 4th-line therapy in patients (pts) with platinum-refractory or resistant OC. Methods: Pts were randomized to V 300 mg IV Q3W or investigator’s choice single-agent CT (pegylated liposomal doxorubicin, topotecan, paclitaxel, gemcitabine) until progression or intolerance. Primary endpoint was 24-wk disease control rate (DCR; % of pts with complete/partial response [PR] or stable disease [SD]). Secondary endpoints included safety, progression-free survival (PFS), best overall response (RECIST 1.1) and explorative biomarkers. Results: 109 pts received V (n=54) or CT (n = 55) for a median (range) of 95 (22–716) and 114 (7–351) days, respectively. Demographic data were balanced between the treatment arms. Overall, median age was 62.0 yr; ECOG PS 0–1: 103 pts; 2 prior CTs: 51 pts; ≥3 prior CTs: 57 pts; platinum-resistant: 78 pts; platinum-refractory: 31 pts; measurable disease: 89 pts. 24-wk DCR (95% CI) for V vs CT was 31% (18–43) vs 43% (30–57), and median PFS was 13.1 vs 20.6 wks (HR = 1.01; 95% CI: 0.66–1.53). Six V pts vs 0 CT pts are ongoing for PFS 1 yr after randomization. Best overall response in pts with measurable disease (V/CT) was: PR, 7/8 pts; SD, 24/24 pts. Adverse events (AEs) led to discontinuation in 20 pts (V, n = 5; CT, n = 15); no V pts and 8 CT pts discontinued due to treatment-related AEs (including neuropathy in 3 CT pts). Most frequent all grade AEs (% of pts) regardless of relatedness were neutropenia (61%), anemia (54%), thrombocytopenia (46%), nausea (37%) and asthenia (33%) with V, and asthenia/nausea (47% each), abdominal pain (38%), anemia (36%) and neutropenia/vomiting (31% each) with CT. There were 3 fatal AEs per arm. Conclusions: Single-agent V showed antitumor activity in OC in a range similar to CT. AEs with V were mainly hematologic and manageable, with fewer non-hematologic AEs than CT. Exploration of potential predictive biomarkers for V activity is ongoing. Clinical trial information: NCT01121406.
Final results of 4-monthly screening in the UK Familial Ovarian Cancer Screening Study (UKFOCSS Phase 2).
Authors: Rosenthal Adam N , Fraser Lindsay , Philpott Susan , Manchanda Ranjit , Badman Philip , Hadwin Richard , Evans D. Gareth , Eccles Diana , Skates Steven James , Mackay James , Menon Usha , Jacobs Ian
Published: March 2020

5507^

Background: Annual transvaginal ultrasound (TVS) and serum CA125 screening for women at high-risk of Ovarian/Fallopian tube cancer (OC/FTC) in Phase 1 of UKFOCSS lacked sensitivity for early stage disease but downstaged disease volume and may have improved optimal debulking rates. More frequent screening might provide greater benefits. Here we report the final results of 4-monthly screening in one of the largest such trials worldwide. Methods: Between 14/06/2007 and 29/03/2012, 4,531 women at an estimated ≥10% lifetime risk of OC/FTC were recruited and screened by 42 UK centres for 14,263 women screen years. Screening comprised 4-monthly CA125 tests analysed by a risk of ovarian cancer algorithm, adjusted for menopausal status. TVS was annual in those with normal algorithm results, but was triggered sooner if results were non-normal. Women with suspicious scan and/or algorithm results were referred for consideration of surgical intervention. Participants were followed prospectively by centres, questionnaire and national cancer registries. Data was censored 365 days after final screen, withdrawal or death. Clinical trial information: 32794457.
Impact of body mass index (BMI) on the prognosis of women with high-risk early breast cancer (BC) receiving adjuvant chemotherapy (CT).
Authors: Gennari Alessandra , Nanni Oriana , Scarpi Emanuela , Cecconetto Lorenzo , Sarti Samanta , Amadori Dino
Published: March 2020

552

Background: Obesity has been shown to impact the prognosis of early BC; this effect was not consistently observed across the different biological subtypes, and is less clear when aggressive tumor phenotypes are considered. The aim of this study was to evaluate the influence of BMI (kg/m2) on the prognosis of women with high risk early BC enrolled into a phase III clinical trial of adjuvant CT. Methods: The relationship between BMI and Disease Free (DFS) or Overall Survival (OS) was assessed in 1066 early BC patients with rapidly proliferating tumors (Thymidine Labeling Index > 3% or G3 or Ki67 > 20%), randomized to receive adjuvant CT with or without anthracyclines (Epirubicin → CMF vs CMF → Epirubicin vs CMF). BMI was defined as follows: normal < 25 kg/m2, overweight 25-30 kg/m2, obese >30 kg/m2. DFS and OS were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to menopausal status, type of CT, hormonal, HER-2 and nodal status. Results: Information on BMI at baseline, was available on 959 women. Of these, 430/959 (44.8%) were normal, 331 (34.5%) were overweight and 198 (20.7%) were obese. Median age was 52 years (range 26 to 70); 48% was node positive, 62% was ER positive and 33% was HER-2 positive. At a median follow-up of 69 mos (range 1-119), 5-year DFS was 80% (95% CI 78-83) and 5-year OS was 94% (95% CI 90–94). 5-year DFS was 81% (95% CI 77-85), 82% (95% CI 77-86) and 76% (95% CI 70-83), in normal, overweight and obese women, respectively (p 0.6). 5-year OS was 92% (95% CI 89-95), 94% (95% CI 91-96) and 89% (95% CI 84-93), respectively (p 0.4). By multivariate analysis only ER, HER-2 and nodal status were significantly associated with differences in DFS and/or OS. Conclusions: BMI at baseline was not associated with the prognosis of early BC patients with rapidly proliferating tumors, receiving adjuvant CT. These results confirm those achieved in triple negative BC and suggest that neither dietary restriction or medical interventions aimed at reducing BMI and/or underlying insulin resistance nor specific anticancer strategies seem to be appropriate in this subgroup.
A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: Angiopoietin-2 as a predictive marker for clinical outcomes.
Authors: Vergote Ignace , Teneriello Michael , Powell Matthew A. , Miller David S. , Garcia Agustin A. , Mikheeva Olga N. , Pinter Tamas , Bidzinski Mariusz , Cebotaru Cristina Ligia , Fan Jean , Ren Min , Meneses Nicole , Funahashi Yasuhiro , Kadowaki Tadashi , O'Brien James P. , Penson Richard T.
Published: March 2020

