bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with osteonecrosis of the jaw in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG 0307 trial.
Authors: Kizub Darya , Miao Jieling , Schubert Mark M. , Paterson Alexander H. G. , Clemons Mark J. , Dees Elizabeth Claire , Ingle James N. , Falkson Carla Isadora , Barlow William E. , Hortobagyi Gabriel N. , Gralow Julie 
Published: May 2019

552 Background: Bisphosphonates reduce the risk of bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of osteonecrosis of the jaw (ONJ). We used the data collected in the S0307 trial to describe factors associated with provoked and unprovoked ONJ. Methods: In S0307, 6097 patients with Stage I-III breast cancer who had surgery were randomized to receive zoledronic acid (ZA) 4mg IV monthly for 6 months, then every 3 months, clodronate (CL) 1600mg daily, or ibandronate (IB) 50mg daily for three years, with no difference in bone metastases or disease-free survival. Patients completed dental procedures prior to and had a dental exam at enrollment. Pearson’s Chi-squared and Student’s T-test were used to test differences in categorical and continuous variables, respectively; logistic regression was used test independent association. Results: Of 5836 evaluable women, 48 developed ONJ, which was associated with bisphosphonate type (28/2124 (1.26%) for ZA, 8/2185 (0.36%) for CL and 12/1527 (0.77%) for IB (p = 0.002). Median time to onset of ONJ was 24.9 (1.4-66.6) for ZA, 41.2 months (range 33.8-67.4) for CL, 23.9 (2.1-75.3) for IB (p = 0.0447). Infection was present in 21 (43.8%) and absent in 20. ONJ was considered unprovoked in 20 (41.7%) and provoked by dental extraction in 20 (41.7%), periodontal disease in 14 (29.2%), denture trauma in 6 (12.5%), other dental surgery in 3 (6.3%). ONJ was associated with dental calculus (OR 2.03 (95% CI: 1.08-3.81), gingivitis (OR 2.11, 95% CI: 1.12-3.98), and periodontal disease (OR 2.87, 95% CI 1.45-5.53) that were moderate/severe and > 4mm periodontitis (OR 2.20, 95% CI 1.18-4.08). Patients with provoked and unprovoked ONJ had similar amounts of dental disease and lesion location. ONJ was not associated with dentures, plaque, chemotherapy, corticosteroids or renal adverse events. In multivariate analysis (limited by small sample), only bisphosphonate type was associated with ONJ. Conclusions: ONJ prevalence was low, likely due to patients completing dental procedures before enrollment. ZA carried a higher risk of ONJ (though current adjuvant dosing interval recommendations are less frequent), with time to onset similar to IB. Oral CL and IB (not currently available in the United States) are thus likely more appropriate for patients with poor dental health. Clinical trial information: NCT00127205.
Omission of adjuvant therapy in stage I clear cell ovarian cancer: Review of the British Columbia (BC) cancer experience.
Authors: Liu Shiru Lucy , Tinker Anna 
Published: May 2019

5536 Background: Standard guidelines recommend adjuvant chemotherapy for stage I clear cell ovarian cancer (CCOC), despite data demonstrating excellent outcomes. Since 2012, the BC Cancer provincial treatment guidelines for surgically staged stage IA/B and IC1 (defined by intraoperative rupture only) CCOC has been to offer observation only. We reviewed the clinical outcomes of stage I CCOC patients since policy implementation. Methods: A retrospective, population-based cohort study of all stage I CCOC patients operated on between April 2012 and December 2017 was conducted. Patient, tumor, surgical and clinical outcome data were collected. Survival analysis was conducted using Kaplan-Meier methods. Results: 78 patients with stage I disease were identified (see Table). Among stage IC1 patients, 9 received adjuvant therapy despite provincial policy, 6 of which were due to sharp dissection. 40 patients with stages IA/B and IC1, who underwent post-operative observation, were included in the analysis. Median duration of follow-up was 36 months. Median age at diagnosis was 55 years and >50% patients had a Charlson Comorbidity Index of 0 (N= 26) and an Eastern Cooperative Oncology Group performance status of 0 (N=28) prior to diagnosis. Lymph node dissection was not performed in 20 patients. All 16 cases tested immunohistochemically for mismatch repair were intact, and 2 of 6 cases with tumour genomic sequencing had an AURKA aberration. There were 4 recurrences (10%), 3 of which were metastatic. 5-year disease-free survival is 90%, and 5-year overall survival is 95% for stage IA/B and 90% for stage IC1 (p=0.645). In comparison, 5-year overall survival for stage IC2 (surface involvement) and IC1 with sharp dissection (all received chemotherapy) is 82% and for stage IC3 (positive washings) is 23% (p<0.001). Conclusions: Outcomes of patients with stage I A/B and C1 CCOC remain excellent. Adjuvant therapy can be safely omitted, with low recurrence rates and survival over 90% at 5 years. Consideration of disease substage is valuable in predicting the clinical outcomes of stage I CCOC. [Table: see text]
First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors.
Authors: Shimizu Toshio , Fujiwara Yutaka , Yonemori Kan , Koyama Takafumi , Shimomura Akihiko , Tamura Kenji , Iwasa Satoru , Sato Jun , Kitano Shigehisa , Ikezawa Hiroki , Nomoto Maiko , Nakajima Ryo , Miura Takuma , Yamamoto Noboru 
Published: May 2019

