bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the quality of reporting surgical procedures in patients undergoing resection for primary gastrointestinal stromal tumors: A reporting tool derived from the EORTC–STBSG 62024 trial.
Authors: Hohenberger Peter , Rutkowski Piotr , Bonvalot Sylvie , van Coevorden Frits , Stoeckle Eberhard , Olungu Christine , Ouali Monia , Casali Paolo Giovanni , Gronchi Alessandro 
Published: March 2020

10096 Background: Features of surgery for the primary tumor (rupture, extent and completeness of resection) contribute significantly on the indication for adjuvant treatment in patients with GIST. No reporting tool for surgery for a primary GIST has been established. EORTC 62024 is a phase III trial evaluating the use of adjuvant imatinib in GIST and was used for an analysis of the data of surgical procedures. Methods: 908 pts. from 11 countries were recruited. At study entry, a copy of the surgical record and pathology report had to be submitted in addition to the case record forms (CRFs) which included a surgical questionnaire on 19 items on the circumstances of the resection (elective/emergency, GIST diagnosis established preop., tumor rupture, R-status, concordance of preop. and intraop. staging, surgical technique, complications). We then reviewed the original documents and compared them with the documentation on the CRFs. The full set of data was available from 793/906 patients (87.3%). Results: The diagnosis of GIST was known preop. in 58% of the cases, and 12% of the pts. had been treated as an emergency. The R0 resection rate was 87%. The incidence of tumor rupture was 9% and 24% of the pts. had undergone lymphadenectomy. The consistency between pre- and intraoperative findings was 82%. The concordance between CRFs and original documents was 77%. Concordance of the original documents with the surgical questionnaire (CRFs) was critical in 4/19 items. Discrepancies and misinterpretation rates were highest when data managers from medical oncologists had completed the CRFs based on letters of patient discharge. Based on the evaluation, the surgical reporting tool can be refined and shortened to 13 items for future applications. Conclusions: Findings at surgery for the primary tumor not properly reported might significantly influence the decision of whether or not to treat patients with adjuvant imatinib. The refined surgical reporting tool could be helpful to gather all relevant information about the intraoperative elements of surgery for the primary GIST. Surgeons are to be asked to report those data themselves.
ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial.
Authors: Somlo George , Sparano Joseph A. , Cigler Tessa , Fleming Gini F. , Luu Thehang H. , Hurria Arti , Mortimer Joanne E. , Frankel Paul Henry , Chew Helen K. , Nanda Rita , Ma Cynthia X. , Chen Alice P. , Garcia Agustin , Vahdat Linda T. , Gandara David R. , Weitzel Jeffrey N. 
Published: March 2020

1010 Background: Platinum and PARP inhibitors have both shown activity in BRCA-associated breast cancer (BC) patients (pts). We have conducted a phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum tolerated dose (MTD). Methods: BRCA 1 or 2 carriers with stage IV BC were eligible. Carb starting at an AUC of 6 was given IV every 21 days (length of planned C) and V was administered orally, BID at dose levels (L) L1 through L5 (highest L planned). Results: 22 pts (21 eligible/evaluable, 20 with measurable BC) carrying BRCA1 (10) or BRCA2 (11), or both (1) mutations were accrued. Median age: 45 years, (32-65); 68% of BCs were ER+, and 10% were HER2+. In the table below are the schema, incidence of DLTs, and # of Cs on study. Toxicities: At L1, grade ¾ DLTs with C 1 were seen in 2/6 evaluable pts (1 pt w/grade 3 hyponatremia, pleural effusion, and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to deescalation of carb (AUC 5) for pts treated at Ls 2-5. At L2, 1 of 6 pts had grade 4 PLT. There were no DLTs at Ls 3 and L4. L5 is currently being expanded to 6 pts (3 currently enrolled, 1 pt with grade 4 granulocytopenia (Gr) and grade PLT reached DLT). Non-DLT dose delays mostly due ≥ grade 2 Gr or PLT were needed at 60%, 53%, 53%, and 43% of Cs in pts treated on Ls 1-4. Response: In 12 eligible pts treated at Ls 1 and 2, 2 complete and 6 partial responders (67%) and a clinical benefit (CB) of 75% were seen. All pts at Ls 3-5 are still being treated, and in pts treated at Ls 3 and 4, 2 unconfirmed PRs, and 4 cases of stable disease were seen, with L5 too early to assess. Conclusions: The combination of Carb at an AUC of 5 and daily V at doses 150 to 200 mg BID is feasible and the MTD is being defined. In preliminary analysis, response and CB rates are better than expected with the individual agents alone, providing justification to proceed with a planned phase II randomized single agent versus combination trial. [Table: see text]
SOLTI NeoPARP: A phase II, randomized study of two schedules of iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC).
Authors: Llombart Antonio , Lluch Ana , Villanueva Cristian , Delaloge Suzette , Morales Serafin , Balmaña Judith , Amillano Kepa , Bonnefoi Herve R. , Casas Ana Maria , Manso Luis , Roche Henri Hubert , Gonzalez-Santiago Santiago , Gavila Joaquin , Sánchez-Rovira Pedro , Di Cosimo Serena , Charpentier Eric , Garcia-Ribas Ignacio , Penault-Llorca Frederique Madeleine , Aura Claudia , Baselga José ,   SOLTI Group
Published: March 2020

