bluuebunny/crossref_metadata_2025_split huggingface dataset:
Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent Francois , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline 
Published: February 2017

LBA4510 Background: Radiotherapy (RT) and long-term androgen deprivation therapy (ADT) is a standard treatment for patients with high-risk prostate cancer. However, the optimal duration of ADT is not yet defined. The purpose of this randomized trial was to compare outcomes between 36 and 18 months of ADT in high-risk prostate cancer treated with RT (PCS IV trial). Methods: PCS IV randomized patients with node-negative high-risk prostate cancer (T3-4, PSA >20 ng/ml or Gleason score >7), to pelvic RT (whole pelvis 44 Gy/4 ½ weeks, prostate 70 Gy/7 weeks) and 36 (arm 1) vs 18 months (arm 2) of ADT (neo- adjuvant, concomitant, adjuvant). ADT consisted of bicalutamide 50 mg for one month and goserelin 10.8 mg every three months for 36 vs 18 months. Overall survival was the primary end point. From randomization, overall and cancer-specific survival rates were compared between arms with Kaplan-Meier log rank test and Cox regression. Results: From October 2000 to January 2008, 310 patients were randomized to arm 1 and 320 to arm 2. Patients' characteristics were well balanced between the two arms (median age 71 years, median PSA 16 ng/ml, median Gleason score 8). Most patients had T2-T3 disease. At a median follow-up of 78 months, 80/310 patients (25.8%) in arm 1 and 85/320 (26.6%) in arm 2 had died (p=0.829). 113 patients died of causes other than prostate cancer. Overall and cancer-specific survival hazard ratios were 1.15 (0.85-1.56), p=0.366 and 1.07 (0.62-1.84), p=0.819, respectively. 5-year overall and disease-specific survival rates were 91.1% (87.9-94.3) vs. 86.1% (82.3-90.0), p=0.06 and 96.6% (94.5-98.7) vs. 95.3% (92.8-97.7), p=0.427 and 10-year overall and disease-specific survival rates were 61.9% (54.1-69.7) vs. 58.6% (49.8-67.4), p=0.275 and 84.1% (77.6-90.6) vs. 83.7% (76.3-91.1), p=0.819 for arm 1 and arm 2, respectively. There were no significant differences in the rates of biochemical, regional, or distant failure between arms. Conclusions: With a median follow-up of 6.5 years, our study shows that long-term ADT can be safely reduced from 36 to 18 months without compromising outcomes. Analysis of treatment impact on quality of life is now under review. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: #NCT00223171.
Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2.
Authors: Hortobagyi Gabriel N. , Piccart-Gebhart Martine J. , Rugo Hope S. , Burris Howard A. , Campone Mario , Noguchi Shinzaburo , Perez Alejandra T. , Deleu Ines , Shtivelband Mikhail , Provencher Louise , Masuda Norikazu , Dakhil Shaker R. , Anderson Ian , Chen David , Damask Amy , Huang Alan , McDonald Robert , Taran Tanya , Sahmoud Tarek , Baselga José 
Published: February 2017

LBA509 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated. Clinical trial information: NCT00863655.
Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): Results of an international Intergroup trial (AGO-OVAR16).
Authors: Du Bois Andreas , Floquet Anne , Kim Jae Weon , Rau Jörn , Del Campo Jose Maria , Friedlander Michael , Pignata Sandro , Fujiwara Keiichi , Vergote Ignace , Colombo Nicoletta , Mirza Mansoor Raza , Monk Bradley J. , Wimberger Pauline , Ray-Coquard Isabelle , Zang Rongyu , Diaz-Padilla Ivan , Baumann Klaus H. , Kim Jae Hoon , Harter Philipp ,   on behalf of an Intergroup consortium
Published: February 2017