5544 Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). We report preliminary results from a FIH Ph1 study of MORAb-202 in pts with FRA-positive solid tumors. Methods: This open-label, ongoing, FIH study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and/or the recommended dose of MORAb-202 (Part 1: Dose finding part with accelerated modified toxicity probability interval design; Part 2: Expansion part). Eligible pts had FRA-positive solid tumors who failed standard therapy and an ECOG PS of ≤1. MORAb-202 was administered by intravenous injection once every 3 weeks and dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle. Efficacy endpoints were assessed with RECIST v1.1 by investigator assessment. Results: As of Nov 16, 2018, 16 pts with confirmed FRA-positive tumors were enrolled and treated with MORAb-202 across 4 dose levels in Part 1 (0.3mg/kg: n = 3 [2 endometrial and 1 ovarian], 0.45mg/kg: n = 3 [3 ovarian], 0.68mg/kg: n = 3 [1 NSCLC, 1 ovarian, and 1 TNBC], 0.9mg/kg: n = 7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC]); all completed > 1 cycle. One pt in the 0.9mg/kg cohort experienced DLTs of alanine aminotransferase increased (grade 3) and gamma-glutamyl transferase increased (grade 3). Treatment-emergent adverse events (TEAEs) occurred in 15 pts (93.8%). The most common TEAEs were leukopenia and neutropenia (50% each). The objective response rate based on RECIST v1.1 was 37.5% (6/16 pts) in Part 1 with 1 complete response (ovarian) at 0.9mg/kg and 5 partial responses including 2 pts (both ovarian) at 0.9mg/kg, 1 pt (endometrial) at 0.3mg/kg, and 2 pts (1 TNBC and 1 NSCLC) at 0.68mg/kg. The disease control rate was 75% (12/16 pts). Exposure to MORAb-202 was dose proportional across the dose range investigated. Conclusions: MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942.
Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment.
Authors: Westin Shannon Neville , Louie-Gao Melinda , Badamgarav Enkhe , Bala Mohan V. , Thaker Premal H. 
Published: May 2019

5548 Background: Limited real-world information is available in ovarian cancer (OC) regarding prognostic factors for disease progression or death after initial treatment. Here, we assessed potential prognostic risk factors in OC patients (pts) who completed first-line (1L) platinum-based chemotherapy (CT) using real-world data. Methods: This retrospective study identified 5535 pts diagnosed with OC from January 2011–October 2018 from the Flatiron database, a longitudinal, demographically and geographically diverse database derived from health records from > 265 cancer clinics and > 2 million US cancer pts. Stage III/IV OC pts who completed 1L platinum-based CT after primary debulking or interval debulking surgery were included. Pts who received a poly(ADP-ribose) polymerase inhibitor (PARPi) in 1L treatment or as maintenance therapy after 1L treatment were excluded. Cox proportional hazards model was used to assess the association between baseline factors (neoadjuvant CT, disease stage, residual disease, BRCA status, ECOG, age, platelet count, hemoglobin, and neutrophil count) and time to next treatment (TTNT; a proxy for progression-free survival) or overall survival (OS) in these pts. Results: 1064 of 5535 pts were eligible per our inclusion/exclusion criteria. Neoadjuvant treatment, stage of disease, residual disease after surgery, and BRCA mutation ( BRCAmut) status were significant prognostic factors for either TTNT or OS. Neoadjuvant chemotherapy pts had a shorter TTNT (hazard ration [HR] = 1.37; P= .001) and OS (HR = 1.64; P= .0002) than pts who underwent primary surgery after adjusting for other covariates. Stage IV pts had a shorter TTNT (HR = 1.26; P= .01) and OS (HR = 1.24; P= .09) than stage III pts. OS was also worse in pts with vs without residual disease (HR = 1.27; P= .04) and worse in BRCAwt than BRCAmut pts (HR = 1.37; P= .10). Conclusions: In this retrospective analysis of a real-world data set, BRCAwt status was associated with higher risk of death. Receipt of neoadjuvant CT, higher stage of disease at diagnosis, or presence of residual disease after surgery were also associated with a shorter TTNT or higher risk of death. These real-world data confirm previously identified prognostic factors.
Delays from neoadjuvant chemotherapy to interval debulking surgery and survival in ovarian cancer.
Authors: Liu Ying L , Zhou Qin , Iasonos Alexia , Filippova Olga T. , Chi Dennis , Zivanovic Oliver , Sonoda Yukio , Gardner Ginger J. , Broach Vance , O'Cearbhaill Roisin Eilish , Konner Jason A. , Aghajanian Carol , Long-Roche Kara C. , Tew William P. 
Published: May 2019