5520

Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. The importance of angiogenesis in endometrial cancer (EC) highlights the need to understand clinical mechanisms of escape (eg, angiopoietin-2 [Ang-2]) from antiangiogenic therapy. Methods: Patients (pts) had metastatic/unresectable EC after 1 or 2 prior platinum-based treatments (Tx), ≤2 prior chemotherapies, and ECOG PS ≤2. Pts received lenvatinib 24 mg once daily until disease progression or development of unmanageable toxicities. Primary endpoint was objective response rate (ORR: complete + partial response [CR+PR]) by RECIST 1.1. Archival tumor tissue and baseline (BL) and post-Tx plasma samples were collected for molecular analyses (reported elsewhere). Results: 133 pts were treated (median age: 62 y) and evaluated for safety, efficacy, and molecular correlative analysis. Dose reduction (31%) or Tx discontinuation (31%) occurred for toxicity. Median Tx duration was 112 days. The most common adverse events were hypertension 55% (Gr 3/4: 33%), fatigue 42% (Gr 3: 12.8%), diarrhea 35% (Gr 3: 5.3%), decreased appetite 35% (Gr 3: 2.3%), and nausea 32% (Gr 3: 3%); 1 pt had Gr 5 asthenia. Bowel obstruction, fistula formation, and perforation occurred in 3.8%, 2.3%, and 1.5%, respectively. Confirmed CR+PRs were observed in 19 pts (14.3%) by independent review (IRR) and 29 pts (21.8%) by investigator assessment (Inv). mPFS was 5.4 mos and mOS was 10.6 mos. Among 50 serum factors tested, only BL plasma Ang-2 correlated with maximal tumor shrinkage, R = 0.36 (Spearman), p < 0.001; ORR; PFS; and OS. The 24 pts with low BL Ang-2 plasma levels (cut-off value <2082 pg/mL) were compared with the 98 pts with high BL Ang-2 (>2082 pg/mL) and improved ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) were observed. Conclusions: Lenvatinib in this population was tolerable and resulted in a 14.3% (IRR) and 21.8% (Inv) ORR and mOS of 10.6 mos.Low BL Ang-2 level appears to predict clinical benefit in a subset of pts with advanced EC who may achieve high response rates and prolonged overall survival. Further assessment is warranted. Clinical trial information: NCT01111461.
PTEN loss as a context-dependent determinant of patient outcomes in obese and non-obese endometrioid endometrial cancer patients.
Authors: Ju Zhenlin , Westin Shannon Neville , Broaddus Russell , Li Jie , Pal Navdeep , Lu Karen H. , Coleman Robert L. , Klempner Samuel , Cantley Lewis , Mills Gordon B. , Myers Andrea P.
Published: March 2020

5521

Background: Aberrations in the PI3K pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid endometrial cancers. We explored the prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss, in the context of patient weight. Methods: Patients (pts) treated for endometrial cancer at a single institution between 2000 and 2009 were identified. Tumor DNA was extracted and exome sequencing performed using a 454 platform with confirmation of hot spot mutations by Sequenom. PTEN protein expression was determined by immunohistochemistry and reverse phase protein array (RPPA). RPPA for 135 relevant proteins was performed using a GeneTAC arrayer to create spot arrays. Slides were scanned, analyzed, and quantitated using Microvigene software. Results: One hundred eighty seven endometrioid endometrial cancer specimens were included. Median age was 61 yrs and median body mass index (BMI) was 33.5 kg/m2. The majority of pts had early stage (I/II) disease (74%) and grade 2 tumors (66%). There were no statistically significant associations between progression free survival (PFS) and PIK3CA, PIK3R1, PTEN mutation or loss. However, when stratified by BMI, PTEN loss was associated with a significantly improved PFS (p< 0.006) in obese (BMI > 30 kg/m2) pts. In contrast, PTEN loss was associated with a worse PFS (p<0.06) in non-obese (BMI < 30 kg/m2) pts. Further, PTEN loss in obese and non-obese pts resulted in distinct protein changes by RPPA, with canonical PI3K pathway activation observed only in the non-obese PTEN loss cohort. PTEN loss in obese pts was associated with decreased expression of CATENIN and phosphorylated FOXO3A. Conclusions: These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of BMI and provide potential explanation for prior discrepant findings on effect of PTEN status on prognosis in endometrial cancer. These data describe a clinically important interaction between metabolic state and tumor genetics that could potentially unveil the biologic underpinning of obesity-related cancers and may be relevant to ongoing clinical trials with PI3K pathway inhibitors.
The impact of diabetes and obesity on endometrial cancer outcomes.
Authors: Ko Emily Meichun , Walter Paige , Clark Leslie Horn , Jackson Amanda Lynn , Franasiak Jason , Havrilesky Laura Jean , Secord Angeles Alvarez , Moore Dominic T. , Gehrig Paola A. , Bae-Jump Victoria Lin
Published: March 2020