1011 Background: Iniparib is an anticancer agent with a mechanism of action still under investigation. A phase 2 randomized neoadjuvant study in patients (pts) with TNBC was designed to explore the activity and tolerability of two schedules of iniparib with weekly paclitaxel (PTX). Here we report the efficacy and safety results from a planned interim analysis (IA). Methods: The trial accrued a total of 141 pts in October 2011, of whom, 74 are included in this IA. All were chemo-naive, histologicallyconfirmed Stage II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. Triple negative status was centrally confirmed [ER/PR <10%, HER2 IHC (0+, 1+) or FISH negative]. Pts were randomized (1:1:1) to receive weekly PTX (80 mg/m2, IV, d 1; N=25) alone or in combination with iniparib, either on a once weekly (QW) (11.2 mg/kg, IV, d 1; N=25) or twice weekly (BIW) (5.6 mg/kg, IV, d 1, 4; N=24) schedule. The total planned treatment duration was 12 wks. The IA endpoint is pathological complete response in the breast (pCR) as assessed by independent pathologists. Results: Two/2/3 pts in the PTX/QW/BIW arms, respectively, discontinued due to progressive disease per RECIST. Another 3/2/2 pts, respectively, discontinued due to investigator decision or an adverse event (AE). Thirteen pts presented with Grade 3/4 Treatment Emergent AE: 3 pts in PTX arm (1 neutropenia, 1 presyncope, 1 ALT elevation), 3 in QW arm (1 lymphopenia, 1 hyperkalemia, 1 pulmonary embolism), and 8 in the BIW arm (1 febrile neutropenia, 3 neutropenia, 1 aphonia, 1 syncope, 1 radius fracture and 1 vertigo). Laboratory Grade 3/4 neutropenia occurred in 4% of pts in PTX, 0% in QW and 21% of BIW arms, with 1/2/3 pts, respectively, requiring G-CSF usage. There were 4/7/6 pts in the PTX/QW/BIW arms with PTX dose modifications. Four pts (16%) in PTX arm, 4 pts (16%) in the QW arm and 6 pts (25%) in the BIW arm had confirmed pCR in the breast. Conclusions: In this IA population, the addition of iniparib regardless of the schedule to weekly PTX did not seem to add clinically significant toxicity. pCR rate in the breast is similar across treatment arms at this IA. NCT01204125.
Tesetaxel: Activity of an oral taxane as first-line treatment in metastatic breast cancer.
Authors: Seidman Andrew David , Schwartzberg Lee Steven , O'Shaughnessy Joyce , D'Andrea Gabriella , Rubin Peter , Katz Seth , Danesi Hassan , Itri Loretta , Hudis Clifford 
Published: March 2020