5552 Background: Prolonged time from primary surgery to chemotherapy is associated with worse survival in ovarian cancer (OC); however, the impact of prolonged time from neoadjuvant chemotherapy (NACT) to interval debulking surgery (IDS) is unknown. Given increasing utilization of NACT, we seek to evaluate the role of delays from NACT to IDS (TIDS) on survival. Methods: At a single center, we prospectively identified 224 women with newly diagnosed stage III/IV OC given NACT from 7/1/15 to 12/1/17. Clinical characteristics were abstracted by two independent reviewers. Delays in TIDS were defined as time from last preoperative carboplatin to IDS > 6 weeks. Fisher’s exact/Wilcoxon rank sum tests were used to compare clinical characteristics by delay in TIDS. Kaplan Meier method was used to estimate progression-free (PFS) and overall survival (OS) from date of IDS. Log-rank test/multivariate CoxPH models were used to examine differences by delay groups, adjusting for covariates. Results: Of the 224 women, 159 underwent IDS, and 34 (21%) experienced TIDS delays. These women were older (median 68 vs. 65 years, p = 0.05) and had more preoperative NACT cycles (median 6 vs. 4, p = 0.003). Patients with delays in TIDS also had a longer interval from pathological diagnosis to start of NACT (TNACT), median 22 vs. 17 days, p = 0.01, and interval from IDS to postoperative chemotherapy (TPOC), median 37 vs. 30 days, p = 0.01; however, neither TNACT nor TPOC predicted survival, p > 0.05. On univariate analysis, delays in TIDS were significantly associated with worse OS (HR 2.4 95% CI 1.2-4.8, p = 0.01); however, this was attenuated in multivariate models (HR 1.66 95% CI 0.8-3.4, p = 0.17), adjusting for age, stage and complete gross resection (CGR). On univariate analysis, delays in TIDS were not associated with PFS (HR 1.55 95% CI 0.97-2.5, p = 0.062), and in multivariate models, increase in number of preoperative NACT cycles (p = 0.005) and lack of CGR (p < 0.001) were the only variables predictive of worse PFS. Conclusions: Delays in TIDS are associated with OS, but not after adjustment for age, stage and CGR, suggesting a need to maximize cytoreduction regardless of delays in NACT. The role of preoperative NACT cycles on survival should be further studied.
Comprehensive genomic analysis of mucinous ovarian cancer reveals unique therapeutic vulnerabilities.
Authors: Cheasley Dane Anthony 
Published: May 2019