5523

Background: Diabetes (DM) is a known risk factor for endometrial cancer (EC), yet its effect on cancer outcomes remains unclear. We sought to investigate of the relationship between DM, obesity, and anti-diabetic medication on EC recurrence and survival. Methods: An IRB approved multi-institution retrospective study included all EC patients diagnosed with carcinosarcoma as well as endometrioid, serous, and clear cell cancers between January 2005 to December 2010. Demographics, comorbidities, and medications were captured at the time of cancer diagnosis. Cohorts for comparison included women with and without DM; and diabetics treated with metformin-only (METFO) were compared to those not treated with METFO. Cox regression models were used to evaluate the effect of selected covariates on PFS and OS. Results: Of 1495 EC patients, 364 (24%) had DM. Diabetics were more likely to be African American (30 v 16%, p<0.0001) and have higher BMIs (median 37.0 v 31.2, p < 0.001). After adjusting for age, race, stage, and BMI, women with DM had a worse OS (HR 1.40, 95CI 1.03-1.79), but similar recurrence risk (HR 1.16, 95CI 0.91-1.48) to non-diabetics. In a subset analysis of women with endometrioid EC (n = 1144), those with DM were 1.6 times more likely to recur (95CI 1.01-1.89, p = 0.04) and 2.4 times more likely to die (95CI 1.6-3.46, p < 0.0001). METFO use was associated with a decreased risk of recurrence (PFS HR 0.54, 95CI 0.3-0.96, p = 0.04), and death (OS HR 0.43, 95CI 0.22-0.83, p = 0.01) compared to no METFO use. METFO users had a similar clinical outcome compared to non-diabetics (PFS HR 1.05, p = 0.82; OS HR 1.3, p = 0.46). Obese women with DM who were treated with non-METFO regimens had a 1.8-fold increased risk of recurrence (95CI 0.94-3.7, p = 0.07) and 2.7-fold increased risk of death (95CI 1.2-5.9, p = 0.01). No survival differences were seen in women with serous, clear cell, or carcinosarcoma. Conclusions: Our data demonstrates worse clinical outcomes for EC patients with DM and improved outcomes for METFO users, suggesting a link between tumor pathogenesis and insulin growth factor and mTOR pathways. Future investigation is required to elucidate the complex relationship between diabetes, anti-hyperglycemic agents, and cancer outcomes.
Outcome parameters in node-negative vulvar cancer: A subset analysis of the AGO Care 1 study.
Authors: Woelber Linn Lena , Jueckstock Julia Kathrin , Hilpert Felix , Neuser Petra , De Gregorio Nikolaus , Iborra Severine , Chen Frank , Habermann Anika , Hillemanns Peter , Fuerst Sophie , Strauss Hans-Georg , Baumann Klaus H. , Thiel Falk , Mustea Alexander , Meier Werner , Harter Philipp , Wimberger Pauline , Hanker Lars Christian , Schmalfeldt Barbara , Mahner Sven
Published: March 2020

5531

Background: Prognosis of node-negative vulvar cancer is generally favorable compared to node positive disease. However, a small proportion of node-negative pts experience early recurrence with subsequent need for radical interventions. Aim of this analysis was to identify possible prognostic factors in this subset of pts. Methods: The AGO CaRE 1 study was designed as retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Pts with primary squamous-cell vulvar cancer stage ≥1b treated at 29 gynecologic cancer centers in Germany 1998-2008 were included in a centralized database. Results: A total of 1618 pts were documented, 802 were node negative (pN0) after surgical staging and further analyzed. Median age was 66 yrs (21-94); 399 (49.8%) had pT1b, 365 (45.5%) pT2, 36 (4.5%) pT3 and 1 pT4 tumors; in 1 pt tumor stage was unknown. Median tumor size was 20 mm (1–345) and depth of invasion 4 mm (0.75–60). 703 (87.7%) pts had an R0 resection with a minimal margin of 5 mm (0.2–33); there were 46 R1 (5.7%) resections and 53 (6.6%) pts with unknown margin status. 692 pts (86.3%) received a full groin dissection (178 after sentinel node dissection) and in 85 pts (10.6%) only a sentinel node procedure was performed; surgery type was unknown in 25 pts (3.1%). 73 pts (9.1%) underwent adjuvant radiotherapy to the vulva. Median follow-up was 40 months. 169 pts (21.1 %) developed disease recurrence (thereof 111 (65.7%) at the vulva only and 53 (31.4%) at other locations, in 5 cases the localization was unknown) after a median of 17.7 months. 101 pts (12.6 %) died. To assess potential prognostic factors, multivariate analyses were performed including age, stage, tumor size, invasion depth, tumor grade, resection margin, adjuvant radiation, and mode of groin dissection [sentinel vs. full]) showing age as the only consistent prognostic factors for recurrence-free and overall survival. Conclusions: Even in the very large patient cohort of the AGO-CaRE database with more than 800 node-negative pts it was not possible to identify reliable clinicopathologic prognostic factors for node-negative disease. Identification of new biological markers will therefore be necessary to select high risk node negative pts for adjuvant treatment.
Malignant germ cell ovarian cancer (MGCOC) in the Cancer Registry of Norway (CRN): A long-term follow-up study of presentation, survival, and second cancers.
Authors: Solheim Olesya , Dahl Alv A. , Nesland Jahn M , Kaern Janne , Trope Claes , Rokkones Erik , Fossaa Sophie D
Published: March 2020

