bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized trial of oral cyclophosphamide (C) with or without veliparib (V), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent BRCA-positive ovarian, or primary peritoneal or high-grade serous ovarian carcinoma.
Authors: Kummar Shivaani , Oza Amit M. , Fleming Gini F. , Sullivan Daniel , Gandara David R. , Erlichman Charles , Villalona-Calero Miguel Angel , Morgan Robert , Chen Alice P. , Ji Jiuping Jay , Allen Deborah , Lih Chih-Jian , Steinberg Seth M. , Williams P. Mickey , Conley Barbara A. , Doroshow James H. 
Published: March 2020

5020 Background: V+C was well tolerated in a phase I trial and responses and prolonged disease stabilization were observed in BRCA + patients (pts).To assess the relative contribution of the PARP inhibitor to the efficacy observed for the combination, we conducted a randomized multicenter trial comparing the response rate (RR) of V and C to the RR of C alone in patients with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, fallopian tube or high-grade serous ovarian cancer. Methods: Pts were ≥ 18 yrs, KPS ≥ 70%, had adequate organ function, prior therapy with PARP inhibitors was allowed.Both drugs were administered orally qd; C 50 mg, V 60 mg; 21 day cycles. Pts were randomized to receive either C alone or V+C. At disease progression, pts on C alone were allowed to cross over to the combination. Radiologic imaging was performed at baseline and q 3 cycles for assessment of response. Dose reduction of V was allowed to 40 mg for gr 3 non-hematologic or gr 4 hematologic toxicities. The study design had an 88% power to detect the difference between a 15% RR for C alone versus 35% for V+C, early closure if fewer responses were observed on the combination arm in the first 65 pts enrolled (half of the total projected accrual). Results: Total of 74 pts were enrolled (36 pts C, 38 pts V+C), median age 58 (37-79 yrs), # of prior therapies: median 4 (1-9), 2 pts had prior PARP therapy. Treatment was well tolerated, Gr ≥ 2 toxicities per arm for initial regimen (# of pts): C alone: lymphopenia (2), mucositis (1); V+C: lymphopenia (4), anemia (2), leucopenia (2), neutropenia (2). Of the 74 pts evaluable for response at the interim analysis, 3 PRs observed in 36 pts on V+C and 5 PRs of 38 pts on C alone arm; thus accrual was stopped. PAR levels assessed by validated ELISA were inhibited (>80%) in PBMCs in 9/10 pts 4 hours post V, no inhibition with C alone. Conclusions: Addition of V, a PARP inhibitor, to C did not improve RR versus C alone. Exomic sequencing, gene expression studies, and Fanconi Anemia triple stain immunofluorescence (FATSI) assay for FancD2 nuclear foci formation using archival tissue are ongoing.
Phase II trial of temsirolimus and bevacizumab for initial recurrence of endometrial cancer.
Authors: Einstein Mark H. , Wenham Robert M , Morgan Robert , Cristea Mihaela C. , Strevel Elizabeth Laureen , Oza Amit M. , Kaubisch Andreas , Fruth Briant , Qin Rui , Erlichman Charles 
Published: March 2020

5025 Background: We report the interim results of the endometrial arm of a multi-tumor protocol using temsirolimus and bevacizumab in endometrial cancer (EMCA) patients at the time of their initial recurrence. The primary aim of this trial is to assess treatment efficacy in terms of both confirmed tumor response and 6-month progression free survival (PFS). Methods: Women with a performance status of 0 or 1 who have had their first recurrence for EMCA were eligible. Subjects who had chemotherapy as part of their adjuvant treatment after front line surgical staging were also eligible. The regimen included Temsirolimus 25 mg IV weekly followed by bevacizumab 10mg/kg IV on days 1 and 15 of a 28 day cycle. A modified two-stage Simon design with fixed sample size was adopted with the null hypothesis being that the true tumor response rate is at most 25% and the true 6 month PFS rate is at most 50%. Results: We enrolled 26 evaluable subjects to the first stage of which one did not proceed with treatment. The median age at enrollment was 60 (range 40-80). 22 (85%) were white and 19 (73%) were not Hispanic/Latino. 19 (73%) of subjects had prior raditation therapy, with 4 having a prior para-aortic boost. 5 (20%) subjects had a confirmed PR and 12 (48%) were progression-free at 6 months, which fell short of the futility stopping rule. An additional 5 (20%) subjects had a best response of confirmed SD, so 10 (40%) had overall clinical benefit from this regimen. AEs attributable to treatment were modest and included 16 grade 3 adverse events, of which the most common ones included hypertension, hyperglycemia, and neutropenia. There were 2 grade 4 events that were possibly treatment related including a duodenal perforation and an anorectal infection. Conclusions: While there was clinical benefit of this regimen in women at the time of their first recurrence of EMCA, the combination of temsirolimus and bevacizumab did not achieve our prespecified efficacy assumptions. This differs from what has been reported with this combination as a second line therapy for recurrent EMCA, where prespecified response assumptions differ. Also, the regimen had comparable safety and toxicity to other cytotoxic chemotherapy regimens used in this setting.
Whole genome sequencing to characterize luminal-type breast cancer.
Authors: Ellis Matthew James , Ding Li , Shen Dong , Luo Jingqin , Suman Vera J. , Goiffon Reece J. , Wallis John W. , Goldstein Theodore C. , Chen Ken , Allred Donald Craig , Leitch A. Marilyn , Olson John A. , Ota David M. , Watson Mark , Piwnica-Worms David , Bose Ron , Stuart Joshua M. , Wilson Richard K. , Hunt Kelly , Mardis Elaine 
Published: March 2020