1016 Background: Tesetaxel, unlike standard taxanes (docetaxel, paclitaxel), is not a substrate for Pgp, a major cause of taxane resistance in tumor models. In a DU4475 breast cancer xenograft that overexpresses Pgp, tesetaxel induced a 94% reduction in tumor size, markedly exceeding the activity of docetaxel (46%) and paclitaxel (26%). Tesetaxel is associated with substantially less neuropathy preclinically than equi-myelotoxic doses of docetaxel. In clinical studies to date, tesetaxel is not associated with hypersensitivity reactions (0% incidence in > 450 patients [pts]), thus eliminating the need for premedication and extended observation. In a prior study, tesetaxel (27-35 mg/m2 Q3 wks) achieved a 38% partial response (PR) rate as 2nd-line therapy in pts with metastatic breast cancer (MBC) who had progressed after multidrug anthracycline-containing regimens. To extend these data, we initiated a phase 2 study of tesetaxel as 1st-line therapy in women with MBC. Methods: Eligibility included MBC; HER2-; ECOG PS 0-1; and adequate organ function. Adjuvant chemotherapy (including taxanes) was allowed. Tesetaxel was administered orally without anti-allergic premedication at a starting dose of 27 mg/m2 once every 3 wks. Overall response rate (ORR; RECIST) was the primary endpoint. Results: All 45 pts have been accrued. Median age is 58 y (range 36-80); median time from diagnosis, 4.0 y (range 0-21); triple negative status, 8 pts at diagnosis, 14 at time of metastasis. Metastatic sites are lung (22 pts), lymph nodes (22), liver (24), and bone (21). Prior treatment includes anti-estrogen therapy (32 pts), adjuvant chemotherapy (31), prior taxane (25), and radiotherapy (28). ORR in 24 pts evaluable for response is 50% (1 CR [4%], 11 PR [46%]); 5 responding pts had prior taxane therapy. Neutropenia is the most common ≥ Grade 3 adverse event with 50% of cases observed after dose escalation to 35 mg/m2; febrile neutropenia and Grade 3 peripheral neuropathy occurred in 2 pts each. There were no hypersensitivity reactions. Conclusions: Tesetaxel is highly active in 1st-line MBC and overcomes multiple limitations of standard taxanes. Updated ORR and PFS for all pts will be presented. Weekly dosing will be evaluated in a new cohort of pts.
Everolimus with paclitaxel plus bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC): A randomized, double-blind, placebo-controlled phase II trial of the Sarah Cannon Research Institute (SCRI).
Authors: Yardley Denise Aysel , Bosserman Linda D. , Peacock Nancy Walker , Favret Anne , Morgan Susan Kay , Priego Victor M. , Bass J. David , Griner Paula L. , Burris Howard A. , Hainsworth John D. , O'Shaughnessy Joyce 
Published: March 2020

1018 Background: Constitutive activation of mTOR and amplified PI3K/Akt/mTOR signaling are common in MBC, and increase as treatment-resistance is acquired. Everolimus (E), an mTOR inhibitor, has single agent activity, combines well with paclitaxel (P) and bevacizumab (B), and prolonged PFS when added to AI therapy in BOLERO-2. In this randomized phase II trial, E was added to P/B as first-line treatment of HER2-negative MBC. Methods: Women with untreated HER2-negative MBC were randomized (1:1) to P 90mg/m2 IV (days 1, 8, and 15) and B10mg/kg IV (days 1 and 15) q28 days with E 10mg PO (Arm 1) or placebo PO (Arm 2) daily. Response assessment was performed q8 weeks until progression or intolerable toxicity. Primary endpoint was PFS. Secondary endpoints: safety, overall response rate, response duration, overall survival. 110 pts allowed detection of improvement in median PFS from 11 to 16 months with 70% power. Results: Between 8/2009 and 6/2011, 112 pts were randomized (Arm 1=55; Arm 2=57). Median age: 58 years (range: 25-79). 88% were ER+ or PR+. Pts received a median 5 treatment cycles (range: <1- 26+); 18 (16%) pts remain on treatment (Arm1, 9; Arm 2, 9). Median PFS were 8.8 months (Arm 1) and 7.1 months (Arm 2) (95% CIs 7.4-9.6; 5.5-9.1 months, p=0.79, HR 0.94). Complete responses were observed in 5% [Arm1, 4 (7%); Arm 2, 2 (4%)] with partial responses in 49% [Arm1, 29 (53%); Arm 2, 26 (46%)]. Responses rates in taxane pretreated pts Arm 1 22%, Arm 2 12%. Hematologic toxicity was similar in both arms; grade 3 mucositis occurred in 13% of E pts. Dose reductions (47% vs 25%) and interruptions (42% vs 26%) were more frequent with E due to mucositis and rash. Treatment discontinuation rates were similar. Conclusions: The addition of E did not result in a significant improvement in the efficacy of weekly paclitaxel/bevacizumab in the first-line treatment of HER2-negative MBC although response rates and median PFS were better with E. Possible explanation for these results may include lower dose intensity in the E arm, treatment of less resistant pts, or intrinsic differences in E activity when added to antiestrogen vs chemotherapy.
NSABP FB-6: Phase II trial of weekly paclitaxel (WP) and pazopanib following doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for HER2-negative locally advanced breast cancer (LABC).
Authors: Tan Antoinette R. , Buyse Marc E. , Rastogi Priya , Jacobs Samuel A. , Robidoux Andre , Flynn Patrick J. , Thirlwell Michael P. , Fehrenbacher Louis , Stella Philip J. , Goel Rakesh , Julian Thomas B. , Provencher Louise , Bury Martin Joseph , Paik Soonmyung , Geyer Charles E. , Swain Sandra M. , Mamounas Eleftherios P , Wolmark Norman 
Published: March 2020