5533

Background: Significant improvements in the management of MGCOC have been achieved during the past two decades. However, data on long term risk conferred by radiation and chemotherapy is scarce. This is a long-term follow-up study of presentation, survival and second cancers. Methods: 360 female patients with histologically confirmed MGCOC, recorded in the CRN between 1953 and 2009 were identified. Patients, diagnosed before 1980 were separated from those with a diagnosis 1980+, reflecting the introduction of cis-platin based chemotherapy. Data on survival and second cancer incidence were obtained by linkage to the CRN. Cox Hazards Models and Kaplan Meier estimates were used. Results: The annual incidence doubled during the observation time. Malignant teratoma was the most common histological subtype (n = 190 [53%]), followed by dysgerminoma (n = 113 [31%]) and other non - dysgerminoma tumors (n = 57 [16%]). Over two thirds of the patients (median age 34 years [range 2-92]) had localized disease with distant disease in 23%. Before 1980 70% of 159 patients received subdiaphragmatic radiotherapy, this percentage was reduced to 24% after 1980, while chemotherapy increased from 11% to 38%. The 10 years ovarian cancer specific survival (OvCSS) (median follow-up time of 9.8 years [range: 0 - 54]) increased significantly to 93% in women treated in 1980+ compared to 62% to those with an earlier diagnosis (p <0.001) . Significant period-related improvement in OvCSS was observed independently from the extent of the disease and for all histological subtypes. Women aged >50 years had a significantly poorer OvCSS than younger ones, (HR=5.98, 95%CI [3.39 to 10.57]) adjusted for histological type and stage. A second cancer was diagnosed in 27 women, 63% of these cancers were located below the diaphragm within or close to the radiation field. Conclusions: The incidence of MGCOC is rising in Norway. We observed significant improvement of ovarian cancer specific survival after the introduction of cisplatin-based chemotherapy. The development of second cancer after treatment for MGCOC seems to be related to abdominal radiotherapy.
A multiplex methylation-specific PCR assay for detection of early-stage ovarian cancer using cell-free serum DNA.
Authors: Kong Beihua , Zhang Qing , Hu Guohong , Yang Qifeng , Dong Ruifen , Xie Xing , Ma Ding , Shen Keng
Published: March 2020

5535

Background: Epithelial ovarian cancer (EOC) remains the most lethal disease among gynecological malignancies. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stage of the disease. So there is an urgent need for better detection methods. Here we performed this work to build up a platform of multiplex methylation-specific PCR (MSP) assay to improve the early detection of ovarian cancer, via identifying the methylation status of cell-free serum DNA. Methods: After screening, we chose seven genes (APC, RASSF1A, CDH1, RUNX3, TFPI2, SFRP5 and OPCML) with a high frequency of methylation as candidate genes to construct the multiplex-MSP assay. When methylation of at least one of the seven genes was observed, the multiplex-MSP assay was considered positive. We performed the retrospective and screening study to verify its specificity and sensitivity in the detection of EOC. Results: The methylation status of cell-free serum DNA was examined in the preoperative serum of 202 patients, including 87 EOC cases (stage I, n=41, stage II-IV, n=46), 53 benign ovarian tumors and 62 healthy controls. As expected, multiplex MSP assay achieved a sensitivity of 85.3% and a specificity of 90.5% in stage I EOC, strikingly higher than that of single CA125, producing a sensitivity of 56.1% at 64.15% specificity [p=0.0036](Table). Conclusions: Multiplex MSP assay analyzing the methylation status of cell-free serum DNA is a suitable and reliable approach to improve the early detection of ovarian cancer, potentially benefiting a broad range of applications in clinical oncology. [Table: see text]
Surgical outcome score (SOS), a new algorithm based on HE4 and CA125, to predict surgical outcome in primary epithelial ovarian cancer (EOC) patients (pts).
Authors: Braicu Elena Ioana , van Gorp Toon , Richter Rolf , Chekerov Radoslav , Timmerman Dirk , Nassir Mani , Sehouli Jalid , Vergote Ignace
Published: March 2020

5549

Background: There are no clinical or biomolecular algorithms to predict surgical outcome in EOC pts. Recently, we showed that the combination of HE4 and CA125 predict surgical outcome in advanced primary EOC (ASCO 2012). We validated the cut-off values in an independent cohort and developed a new algorithm to predict surgical outcome-SOS. Methods: Pts with primary EOC (n = 193) were selected for a retrospective study between 2003 and 2011. Preoperative serum HE4 and CA125 levels were measured. The predictive values of HE4 and CA125 were analyzed using the receiver operator characteristic (ROC) with the corresponding area under the curve (AUC). Separate logistic regression algorithms for pre- and postmenopausal women were utilized to categorize pts into low and high-risk for residual disease, using CA125 and HE4 within SOS algorithm. Furthermore we performed a multivariate analysis for prediction of progression free- (PFS) and overall survival (OS). Results: Maximal cytoreduction was achieved in 67.4% pts. Serum HE4 expression correlated with residual disease (p<0.001, RR: 2.74, 95%CI 1.65-4.54), reaching a 76.2% sensitivity (Se), 56.9% specificity (Sp) and 83.1% negative predictive value (NPV), with 235 pM cut-off value. CA125 correlated with residual disease in premenopausal pts (p=0.031, RR: 3.13, 95%CI 1.28-7.65). For a CA125 cut-off of 500 IU/l, the Se, Sp and NPV were 39.7%, 69.8%, and 70.3%, respectively. ROMA predicted surgical outcome (AUC = 0.70, p <0.001, 95% CI = 0.624-0.776, RR = 2.54), reaching a 76.2% Se, 53.5% Sp for 81% cut-off value. SOS algorithm performed better than HE4 or CA125 alone, and ROMA (AUC= 0.741, p < 0.001, 95% CI 0.670-0.812, RR = 4.98). The Se, Sp and NPV was 90.5%, 46.5% and 90.9%, respectively, for a SOS cut off value of 21.5%. FIGO stage and residual disease were the only prognostic factors for both PFS and OS. SOS was an independent prognostic for PFS (p = 0.009, HR = 1.014, 95% CI = 1.004-1.025), but not for OS. Conclusions: This independent validation study confirm the predictive value of CA124 and HE4 on surgical outcome. The combination of HE4 and CA125 within the SOS score improve the prediction of surgical outcome, and therefore of PFS.
Benefit of adjuvant chemotherapy for stage I epithelial ovarian cancer according to the histologic type.
Authors: Fujiwara Hiroyuki , Takei Yuji , Saga Yasushi , Machida Shizuo , Sato Naoto , Yoshida Chikako , Takahashi Suzuyo , Taneichi Akiyo , Suzuki Mitsuaki
Published: March 2020