503 Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.
Use of an optimized primary ovarian cancer xenograft model to mimic patient tumor biology and heterogeneity.
Authors: Dobbin Zachary C. , Katre Ashwini A. , Ziebarth Angela , Shah Monjri , Steg Adam D. , Alvarez Ronald David , Conner Michael G. , Landen Charles N. 
Published: March 2020

5036 Background: Current xenograft and transgenic models of ovarian cancer are mainly homogeneous and poorly predict response to therapy. Use of patient tumors may represent a better model for tumor biology and offer potential to test personalized medicine approaches, but poor take rates and questions of recapitulation of patient tumors have limited this approach. We have developed a protocol for improved feasibility of such a model and examined its similarity to the patient tumor. Methods: Under IRB and IACUC approval, 23 metastatic ovarian cancer samples were collected at the time of tumor reductive surgery. Samples were implanted either subcutaneously (SQ), intraperitoneally (IP), in the mammary fat pad (MFP), or in the subrenal capsule (SRC) and monitored for tumor growth. Cohorts from 8 xenolines were treated with combined carboplatin and paclitaxel or vehicle, and response to therapy compared between xenografts and patients. Expression of tumor-initiating cell (TIC) markers ALDH1, CD133, and CD44 was assessed by immunohistochemistry in tumors from patients and treated and untreated xenografts. Results: At least one SQ implanted tumor developed in 91.3% of xenografts, significantly higher than in the MFP (63.6%), IP (23.5%), or SRC (8%). Xenografts were similar in expression of putative TIC’s compared to patient tumors. The patients and the xenografts also have similar responses to chemotherapy in that xenografts from patients with a partial response responded more slowly than those from patients achieving a complete response (45 vs 21 days, p=.004). Treated xenografts were more densely composed of TICs. ALDH1 increased to 36.1% from 16.2% (p=0.002) and CD133 increased to 33.8% from 16.2% (p=0.026). Conclusions: Xenoline development can be achieved at a high rate when tumors collected from metastatic sites are implanted SQ. These xenografts are similar to patient tumors with regard to chemotherapy response and TIC expression.. This model may be a more accurate model for in vivo pre-clinical studies as compared to current models. Also, as treated xenografts become chemoresistant, this model is well positioned to evaluate targeted therapies aimed at the most aggressive populations in a heterogeneous tumor.
Effect of weekly administration of bevacizumab, gemcitabine, and oxaliplatin in patients with heavily pretreated ovarian cancer.
Authors: Ikeda Yuji , Kikuchi Yoshihiro , Takano Masashi , Goto Tomoko , Kouta Hiroko , Sasaki Naoki , Kudoh Kazuya , Oda Katsutoshi , Nagasaka Tsuneki , Kita Tsunekazu 
Published: March 2020