5571 Background: Mucinous ovarian carcinoma (MOC) is a rare subtype of epithelial ovarian cancer that responds poorly to ovarian chemotherapies and has an unknown etiology. It is diagnostically challenging and can be confused with metastases from gastro-intestinal tract primaries. The GAMuT study is a multi-national effort to understand molecular drivers and cell of origin of this rare tumour, including identification of a genetic progression model and novel therapeutic options. Methods: We performed RNAseq (n = 67), exome sequencing (n = 61), SNP arrays (n = 67) and whole genome sequencing (n = 5) on MOC and precursor lesions. A subset of ~500 genes was further evaluated by targeted sequencing, including 129 MOC, 23 borderline mucinous tumours (non-invasive) and 23 extra-ovarian mucinous metastases. Immunohistochemistry data was collected for CK7, CK20, ER, PAX8, p53 and HER2 (n = 162-256). Extensive pathology review was performed and associated clinical data obtained. Results: Comparison with TCGA and other data sets showed that MOC are distinct from mucinous tumours from other organs, including colorectal, appendiceal and gastric cancers. Our data supports a clear genetic progression model from benign and borderline precursors to both low- and high-grade MOC. TP53 mutation, ERBB2 amplification and increasing copy number changes were key events associated with progression to invasive disease, including a novel amplicon on 9p13. Copy number aberration burden was significantly associated with poor survival. We identified several recurrent mutational events suggesting utility of an existing targeted therapy, including ERBB2 amplification (26%), ERBB3 mutation (4%) and BRAF mutation (9%). MOC could be included in clinical trials for novel agents targeting TP53 missense mutation (46%), RNF43 mutation (12%), PIK3CA mutation (8%) and KRAS/ NRAS mutations (66%). Other frequent events included CDKN2A inactivation (57%), ARID1A mutation (9%) and TP53 inactivating mutations (15%). Conclusions: MOC of any grade can derive from a primary ovarian tumour precursor, and is distinct from extra-ovarian metastases. MOC is genetically diverse and advanced disease should be assessed for targetable mutations which may provide novel therapeutic options.
BRCA tumor test in ovarian cancers: The changing role of molecular pathology in the era of PARP inhibitor (PARPi) therapy.
Authors: Fumagalli Caterina , Guerini Rocco Elena , Tomao Federica , Betella Ilaria , Rappa Alessandra , Viale Giuseppe , Peccatori Fedro , Colombo Nicoletta , Barberis Massimo 
Published: May 2019

5572 Background: The PARPi Olaparib has been approved in maintenance setting of recurrent platinum-sensitive and BRCA mutated, ovarian cancer (OC) patients. However, according to the striking results of SOLO 1 trial, it could be shortly proposed even to newly diagnosed BRCA mutated OC women. We report the results of the implementation of tumor BRCA test in diagnostic setting within the frame of institutional workflow for the management of OC patients. Methods: 223 women with OC were consecutively referred over 25 months to tumor BRCA test. The test was requested by gynecologic oncologist at the diagnosis of non-mucinous and non-borderline OC, upon discussion on the implications of the test result and written consent collected for each patient. Formalin-fixed paraffin embedded (FFPE) specimens of OC were tested using the automatized “Oncomine BRCA Research Assay” Next Generation Sequencing (NGS) panel. The tumor BRCA test was also performed on 5 archetypal cytological samples from ascites. Results: All the cases were considered adequate for the NGS analysis according to the tumor cell content (more than 10%) and the DNA yield extracted (more than 10 ng). The tumor BRCA test had a successful rate of 99.1% . The median Turn-Around Time (TAT) was 17 calendar days, from 33 days of the first trimester to 14 days of the last trimester of this analysis. Overall BRCA1 or BRCA2 pathogenic (P)/likely pathogenic (LP) mutations were found in 62 (28.1%) cases and variants of uncertain significance (VUS) in 25 (11.3%) cases, including 3 cases with a BRCA1 P variant and a concurrent BRCA2 VUS alteration. In detail, 47 P/LP variants and 16 VUS were identified in BRCA1 whereas 15 P/LP mutations and 9 VUS occurred in BRCA2. Complete concordance in tumor BRCA test results were seen between ascites cytological samples and matched tumors. Conclusions: The tumor BRCA test could be implemented in routine diagnostic setting, at diagnosis of non-mucinous and non-borderline OC. The test could be performed on FFPE specimens, had an high successful rate and a TAT compatible with clinical needs. The promising data on cytological samples will be confirmed in larger series.
Real-world bevacizumab utilization and outcomes in first-line ovarian cancer.
Authors: Monberg Matthew J. , Hall Jennifer P , Moon Rebecca , Higson Olivia , McLaurin Kimmie , Dalvi Tapashi 
Published: May 2019

5578 Background: Bevacizumab (B) is approved in combination with carboplatin and paclitaxel, followed by B monotherapy, for the treatment of advanced ovarian cancer (OC) following surgery. We sought to describe B utilization and outcomes of B in first-line (1L) OC within the US and EU. Methods: This cross-sectional study included patients who were actively receiving treatment for OC. Data were collected at a single time point from 2496 patient forms between December 2017 and March 2018 from 340 oncologists/ gynecologists across the US, France, Germany, Italy, Spain, and the UK. Patients were platinum sensitive if progression was noted > 6 months after frontline platinum therapy and resistant if the interval was 0-6 months. This analysis included patients who received 1L chemotherapy (chemo) with no maintenance or 1L chemo with bevacizumab maintenance. Results: B was used in combination with chemo at 1L and as 1L maintenance monotherapy in 11% total study patients. Those receiving 1L + B were more likely to have Stage IV disease, have good performance status (PS) at diagnosis, and receive BRCA testing than patients receiving chemo only. Treatment response, platinum sensitivity, and activities of daily living are shown in the Table. Results did not vary by BRCA status. Conclusions: This study highlights differences in patient characteristics and outcomes between patients receiving/ who received 1L chemo only and those receiving/ who received B, however, this study was not designed to formally compare 1L treatment options. [Table: see text]
Lynch-like syndrome in endometrial cancer: Features of a growing population.
Authors: Gordhandas Sushmita , Kahn Ryan , Maddy Brandon Paul , Baltich Nelson Becky , Askin Gulce , Christos Paul J. , Holcomb Kevin , Caputo Thomas A. , Chapman-Davis Eloise , Frey Melissa Kristen 
Published: May 2019