5552

Background: The benefit of adjuvant chemotherapy in stage I epithelial ovarian cancer (EOC) remains controversial. We retrospectively examined stage I EOC patients to clarify the benefits of adjuvant chemotherapy according to the histological type. Methods: The outcomes of 131 patients with stage I EOC that was diagnosed by exact staging laparotomy at the Jichi Medical University Hospital over a 22-year period from 1988 to 2009 were evaluated. Eighty-seven of the patients had received adjuvant chemotherapy (stage: IA 17, IC(intraoperative rupture;R) 27, IC(other) 43; histological type: clear cell adenocarcinoma(CCC) 38, mucinous adenocarcinoma(MC) 18, endometrioid adenocarcinoma(EC) 18, serous adenocarcinoma(SAC) 13), while 44 had undergone observation alone (stage: IA 31, IC(R) 12, IC(other) 1; histological type: CCC 11, MC 17, EC 11 and SAC 5). Outcomes for patients were compared between the two groups. Results: The overall recurrence rate in the adjuvant chemotherapy group was 18.4% (16/87). The rates of recurrence according to stage were IA 5.9% (1/17), IC(R) 14.8% (4/27), and IC (other) 25.6% (11/43). Recurrence by histological type were CCC 12, SAC 2(G1and G2), and one each for EC and MC. Recurrence was seen in all stages in CCC patients; however, there was no recurrence in stage IA in patients with non-CCC. The overall recurrence rate in the observation group was 11.4% (5/44). All five recurrences occurred in CCC patients, and no recurrence was observed in the 33 non-CCC patients (IA 26, IC(R) 7). In patients with IC(R) CCC, the recurrence rate was significantly higher in the observation group (80%;4/5) than in the adjuvant chemotherapy group (18.8%; 3/16) (p = 0.025). Conclusions: This retrospective study showed that the CCC is associated with recurrence in stage I EOC and adjuvant chemotherapy for these patients may improve outcomes. The recommended states for adjuvant chemotherapy in stage I EOC are as follow: 1) all subtype of stage I for CCC, and 2) IC(other) for non-CCC. Although further prospective studies are required, these results afford useful information with which to determine the adjuvant chemotherapy in stage I EOC.
Validation of urinary HE4 as a biomarker for ovarian cancer.
Authors: Li Zhong-Qian , Fermer Christian , Radwan Rachel R. , Hellman Maria , He Kuanglin , Falcone Katherine L. , Raju Savitha S. , Fegely Maryellen , Vucetic Zivjena , Dickson Diana L. , Kettlety Timothy R. , Moore Richard G. , Barnes Grady
Published: March 2020

5563

Background: Urinary HE4 has been reported as a promising biomarker for ovarian cancer (OC). In the current study, a large validation was performed to evaluate urinary HE4 as a biomarker for the stratification of OC from benign pelvic masses. Methods: Normalized HE4 was obtained from the ratio of HE4 (pmol/L measured with HE4 EIA) and creatinine (mg/dL measured with a Jaffe Reaction) in single-point urine samples from female subjects with a pelvic mass (N = 809). The samples were from one case-control prospective study (Moore RG, 2008) and two prospective clinical trials (NCT00315692 and NCT00987649). R Package was used to randomly distribute the subjects into the Training and Testing Sets. Analyze-it was used to analyze the clinical performance. Results: Medians of Normalized HE4, sensitivities (SN) and likelihood ratios (LR) (+) of Normalized HE4 at two levels of specificity (SP) are presented in the Table. Conclusions: Urinary HE4 normalized with urinary creatinine appears to be a valid biomarker for the stratification of OC from a benign pelvic mass. [Table: see text]
Prognostic effect of EIF4EBP1 on ovarian cancer: A single gene biomarker for overall survival and platinum response.
Authors: Villalobos Victor Manuel , Wang Yan , Willis Scooter , Leyland-Jones Brian , Sikic Branimir I.
Published: March 2020

5565

Background: Using a novel computational approach, Gene Set Outcome Analysis (GSOA), we were able to identify an area of amplification on chromosome 8p12 that leads to worse prognosis in high grade/high stage ovarian cancer. Located within this amplicon is EIF4EBP1, an effector of DNA translation that is activated by mTOR. Methods: We utilized the MSKCC CBIO cancer genetics portal and the ovarian TCGA clinical dataset, to detect variation in mRNA expression (EXP), (z-scores thresholds ± 2) and copy number variation (CNV), determined using GISTIC 2.0, that are associated with significant differences in PFS and overall survival in grade 3 and stage III/IV ovarian cancer. Results: 6.7% of tumors exhibited upregulation of EIF4EBP1 (CNV amplified and mRNA z > 2) and poorer prognosis with OS of 30.2 vs. 43.8 months (p = 0.0007, n = 445) in tumors not upregulated. Patients with upregulated vs. normal expression showed inferior PFS with first line, platinum based therapy, 10.0 vs. 15.2 months (p = 0.0406, n = 400), respectively. An additional 4.9% of cases had downregulation of EIF4EBP1, with homozygous deletion or mRNA expression z-scores < -2. Downregulation vs. normal expression also showed worse OS of 27.0 vs. 42.1 months (p = 0.0178) and PFS of 11.0 vs. 15.0 months (p = 0.028), respectively. As these groups are mutually exclusive and show a similar trend towards poor prognosis, when combined to compare aberrant vs. normal mRNA expression and copy number, we found an OS of 28.2 vs. 44.6 months (p = <0.0001) and PFS for first line platinum therapy of 10.2 vs. 15.3 months (p = 0.0024), respectively. Conclusions: In this dataset of 445 high-risk ovarian cancer patients, 11.8% exhibited aberrant expression of EIF4EBP1. While amplification of this region showed highly significant changes in OS and PFS, inclusion of both increased and decreased EIF4EBP1 mRNA expression achieved high statistical significance, demonstrating a “Goldilocks effect”, wherein normal expression leads to better outcomes. The potential relationship of gene expression levels of EIF4EBP1 to responsiveness to mTOR inhibitors should be explored in ovarian carcinomas.
Adverse event profile by therapy cycle for vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in platinum-resistant ovarian cancer.
Authors: Symanowski James Thomas , Kutarska Elzbieta , Bidzinski Mariusz , Nguyen Binh , Rangwala Reshma A. , Naumann R. Wendel
Published: March 2020