5037 Background: The combination therapy of gemcitabine with oxaliplatin (GEMOX) has high activity in patients with ovarian cancer. Bevacizumab (B), a vascular endothelial growth factor specific antibody, enhances chemotherapeutic efficacy through its anti-angiogenic function in various types of tumors. We evaluated the effect of weekly administration of B and GEMOX in heavily-pretreated patients with recurrent or refractory ovarian cancers (ROC). Methods: Nineteen patients with ROC received at least three or more cycles of weekly-B and GEMOX consisting of B (2mg/kg), gemcitabine (300mg/m2) and oxaliplatin (30mg/m2). The treatment was continued until the development of progressive disease. The response and adverse effects (AE) were evaluated using the response evaluation criteria in solid tumors (RECIST), CA125 Gynecologic Cancer Intergroup (GCIG) criteria, and common terminology criteria for adverse events (CTCAE) version 3.0. Results: Seventeen (89%) of the 19 patients were primarily stage 3 or 4. Fifteen patients (79%) had received more than three regimens of chemotherapy. All patients were pretreated with a platinum-containing regimen within 6 months and 16 of these patients (84%) were pretreated within 3 months. According to the RECIST evaluation, 2 patients (11%) had a complete response (CR), 6 patients (32%) had a partial remission (PR) and 5 patients (26%) had a stable disease (SD). The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD) were 42% and 68%, respectively. In 10 patients with serous adenocarcinoma, RR was 60%. In 6 patients pretreated with weekly B and pegylated liposomal doxorubicin (PLD), RR was 50%. Median progression-free survival was 5 months (range: 2-11 months). Hematological adverse effects (AE) with grade 3/4 were leukopenia (16%), neutropenia (10%), thrombocytopenia (5%), however, all AE were manageable. Conclusions: Weekly B and GEMOX administration had significant activity with mild AE in patients with ROC especially in serous adenocarcinoma. Notably, the activity was also observed in patients pretreated with weekly B and PLD. These results warrant further prospective study.
ESA use in women with cancer: Consequences of the 2008 FDA clinical alert.
Authors: Dickinson Kimberly M. , Sakr Bachir Joseph 
Published: March 2020

5040 Background: Erythropoietin stimulating agents (ESA) are used clinically as an alternative to blood transfusions in cancer patients suffering from symptoms of anemia. However, more recent randomized controlled trials of ESA usage concluded that its use is associated with an increased risk of tumor progression and death. As a result, in July 2008 the FDA issued a clinical alert restricting the use of ESA. A reduction in the prescribing of ESA was immediately seen but changes in blood transfusion rates have not been examined. Methods: A retrospective chart review was conducted drawing from patients under treatment in the Program in Women’s Oncology at Women and Infant’s Hospital from one year before the clinical alert (August 2007-July 2008) to one year afterward (August 2008-July 2009). The primary outcomes were blood transfusion and ESA administration rates compared across the two time periods. Results: The study population (n=776) included patients with a cancer diagnosis who received chemotherapy during one or both time periods. 165 (21.3%) patients received ESA treatment. The total number of ESA treatments administered in the study period of interest was 1,277, with the majority (60%) given prior to the FDA alert. The mean number of ESA treatments in the first time period was 6.39 per person as compared to 0.61 per person in the second time period. Of the study population, 186 (23.8%) patients received at least one blood transfusion. A total of 463 blood transfusions were administered during the entire study period but a significant difference was not observed in the proportion of those delivered prior to the FDA alert (52%) versus after the FDA alert (48%). The average number of transfusions given in the first time period was 2.34 per person, as compared to 2.17 per person in the second period. Conclusions: Our results indicate that despite a steep decline in the use of ESA for chemotherapy-induced anemia, blood transfusion rates were not significantly different between the two periods. Interestingly, a slight downward trend was observed from before the FDA alert to after the alert. While more work is needed to understand the implications of these findings, it suggests that resource utilization did not increase despite the reduction in ESA use.
Panitumumab and pegylated liposomal doxorubicin in platinum-resistant epithelial ovarian cancer with KRAS wild-type: The PaLiDo study, a phase II nonrandomized multicenter study.
Authors: Steffensen Karina Dahl , Waldstrøm Marianne , Pallisgaard Niels , Lund Bente , Bergfeldt Kjell , Wihl Jessica , Keldsen Nina , Marth Christian , Vergote Ignace B. , Jakobsen Anders Kristian Moeller 
Published: March 2020

5052 Background: Ovarian cancer (OC) patients with platinum-resistant recurrent disease have few therapeutic options and the response rates are only 10-20% using non-cross-resistant chemotherapeutic agents. The increasing number of negative trials for OC treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may result in improvement in survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). No previous studies have evaluated the effect of panitumumab in OC based on KRAS mutation status. The main purpose was to investigate the response rate in platinum-resistant, KRAS wild-type OC patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. Methods: Major eligibility criteria were confirmed stage I-IV primary epithelial ovarian/fallopian/peritoneal cancer patients with progression either during or within 6 months after end of first or second line platinum-based chemotherapy. Only patients with measurable disease by CA125 criteria and with KRAS wild type were eligible. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m² day 1, every 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CA-125 criteria. Results: A total of 46 patients were enrolled by 6 study sites in this multi-institutional phase II trial. Within the population evaluable for response (N=33), there was 8 CA125 responders for an overall response rate of 24.3 %. Progression-free and overall survival in the intention-to-treat population (N=43) was 2.7 months (2.5-3.2 months, 95%CI) and 8.1 months (5.6-11.7 months, 95%CI), respectively. The most common treatment related grade 3 toxicities included skin toxicity (42%), fatigue (19%) and vomiting (12%). Conclusions: The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients although the dermatologic toxicity was considerable.
The impact of obesity on time to recurrence in ovarian cancer: A retrospective study.
Authors: Hew Karina E , Bakhru Arvind , Harrison Evan , Turan Mehmet Ozhan , Rosenshein Neil B. 
Published: March 2020