LBA5503 Background: Pazopanib is an oral, multikinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β, and c-Kit. Preclinical and clinical studies support VEGF(R) and PDGF(R) as targets for AEOC treatment. This study evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients who have not progressed after first-line chemotherapy for AEOC. Methods: Patients with histologically confirmed AEOC, FIGO II-IV, and no evidence of progression after surgery and ≥ 5 cycles of platinum-taxane chemotherapy were randomized 1:1 to receive 800 mg pazopanib once daily or placebo for up to 24 months. Primary endpoint was progression-free survival (PFS) by RECIST. Secondary endpoints included overall survival, PFS by GCIG criteria, safety, and quality of life. Results: Most of the 940 randomized patients had stage III/IV disease (91%) at initial diagnosis, and no residual disease after surgery (58%). The median time from diagnosis to randomization was 7.1 months in the placebo arm and 7.0 months in the pazopanib arm. The median follow-up was 24 months. Patients in the pazopanib arm had a prolonged PFS vs placebo (HR = 0.766; 95% CI: 0.64-0.91; p = 0.0021; medians 17.9 vs 12.3 months, respectively). Sensitivity and subgroup analyses of PFS, and analysis of PFS by GCIG criteria, were consistent with the primary analysis. The first interim analysis for OS (only 189 OS events = 20.1% of population) showed no difference between arms. Pazopanib mean exposure was shorter vs placebo (8.9 vs 11.7 months). Pazopanib treatment was associated with a higher incidence of adverse events (AEs) and serious AEs (26% vs 11%) vs placebo. The most common AEs were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia. Fatal SAEs were reported in three patients on pazopanib and one patient on placebo. Conclusions: Pazopanib maintenance therapy provided a statistically significant and clinically meaningful PFS benefit in patients with AEOC; OS data are not mature. The safety profile of pazopanib in this setting was consistent with its established profile. Clinical trial information: NCT00866697.
Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Preplanned interim results for the AVAST-M trial.
Authors: Corrie Philippa , Marshall Andrea , Goonewardena Madusha , Dunn Janet A. , Middleton Mark R. , Nathan Paul D. , Gore Martin Eric , Davidson Neville , Nicholson Steve , Kelly Charles G. , Marples Maria , Danson Sarah , Marshall Ernest , Houston Stephen , Board Ruth E. , Waterston Ashita Marie , Nobes Jenny , Harries Mark , Barber Jim , Lorigan Paul 
Published: February 2017

LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. Methods: AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality of life (QoL). An associated translational study is ongoing. Results of the first pre-planned interim analysis (agreed by the IDSMC) are reported here. Results: Between July 2007 and March 2012, 1,343 pts were recruited. 56% were male; median age 56 years (range 18-88 years), 16% were stage IIB, 11% IIC, 15% IIIA, 36% IIIB, 20% IIIC, and 2% unknown stage. Ulceration status of the primary melanoma was: 38% present, 45% absent, 17% unknown. At the time of the interim analysis, 286 (21%) patients had died. Median follow-up for survival was 25 months. Median duration of Bev treatment in 671 treated pts was 51 weeks (dose intensity 86%). Main outcomes are shown in the table. Grade 3/4 adverse events were experienced in 101 (15%) Bev pts and 36 (5%) Obs pts. Conclusions: Interim analysis of this large, multicenter trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev monotherapy is well tolerated and improved DFI. Longer follow-up is required to determine an impact on the primary endpoint of 5-year OS. Clinical trial information: 81261306. [Table: see text]
OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma.
Authors: Andtbacka Robert Hans Ingemar , Collichio Frances A. , Amatruda Thomas , Senzer Neil N. , Chesney Jason , Delman Keith A. , Spitler Lynn E. , Puzanov Igor , Doleman Susan , Ye Yining , Vanderwalde Ari M. , Coffin Robert , Kaufman Howard 
Published: February 2017