5572

Background: Vintafolide (EC145), a folic acid/desacetylvinblastine conjugate, binds with high affinity to folate receptors expressed in epithelial ovarian cancers. This analysis evaluated the incidence of adverse events (AEs) by treatment cycle and as a percent of total treatment cycles administered in the PRECEDENT trial, a randomized open-label study of subjects with platinum-resistant ovarian cancer receiving either vintafolide+PLD or PLD alone. Methods: Women ≥18 years old with ECOG status 0-2 and exposure to ≤2 prior systemic cytotoxic regimens were randomized 2:1 to vintafolide (2.5 mg IV tiw, weeks 1 and 3, q28 days)+PLD (50 mg/m2 IV day 1, q28 days) or PLD alone (same dose + schedule). AEs in the safety population (received at least 1 dose of study drug) were evaluated by cycle. Results: 157 patients received a total of 720 treatment cycles (518 vintafolide+PLD, 202 PLD alone). AEs (all grades, vintafolide+PLD vs PLD alone): 85.9% and 80.2% of cycles. Anemia, neutropenia, and thrombocytopenia were observed in 16.6% (vs 10.4% administered PLD alone), 19.1% (vs 10.4%), and 2.7% (vs 3.0%) of all cycles, respectively. Febrile neutropenia was observed in 0.2% (vs 0.5%) of cycles, respectively. Stomatitis and hand-foot syndrome (HFS) occurred in 16.6% (vs 22.8%) and 19.1% (vs 15.8%) of cycles, respectively. Peripheral sensory, motor, or sensorimotor neuropathy or polyneuropathy occurred in 10.1% (vs 2.5%) of cycles, and constipation and small intestinal obstruction/ileus were observed in 12.7% (vs 10.4%) and 2.9% (vs 4.0%) of cycles, respectively. Fatigue was similar between arms—15.8% of vintafolide+PLD vs 14.9% of PLD cycles. All AEs were noncumulative except for HFS, which for both arms increased in frequency through Cycle 6 compared with Cycles 1 and 2. Grade 3/4 AEs (vintafolide+PLD vs PLD alone): 29.3% vs 18.3% of cycles. Conclusions: After the number of treatment cycles was accounted for, anemia, neutropenia, and neuropathy were numerically greater in patients on vintafolide+PLD. Thrombocytopenia, constipation, small intestinal obstruction/ileus, fatigue, and HFS were similar. Stomatitis was numerically greater in patients administered PLD alone. Clinical trial information: NCT00722592.
Statin and aspirin use and risk of VTEs in ovarian cancer patients.
Authors: Rennert Hedy S , Rennert Gad , Lavie Ofer , Sagi Shlomi , Leviov Michele , Steiner Mariana , Shai Ayelet
Published: March 2020

5576

Background: Deep vein thrombosis and pulmonary embolism - venous thromboembolic events (VTEs) - are associated with significant morbidity and increased risk of mortality in cancer patients. Ovarian cancer patients are at a particularly increased risk for VTEs. Statins and aspirin have been shown to reduce the risk of VTEs in the general population in randomized trials. However, the effect of these medications on the incidence of VTEs in ovarian cancer patients has not been studied. Methods: Patients diagnosed with ovarian cancer between years 2000 and 2011 were identified through the Israeli Cancer Registry (ICR). Patients insured by Clalit Health Services, the largest HMO in Israel, were included. Data regarding medication use, chronic diseases and VTE diagnosis were extracted from the computerized database. Patients taking Warfarin or Low Molecular Weight Heparin for 3 months or longer were excluded. Statistical analysis was performed using SPSS (v 18). Use of medications was analyzed as a time dependent covariate in a Cox regression model. Results: Of 1,886 patients 179 (9.5%) had a VTE during a median follow up of 3.13 years. 95 patients (5%) had a VTE 2 years after diagnosis of ovarian cancer. In a multivariate analysis use of chemotherapy and stage 3 or 4 at presentation were associated with an increased risk for VTE's 2 years after diagnosis. Age was associated with a trend for increased risk. Statins were used by 43.2% of the patients, and 31.9% used aspirin. Aspirin use was associated with a reduced incidence of a VTE, which was borderline statistically significant (p=0.054). Statin use did not affect the incidence of VTE's in the group of ovarian carcinoma patients. Conclusions: Our results suggest that in patients with ovarian cancer aspirin use is a possible protector from deep vein thrombosis and pulmonary embolism. Prospective trials are warranted to assess the benefit of aspirin and statins for prevention of VTE's in the high risk population of ovarian cancer patients. [Table: see text]
Utilizing propensity scores to determine the risk of recurrence and death in epithelial ovarian cancer.
Authors: Warner Lindsay Louise Morgenstern , Dowdy Sean Christopher , Martin Janice , Lemens Maureen , McGree Michaela , Weaver Amy , Podratz Karl C. , Bakkum-Gamez Jamie Nadine
Published: March 2020