5055 Background: There has been conflicting data regarding the relationship between obesity and progression free survival in patients with ovarian cancer. There has been some evidence to suggest that obesity results in altered tumor biology and a poorer prognosis in these patients. The aim of this study was to examine whether obesity is a risk factor for time to recurrence in primary epithelial ovarian cancer. Methods: A multicenter retrospective chart review was performed at Mercy Medical Center and University of Michigan Medical Center. 591 patients were diagnosed with primary epithelial ovarian cancer between 2004-2009. However, 221 patients were excluded from the analysis because of persistent or progressive disease, treatment with neoadjuvant chemotherapy, presence of synchronous tumors or incomplete follow-up data. 370 patients were eligible for analysis. Data collected included: height and weight at the time of surgery, age, race, medical co-morbid illnesses, tumor stage, grade and histology. Treatment related data such as number of cycles of adjuvant chemotherapy; and optimal versus suboptimal tumor debulking was also collected. Body mass index (BMI) was defined according to WHO 2004 criteria. Women with a BMI greater than 30 were categorized as obese. The diagnosis of recurrence was made by positive radiological or pathological diagnosis of cancer recurrence after patient had surgery, received adjuvant chemotherapy and had no clinical, radiological or serological evidence of recurrence during this time. The time to recurrence was then quantified in terms of months from the initial surgery. Survival analyses were performed with the Kaplan-Meier method and compared using log-rank testing. Time to recurrence was analyzed using Mann-Whitney U and Wilcox W tests. Results: 130 (35%) obese patients were compared with 240 (65%) non obese patients. A recurrence was documented in 125 (47.9%) non obese patients and 49 (37.7%) obese patients. Time to recurrence between both BMI groups was found to be identical, at 15 months (p=1.0). The progression free survival was similar in both obese and non obese subjects (p=0.118). Conclusions: Obesity does not impact the time to recurrence in patients with primary ovarian cancer.
A phase Ib study of the combination of temsirolimus (T) and pegylated liposomal doxorubicin (PLD) in advanced or recurrent breast, endometrial, and ovarian cancer.
Authors: Boers-Sonderen Marye , Desar Ingrid , Van Der Graaf Winette T.A. , Ottevanger P. B. , Van Herpen Carla 
Published: March 2020

5061 Background: PLD is active in metastatic breast, endometrial and ovarian cancer. Preclinical studies suggest that mTOR inhibitors (mTORi), such as T, have an additive therapeutic effect to chemotherapy and resistance to doxorubicin can be reversed by adding an mTORi. Therefore, the combination of T and PLD is highly promising. Methods: This phase I study assessed the maximum tolerated dose (MTD), safety and activity of the combination of T and PLD in advanced or recurrent breast, endometrial or ovarian cancer. Patients (pts) who were not previously treated with PLD or T, with adequate organ function were eligible. After a two week run in period with T iv once weekly, PLD iv once every four weeks was added. In case of clinical benefit, pts were treated for a maximum of 9 cycles combination therapy. T could be continued as monotherapy afterwards. The MTD was defined as the highest dose at which ≤ 1 dose limiting toxicity (DLT) had been observed among 6 pts. FDG PET scans were performed at baseline and after 2 and 6 wks to assess the effect on tumor metabolism. Pharmacokinetic (PK) sampling was performed during cycle 1. Results: 20 pts were enrolled. On the 4th dose level with 20 mg T and 40 mg/m2 PLD 2 DLTs occurred in 6 pts: a grade 3 thrombocytopenic bleeding and a grade 3 skin toxicity. Therefore, the MTD was assessed at 15 mg T and 40 mg/m2 PLD. Adverse events (all grades/grade 3-4 in %) occurring most frequently were fatigue (84/5), nausea (84/16), mucositis (79/21), vomiting (74/16) and anorexia (74/0) Furthermore, rash and hand foot syndrome occurred both in 53% of pts, with 11% and 21% grade 3 respectively. 3 pts had a confirmed PR and 9 had SD (> 3 months). The mean progression free survival (PFS) was 4.9 months with 2 pts still on treatment. Results of FDG PET and PK data are currently being analyzed and will be presented. Conclusions: The combination of T and PLD is safe and tolerable. The MTD was assessed at PLD 40 mg/m2 once every 4 weeks and T 15 mg weekly. The activity of this combination in breast, endometrial and ovarian cancer pts is promising and warrants further studies.