1025 Background: Pazopanib is an oral, small molecule inhibitor of VEGFR-1, -2, and-3, PDGFR-α, and -β, and c-kit tyrosine kinases. The purpose of this trial was to determine the activity and safety profile of pazopanib when added to neoadjuvant WP following AC in LABC. The primary endpoint was pathologic complete response in the breast and nodes (pCR-BN). Methods: Women with HER2-negative stage IIIA-IIIC breast cancer were treated with AC (60 mg/m2/600 mg/m2) for 4 cycles every 3 weeks followed by WP 80 mg/m2 on days 1, 8, and 15 every 28 days for 4 cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Postoperatively, pazopanib was given for 6 months. The regimen would be considered active if ≥14 responses (16% pCR rate in breast and nodes) were observed in 87 evaluable patients. Patients were considered evaluable if they received at least 1 dose of pazopanib. Results: Between July 2009 and March 2011, 101 pts (median age 51 yrs, range 30-71) were enrolled; 56% had stage IIIA, 34% stage IIIB, and 10% stage IIIC disease. 74 pts (73%) had ER-and/or PR-positive tumors and 27 pts (27%) were triple negative. 8 patients did not begin pazopanib. The pCR-BN rate in evaluable patients for whom surgical information was known was 18% (16/89). The pCR-BN rate in ER positive disease was 9% (6/65) and was 42% (10/24) in TNBC. Toxicities observed with WP and pazopanib included diarrhea (gr 2/3, 10%/5%), hand-foot syndrome (gr 2/3, 11%/1%), hypertension (gr 2/3, 12%/3%), neuropathy (gr 2/3, 14%/1%), and neutropenia (gr 3/4, 25%/1%). Liver toxicity during WP and pazopanib included ALT (gr 2/3/4, 13%/7%/1%), AST (gr 2/3, 7%/7%), and total bilirubin (gr 2, 2%). Conclusions: A regimen of WP and pazopanib following AC was active as neoadjuvant therapy in women with LABC and met the pre-specified criteria of interest. The activity in TNBC was notable. The toxicity profile of WP and pazopanib was consistent with previous experience. Support: GlaxoSmithKline.
Molecular comparison of human triple-negative inflammatory breast cancer (TN-IBC) and human triple-negative noninflammatory breast cancer (TN-non-IBC).
Authors: Masuda Hiroko , Baggerly Keith , Wang Ying , Iwamoto Takayuki , Brewer Takae , Pusztai Lajos , Kai Kazuharu , Woodward Wendy A. , Reuben James M. , Van Laere Steven J. , Bertucci François , Hortobagyi Gabriel N. , Ueno Naoto T. 
Published: March 2020