LBA9008 Background: T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM is a randomized, phase III trial of T-VEC or GM-CSF in patients (pts) with unresected melanoma with regional or distant metastases. We report the primary results of the first phase III study of OI. Methods: Key criteria: age ≥18 yrs; ECOG ≤1; unresectable melanoma stage IIIB/C or IV; injectable cutaneous, SC, or nodal lesions; LDH ≤1.5X upper limit of normal; ≤3 visceral lesions (excluding lung), none >3 cm. Pts were randomized 2:1 to intralesional T-VEC (initially ≤ 4 mL x106 pfu/mL then after 3 wks, ≤ 4 mL x108 pfu/mL Q2W) or SC GM-CSF (125 µg/m2qd x 14 days q28d). The primary endpoint was durable response rate (DRR): partial or complete response (CR) continuously for ≥6 mos starting within 12 mos. Responses were per modified WHO by blinded central review. A planned interim analysis of overall survival (OS; key secondary endpoint) was performed. Results: 436 pts are in the ITT set: 295 (68%) T-VEC, 141 (32%) GM-CSF. 57% were men; median age was 63 yrs. Stage distribution was: IIIB/C 30%, IVM1a 27%, IVM1b 21%, IVM1c 22%. Objective response rate with T-VEC was 26% (95% CI: 21%, 32%) with 11% CR, and with GM-CSF was 6% (95% CI: 2%, 10%) with 1% CR. DRR for T-VEC was 16% (95% CI: 12%, 21%) and 2% for GM-CSF (95% CI: 0%, 5%), p<0.0001. DRR by stage (T-VEC, GM-CSF) was IIIB/C (33%, 0%), M1a (16%, 2%), M1b (3%, 4%), and M1c (8%, 3%). Interim OS showed a trend in favor of T-VEC; HR 0.79 (95% CI: 0.61, 1.02). Most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. Serious AEs occurred in 26% of T-VEC and 13% of GM-CSF pts. No ≥ grade 3 AE occurred in ≥ 3% of pts in either arm. Conclusions: T-VEC demonstrated both a statistically significant improvement in DRR over GM-CSF in pts with unresectable stage IIIB-IV melanoma and a tolerable safety profile; an interim analysis showed a trend toward improved OS. T-VEC represents a novel potential tx option for melanoma with regional or distant metastases. Clinical trial information: NCT00769704.
L-Dex ratio in detecting and diagnosing breast cancer-related lymphedema: Reliability, sensitivity, and specificity.
Authors: Fu Mei R. , Cleland Charles M. , Guth Amber Azniv , Kayal Maia , Haber Judith , Cartwright Francis , Kleinman Robin , Kang Yang , Scagliola Joan , Axelrod Deborah M. 
Published: February 2017

12 Background: It remains a great challenge to accurately diagnose breast cancer-related lymphedema. Advances in bioelectrical impedance analysis (BIA) permit the assessment of lymphedema by directly measuring lymph fluid changes. Despite its value in assessing lymphedema, the use of BIA in clinical settings is still very limited. In part, this may be due to anecdotal complaints from clinicians about BIA’s ability to identify true case of lymphedema in the clinical settings using L-Dex ratio >+10 as the cutoff point for lymphedema diagnosis. This may also be due to lack of large clinical data to support the reliability, sensitivity, and specificity of using L-Dex ratio. The objective of the study was to examine the reliability, sensitivity, and specificity of BIA in a clinical setting. Methods: BIA was used to measure lymph fluid changes. Data were collected from 250 women, including healthy female adults, breast cancer survivors with lymphedema, and those at risk for lymphedema. Reliability, sensitivity, specificity and area under the ROC curve were estimated. Results: BIA ratio, as indicated by L-Dex ratio, was highly reliable among healthy women (ICC=0.99; 95% CI = 0.99 - 0.99), survivors at-risk for lymphedema (ICC=0.99; 95% CI = 0.99 - 0.99), and all women (ICC=0.85; 95% CI = 0.81 – 0.87); reliability was acceptable for survivors with lymphedema (ICC=0.69; 95% CI = 0.54 to 0.80). The L-Dex ratio with a diagnostic cutoff of >+7.1 discriminated between at-risk breast cancer survivors and those with lymphedema with 80% sensitivity and 90% specificity (AUC=0.86). Conclusions: The L-Dex ratio may have a role in clinical practice despite its cost to add confidence in the diagnosis of arm lymphedema among breast cancer survivors. Lymphedema is a progressive and debilitating condition and early treatment usually leads to better clinical outcomes, given that BIA using a diagnostic cutoff of L-Dex ratio > +7.1 still misses 20% of true lymphedema cases, it is important for clinicians to integrate other assessment methods (such as self-report, clinical observation, or perometry) to ensure the accurate diagnosis of lymphedema.
National survey of breast cancer screening in rural America.
Authors: Peppercorn Jeffrey M. , Houck Kevin , Wogu Adane Fekadu , Villagra Victor , Lyman Gary H. , Wheeler Stephanie B. 
Published: February 2017