5577

Background: Perioperative red blood cell transfusion (PRBCT) may be a negative prognostic marker in surgical oncology. We assessed PRBCT as an independent risk factor for recurrence and death from epithelial ovarian cancer (EOC) in the largest cohort to date. Methods: Patient characteristics and process-of-care variables (NSQIP-defined, >130 variables) were retrospectively abstracted from 587 women who underwent primary staging and cytoreduction for EOC (1/1/03-12/29/08). Evaluated using propensity scoring with univariate logistic regression and odds ratios (OR) and Cox proportional hazards regression and hazard ratios (HR). Factors with p<0.1 used in multivariate models. Results: Rate of PRBCT was 77.0% (452/587). In univariable analysis, PRBCT was associated with older age (OR 1.25[95% CI 1.06, 1.48]/10yr increase), stage≥IIIa (4.66[3.04, 7.13]), splenectomy (26.63[3.67, 193.17]), higher surgical complexity (1.86[1.17, 2.95] score 2; 21.48 [7.37, 62.59] 3; referent 1), serous histology (2.36[1.57, 3.55]vs non-serous), longer operating time (1.58[1.36, 1.83]/hr increase), and residual disease (3.26[1.97, 5.41]≤1cm; 1.97[1.09, 3.56]>1cm), and lower preop hemoglobin (Hb) (1.89[1.59, 2.27]per 1g/dL decrease). In univariable analysis, PRBCT was associated with a higher risk of recurrence (HR 1.96[95% CI 1.43, 2.68]) and death (1.71[1.28, 2.28]). However, in multivariable analysis, stage≥IIIa (4.03[2.05, 6.49]), splenectomy (1.41[1.02, 1.95]), residual disease (1.86[1.41, 2.46]≤1cm; 2.91[2.02, 4.18]>1cm), and lower preop Hb (1.09[1.01, 1.19]) were associated with higher risk of recurrence. Older age (1.24[1.12, 1.37]), stage≥IIIa (3.07[1.93, 4.90]), albumin ≤3 g/dL (2.06[1.28, 3.31]), residual disease (1.63[1.22, 2.19]≤1cm; 3.03[2.19, 4.18]>1cm), and low Hb (1.08[1.00, 1.19]) were associated with higher risk of death. Serous histology (0.70[0.52, 0.95]) associated with lower risk of death. Conclusions: PRBCT does not appear to be directly associated with disease-free and overall survival in EOC. Lower preoperative Hb was associated with a higher risk of both recurrence and death. The need for PRBCT appears to be a stronger prognostic indicator than the receipt of PRBCT.
High-grade endometrial cancer: Revisiting tumor size and the lower uterine segment.
Authors: Doll Kemi M. , Denslow Sheri , Tseng Jill , Gehrig Paola A. , Nickles Fader Amanda
Published: March 2020

5589

Background: Tumor size is an independent poor prognostic factor in endometrial cancer, while tumor location has shown mixed results, with few studies addressing high-grade disease. We aim to determine if tumor size (TS) or lower uterine segment involvement (LUS) is associated with nodal disease and recurrence in high-grade endometrial cancer. Methods: In an IRB-approved, multi-institutional cohort study of patients with clinically early-stage, high-grade endometrial cancer (grade 3 and all non-endometrioid histologies), records were reviewed for demographic, pathologic, and treatment data. Recurrence as a function of tumor size and location were analyzed using logistic regression and exact tests for significance. Hazard ratios were calculated. Results: 208 patients with high-grade histology were identified from Jan 2005 to Jan 2012 with 188 patients having tumor location identified and 183 having tumor size reported. Both pelvic and para-aortic lymphadenectomy were completed in 100% of patients. There were 75 endometrioid (36.1%), 35 papillary serous (16.8%), 12 clear cell (5.8%), 26 carcinosarcoma (12.5%), and 60 (28.8%) with undifferentiated or mixed histology. Median follow up time was 17.2 months (0.2 – 67.6 mo) with 55 recurrences. LUS tumors were more likely to have pelvic and para-aortic nodal disease (OR 3.83, 95%CI 1.70 – 8.60, OR 5.13, 95% CI 1.96 – 13.45) and increased recurrence rates (HR 2.21, 95% CI 1.16-4.20) on univariate analysis. Tumors size ≥2cm was associated with pelvic nodal disease (27.4% vs. 0%, p = 0.01; OR 10.00, p = 0.01). TS was not independently associated with recurrence and patterns of failure did not significantly differ with LUS involvement. Conclusions: In patients with clinically early stage, high-grade endometrial cancers, TS and LUS tumor location are significantly associated with lymph node metastasis and advanced stage disease at the time of comprehensive surgical staging. Tumor location in particular is strongly associated with distant nodal disease and is a poor prognostic indicator for recurrence. Studies evaluating the role of adjuvant therapy based on tumor size and tumor location would be helpful in improving patient related outcomes.
Statin use in uterine malignancies.
Authors: Spoozak Lori Ann , Girda Eugenia , Van Arsdale Anne , Einstein Mark H. , Goldberg Gary L. , Nevadunsky Nicole
Published: March 2020