5585 Background: Current guidelines recommend screening all endometrial cancers (EC) and colorectal cancers (CRC) for defects in DNA mismatch repair (MMR). Tumor screening combined with germline genetic testing can categorize patients into three groups: intact-MMR, Lynch syndrome (LS), and Lynch-like syndrome (LLS). Our objective was to describe features of the growing population of patients with LLS in EC and compare to existing CRC literature. Methods: A systematic search of databases between 1990-2018 identified studies of EC patients with tumor testing (MMR immunohistochemistry or microsatellite instability) and germline assessment for LS. Data on clinicopathologic features was abstracted when available. Associations between LS, LLS, and intact-MMR were analyzed using descriptive statistics. Results: The comprehensive search produced 3,427 publications; 29 met inclusion criteria. Abstracted data and features of each group are presented in the table. Conclusions: In EC, LLS closely resembles LS with younger age at diagnosis, more advanced stage and higher grade as compared to patients with intact-MMR. LLS in EC is similar to intact-MMR in regard to histology, and family history of LS-associated cancer. The CRC literature is limited, but reports LS and LLS have similar stage, grade and histology. In CRC, LS and LLS are diagnosed at a younger age, and are more likely to have family history of LS-associated cancers than intact-MMR. Features of EC with intact-MMR, LLS, and LS. [Table: see text]
Genomic biomarkers of recurrence in low-grade, early-stage endometrial adenocarcinoma.
Authors: Hwang Katie Lee , Hwang William L. , Howitt Brooke E. , King Martin T. , Stover Elizabeth , Matulonis Ursula A. , Lee Larissa Janeen 
Published: May 2019

5588 Background: Endometrial cancer is the most common gynecologic malignancy in developed countries with over 60,000 new cases diagnosed in the United States each year. Adjuvant therapy is often omitted for low-risk, early-stage disease (FIGO stage IA, grade 1) but 1 in 20 women suffer recurrence after surgery alone. Hence, there is an important need for biomarkers of recurrence in this population to guide therapeutic management. Methods: We retrospectively analyzed 74 patients with FIGO stage 1A, grade 1 endometrial endometrioid adenocarcinoma treated at our institution with hysterectomy alone between 2009-2016. All patients had targeted genomic assessment of their tumors (OncoPanel; somatic mutations, copy number variations and structural variants across 300 cancer genes). The primary outcome of interest was freedom from recurrence (FFR). Outcomes were compared by the logrank test and survival estimates calculated by Kaplan-Meier method. Results: We identified 14 patients who recurred at a median time of 23.6 months after surgery and 60 patients without recurrence at a median follow-up of 38.9 months. Age (median 57 years; log-rank p = 0.91) and BMI (median 31 kg/m2; log-rank p = 0.21) were not associated with risk of recurrence. The median somatic mutation count in the cohort was 8. Patients with more than 8 somatic mutations had a significantly higher risk of recurrence (3-year FFR: 74% vs 90%; log-rank p = 0.004). At the level of individual genes, there were four genes that were significantly associated with recurrence: CTNNB1 (p = 0.046), RHPN2 (p = 0.020), SF1 (p = 0.044), SQSTM1 (p = 0.034). Patients with a mutation in one or more of these four genes had a significantly higher risk of recurrence (3-year FFR: 62% vs 93%; log-rank p = 0.0004). Conclusions: We have identified overall somatic mutation burden and mutations in a subset of four genes ( CTNNB1, RHPN2, SF1, SQSTM1) as determined by a validated 300-gene panel used in routine clinical practice as prognostic biomarkers for patients with low-risk, early-stage endometrial endometrioid adenocarcinoma. These patients may benefit from the addition of adjuvant therapy. Validation with larger cohorts and prospective studies is warranted.