13 Background: Screening mammography leads to early detection of breast cancer and improved survival. We conducted a survey of predominantly rural U.S. women who receive health insurance through the National Rural Electric Cooperative Association (NRECA) to evaluate the prevalence of annual and biennial screening and to identify potential disparities and barriers to breast cancer screening. Methods: We conducted a national cross-sectional survey of women between ages 40 and 65 who are insured by the NRECA regarding their utilization of mammography screening and barriers to screening. A study specific survey was mailed to 2,000 randomly selected eligible women without prior diagnosis of breast cancer. We assessed demographics and receipt of mammography within past 12 months (all women) and number of screening mammograms within the past 4 years (among women age 44 and older) to identify consistent annual screening and biennial screening patterns. Results: 1,204 women responded to the survey (response rate 60.2%). 74% live in rural areas, 18% suburban, 8% urban. 73% report less than 4 years college education and 19% have family incomes < $50,000/year. Overall, 72% reported screening mammography within 12 months, 59% reported consistent annual screening and 84% reported at least biennial screening. Rural women were less likely to undergo consistent annual (56% vs. 66%, p = 0.003) or biennial screening (82% vs. 89%, p = 0.01) compared to women in non-rural areas. Women under 50 were less likely to report screening within 12 months (67% vs. 77%, p = 0.0002), consistent annual (49% vs. 63%, p < 0.0001) or biennial screening (79% vs. 86%, p = 0.002). Significantly more rural women cited cost and distance as barriers, while busy schedule, fear of diagnosis, and fear of discomfort were important barriers among all demographic groups. Fear of the test was a greater barrier among younger vs. older women (p < 0.02). In univariate analysis; household income did not correlate with screening, and education was only a factor among younger women. Conclusions: A substantial percentage of rural U.S. women fail to undergo screening mammography. Potentially modifiable barriers include out of pocket expenses, convenience of screening, and fear of diagnosis and the test itself.
BRCA-1 promotor methylation as predictor of benefit from adjuvant CMF in triple-negative breast cancer not responsive to taxane-based neoadjuvant chemotherapy.
Authors: Bartsch Rupert , Födermayr Mathilde , Sebesta Miriam , Rudas Margaretha , Berghoff Anna Sophie , Promberger Regina , Preusser Matthias , Dubsky Peter Christian , Fitzal Florian , Gnant Michael , Weltermann Ansgar , Zielinski Christoph , Steger Guenther G. , Zach Otto 
Published: February 2017