5592

Background: Statins, or 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are commonly used to manage hyperlipidemia. Epidemiologic studies have recently linked statins to improved cancer survival. Molecular pathways that explain this effect are not well defined, but may involve cell death and angiogenesis. Our aim was to determine the association between statin use and overall survival in a cohort of women with uterine malignancies. Methods: After IRB approval, a retrospective review of consecutive patients with uterine malignancies diagnosed between 01/2005 and 12/2009 at a single institution was performed. Age, race, diagnosis of hyperlipidemia, diabetes, hypertension, medication use including statins, beta-blockers, aspirin, pathology, and exposure to chemotherapy or radiation were abstracted from the time of initial diagnosis and treatment. Kaplan-Meier analysis, univariate, and multivariate Cox Proportional Hazard Regression were performed to assess the association between statin use, aspirin use, and survival. Results: Of 554 patients identified, 333 (60%) were not hyperlipidemic (NH), 165 (30%) were hyperlipidemic on statins (HS), and 56 (10%) were hyperlipidemic and not on statin therapy (HNS). The HS cohort was older, diabetic, hypertensive, used beta-blockers and aspirin. Stage, grade, and chemotherapy use were similar, but HS and HNS received more radiation (p<0.05). Both patients in the HS and HNS groups had improved overall survival compared to NH patients (p=0.04). Further stratifying our subgroups by aspirin use revealed that HS+aspirin users had significantly improved survival compared to other non-HS+aspirin users (p=0.01). In multivariate analysis, women who used statins had a 45% decreased hazard of death compared to NH women (HR = 0.55, 95% CI; 0.35, 0.87). Additionally, aspirin users had improved survival compared to non-users (HR = 0.47, 95% CI; 0.29, 0.76). Women using statins and aspirin had an 84% decreased hazard of death in comparison to other groups (HR = 0.16, 95% CI; 0.07,0.38, p<0.01). Conclusions: Statin and aspirin use are associated with improved overall survival in patients with uterine malignancy. Prospective evaluation of statin and aspirin use in uterine cancer is warranted.
Cridanimod and progestin therapy in hormone-resistant endometrial cancer.
Authors: Carlson Matthew J. , De Geest Koen , Wang Xiaofang , Leslie Kimberly K. , Dai Donghai
Published: March 2020

5597

Background: Cridanimod is a novel small molecule that has been shown to increase progesterone receptor (PR) expression in rat endometrium. We hypothesize that cridanimod, in combination with progestin therapy, will increase PR expression and, thus improve survival in a mouse model of advanced, high grade endometrial cancer. Methods: Hec50co cells, established in our laboratory to represent genetically and phenotypically type II endometrial cancer, were injected into the peritoneal cavity of 96 athymic mice. These mice were randomly divided into 6 groups, receiving the following therapies: control (no therapy), medroxyprogesterone acetate (MPA) alone, cridanimod 1mg IM twice a week plus MPA, cridanimod 3mg plus MPA, cridanimod 6mg plus MPA, and adenovirus-mediated PR expression plus MPA. PR expression in tumor tissue and serum interferon (IFN) levels were assayed via Western blot and ELISA, respectively. Results: Kaplan-Meier survival analysis showed that the group receiving MPA plus 6 mg cridanimod twice a week had a significantly longer survival time than the control or MPA alone (62 ± 7.0 days vs 38 ± 5 or 33 ± 3, respectively, p < 0.05). The group with MPA plus 3 mg cridanimod had a significantly longer survival than the group with MPA alone (56 ± 8.0 days vs 33 ± 3, p < 0.05). Western blot analysis showed that PR proteins were substantially higher in xenograft tumors from animals treated with cridanimod at doses of 3mg and 6mg when comparing to the control and MPA alone groups, ELISA data showed significant increases in IFNα and -β in cridanimod-treated mice in a dose-dependent manner. Conclusions: Combined progestin and cridanimod therapy significantly improved survival of mice with high-grade, advanced endometrial cancer. Cridanimod significantly increased PR expression, suggesting that the therapeutic benefit of combined therapy is mediated by up-regulation of PR, which is likely to be mediated through cridanimod induction of IFNα and IFNβ expression. Further investigation is warranted to determine the utility of this promising agent.
Incidence, management, and resolution of noninfectious pneumonitis in BOLERO-2.
Authors: Ito Yoshinori , Noguchi Shinzaburo , Deleu Ines , Baselga José , Hortobagyi Gabriel N. , Bachelot Thomas Denis , Masuda Norikazu , Pistilli Barbara , Pritchard Kathleen I. , Iwata Hiroji , Gnant Michael , Eakle J F , Csõszi Tibor , Srimuninnimit Vichien , Puttawibul Puttisak , Roila Fausto , Panneerselvam Ashok , Taran Tanya , Sahmoud Tarek , Rugo Hope S.
Published: March 2020

561

Background: The BOLERO-2 trial showed that adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival (PFS) without reducing quality of life versus placebo (PBO) + EXE alone in postmenopausal women with hormone-receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) progressing on/after nonsteroidal aromatase inhibitor (NSAI) therapy. Although generally well tolerated, mTOR inhibitors such as EVE have been associated with noninfectious pneumonitis (NIP). Methods: Patients (pts) were randomized 2:1 to receive EVE+EXE or PBO+EXE. Incidence and severity of NIP, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: Median duration of exposure to EVE was 24 weeks with median dose intensity of 8.6 mg/d. Pulmonary adverse events (AEs) of any grade (NIP, interstitial lung disease, lung infiltration, pneumonia, or pulmonary fibrosis) were recorded in 97 of 482 pts (20%) in the EVE+EXE arm versus 1 of 238 pts (<1%) in the PBO+EXE arm. Of these, 16% of pts (77 of 482) in the EVE+EXE arm versus 0 in the PBO+EXE arm had a diagnosis consistent with NIP. In the EVE+EXE arm, grade 1 (no symptoms), grade 2 and 3 NIP occurred in 7%, 6% and 3% of pts, respectively, and no grade 4 events were reported. Complete resolution of NIP to grade ≤1 was recorded for all but 4 pts for whom NIP was still observed at last follow-up before study discontinuation. Overall, in the EVE+EXE arm, NIP was recorded as the reason for dose interruption and treatment discontinuation in 7.5% and 5.6% of pts, respectively. Conclusions: Data from BOLERO-2 support the combination of EVE and EXE to significantly prolong PFS in postmenopausal women with HR+, HER2– ABC progressing on/after NSAI. The incidence of NIP in this study was generally consistent with reports from other oncology settings, was of mild to moderate severity, and was generally reversible with appropriate interventions and temporary dose modifications. Patient and healthcare provider education for early diagnosis and management of NIP are highly recommended. Clinical trial information: NCT00863655.