148 Background: Triple-negative breast cancer (TNBC) patients (pts) without pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) have an unfavourable prognosis. ABCSG trials 14 and 24 defined 6 cycles of epirubicin/docetaxel (+/- capecitabine) as active NAC regimen; pts without pCR commonly received another 4-8 cycles of adjuvant CMF. Different studies suggested that breast tumours harbouring BRCA-1 germline mutations were resistant to taxane-based therapy while sensitivity to DNA-damaging agents was retained. BRCA-1 mutations are rare in sporadic BC; BRCA-1 promotor methylation (PM), however, is frequently observed. We hypothesized that pts with TNBC harbouring BRCA1 PM would benefit from adjuvant CMF salvage therapy. Methods: For this analysis, we included all pts with TNBC refractory to taxane-based NAC who received adjuvant CMF. DNA was extracted from formalin-fixed paraffin-embedded tissue samples, purified and bisulfite-converted. The TaqMan assay was used in order to perform a quantitative methylation-specific PCR. Actin-b was used as reference gene to normalise the amount of provided DNA; bisulfite-converted, artificially methylated DNA was used as positive control. Results: Twenty-four pts, median age 47 years, were available for this analysis. In 9/24 pts (37.5%), BRCA-1 PM was detected. At a median follow-up of 27.5 months, 1/9 pts (11.1%) with BRCA-1 PM had a disease-free survival (DFS) event, as compared to 10/15 (66.6%) in the non-methylated group (p = 0.013; Fisher’s exact test). Kaplan Meier estimation of DFS in the non-methylated group was 24 months (95% CI 14.06-33.94) and was not reached in the methylated group (n.s.). Conclusions: In TNBC refractory to taxane-based NAC, adjuvant CMF is of limited efficacy. In tumours harbouring BRCA-1 PM, however, a significant decrease of DFS events was observed. Therefore, tumours harbouring defects in genetic repair mechanism might be exceptionally sensitive to drugs causing DNA-damage. Further clinical investigation of this concept is warranted.
A phase I pharmacokinetics trial comparing PF-05280014 (a potential biosimilar) and trastuzumab in healthy volunteers (REFLECTIONS B327-01).
Authors: Yin Donghua , Barker Kerry B. , Li Ruifeng , Meng Xu , Reich Steven D. , Ricart Alejandro D. , Rudin Dan , Taylor Carrie T. , Zacharchuk Charles M. , Hansson Arne G. 
Published: February 2017

171 Background: PF-05280014, a proposed biosimilar to trastuzumab, has an identical amino acid sequence and similar physicochemical and in vitro functional properties to trastuzumab. This study was designed to demonstrate PK similarity of PF-05280014 to trastuzumab from the US (trastuzumab-US) and EU (trastuzumab-EU), and between the licensed drugs. Safety and immunogenicity were also evaluated. Methods: In this double-blind trial (NCT01603264), 105 healthy male volunteers, 18-55 years old were randomized 1:1:1 to receive a single 6 mg/kg IV dose of PF-05280014, trastuzumab-US or trastuzumab-EU. All subjects provided informed consent. PK, safety and immunogenicity assessments were conducted for 70 days. PK similarity for a given test-to-reference comparison was considered to be demonstrated if the 90% CI of the test-to-reference ratio of the AUC from time 0 to the last time point (AUCT) and maximum concentration (Cmax) were within 80% – 125%. Results: The baseline demographics for the 101 subjects evaluable for PK were similar among 3 treatment arms. The 3 study drugs exhibited similar characteristics of target-mediated disposition and similar PK parameters (Table). The 90% CI for the ratios of Cmax, AUCT, and AUC0-∞were within 80% – 125% for the comparisons of PF-05280014 to trastuzumab-EU or trastuzumab-US, and trastuzumab-EU to trastuzumab-US. Adverse events (AE) were similar for the 3 arms with treatment-related AEs reported by 71.4%, 68.6%, and 65.7% subjects in the PF-05280014, trastuzumab-EU and trastuzumab-US, respectively. No serious AEs were reported. Only 4 subjects had treatment interruptions; 2 discontinued. Only 1 subject (trastuzumab-EU) developed anti-drug antibodies after dosing. Conclusions: This study demonstrates PK similarity of PF-05280014 to both trastuzumab-US and trastuzumab-EU and of trastuzumab-EU to trastuzumab-US. The 3 study drugs also showed similar safety profiles. Clinical trial information: NCT01603264. [Table: see text]