1047 Background: IBC has a poor prognosis because of its high rate of recurrence. There is an urgent need to define the biology of IBC to develop molecular-based targeted therapies for this disease. TNBC has a similar poor prognosis. Recently, Lehmann et al. (JCI, 2011) identified 7 subtypes of TNBC: basal-like (BL) 1 and 2, immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and “unknown.” In light of these findings, we hypothesized that the distribution of TNBC subtypes differs between TN-IBC and TN-non-IBC. Methods: We qualitatively reproduced the Lehmann et al. experiments using Affymetrix CEL files from the same datasets to ensure the reproducibility of their findings. We quantified all arrays using frozen robust multiarray analysis with a linear model adjustment to account for batches. Then validated the results in a TNBC cohort from the World IBC Consortium for which IBC status was known (41 cases of TN-IBC; 53 cases of TN-non-IBC). We used the Fisher exact test to determine associations between TNBC subtypes and IBC status. We used Kaplan-Meier curves and log-rank tests to compare clinical outcomes between TNBC subtypes. Results: We found the 7 subtypes for both TN-IBC and TN-non-IBC. While the correspondence between our findings and those of Lehmann et al. was not perfect, there was a very significant correlation (P<2.2x10-16). We found no association between TNBC subtype and IBC status (P=.5023). As expected, we found that patients with IBC had significantly worse recurrence-free survival (RFS) than a comparison cohort of patients with advanced non-IBC that included not only patients with TNBC but also patients with ER-positive and HER2-amplified tumors (P=.0054). However, TNBC subtype did not predict RFS. IBC status was not a significant predictor of RFS or overall survival in the TNBC cohort. Conclusions: Both TN-IBC and TN-non-IBC are heterogeneous. TNBC subtypes are unrelated to IBC status. TN-IBC and TN-non-IBC have the same subtypes and clinical outcome. [Table: see text]
Evaluation of a multiparametric system able to predict nonsentinel lymph node status in breast cancer patients with a micrometastatic sentinel node assessed by the one step nucleic acidamplification (OSNA) assay.
Authors: Buglioni Simonetta , Mottolese Marcella , Casini Beatrice , Gallo Enzo , Terrenato Irene , Pescarmona Edoardo , Di Filippo Simona , Marandino Ferdinando , Ferretti Gianluigi , Di Filippo Franco 
Published: March 2020

1050 Background: Axillary lymph node dissection (ALND) may not be necessary in women with breast cancer (BC) who have micrometastasis in a sentinel lymph node (SLN), owing to the low risk of non-SLN (NSLN) involvement. In our Institute we validated and adopted the molecular diagnostic tool OSNA based on the quantitative measurement of Cytokeratin 19 (CK19) mRNA.The aims of our work in a subgroup of women with micrometastatic SLN, were: 1) to correlate the copy numbers of CK19 mRNA with the risk of additional positive NSLNs; 2) to assess the relationships between the molecular subtype classification and the probability of a positive ALND; 3) to verify whether a combination of the new above mentioned parameters is able to identify a subgroup of patients with a micrometastatic SLN and a negligible risk of positive NSLNs in whom ALND may be avoided. Methods: The SLN lysates from 709 patients were analyzed by OSNA assay. We considered only patients with a micrometastatic SLN (copy numbers between 250 and 5000/μL) and the probability of having a positive ALND was calculated by the logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification as defined by a combination of estrogen, progesteron receptors and HER2 status. Results: OSNA positivity for micrometastasis was reported in 91/709 cases (12,8%).The number of patients with positive ALND was 20 (22%). The statistical analyses showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers (>2000) of CK19 mRNA together with HER2 subtype. Otherwise none of the luminal A patients with a positive SLN but presenting a copy number <1000, had a positive NSLNs. Conclusions: We showed that biologically-driven analyses may be able to build new models with higher performance in terms of breast cancer axillary status prediction after positive SLN biopsy for micrometastasis. The copy numbers of CK19 mRNA and the molecular subtypes are more advantageous than traditional parameters because they are not pathologist-dependent and therefore they are more reliable and reproducible.
DEAR1, a novel tumor suppressor, negative regulator of epithelial-mesenchymal transition, and prognostic factor in non-small cell lung cancer.
Authors: Quintas-Cardama Alfonso , Post Sean M. , Solis Luisa , Xiong Shunbin , Wistuba Ignacio I. , Lozano Guillermina 
Published: March 2020

10506 Background: DEAR1, also known as TRIM62, maps to 1p.35, a genomic interval within which loss of heterozygosity occurs at high frequency in carcinomas. DEAR1 has been proposed as a regulator of cell polarity in vitro. Methods: We genetically engineered mice lacking DEAR1 alleles at murine chromosome 4. To study the impact of DEAR1 loss in lung cancer, DEAR1 deficient mice were crossed to mice carrying the latent mutant K-rasG12D allele (K-rasLA1). Results: No survival difference was observed between DEAR1+/─ and DEAR1─/─ mice (729 vs 699 days, p=0.98) but they were markedly shorter than that of DEAR1 wild-type littermates (803 days, p=0.01). Over 90% of mice developed tumors, mainly adenocarcinomas, including invasive and/or metastatic lung cancer in 23% of cases. DEAR1-deficient K-rasLA1 mice had reduced life span compared with DEAR1+/+:K-ras+/LA1 littermates (184 vs 291 days, p<0.0001). The survival of DEAR1+/─:K-ras+/LA1 and DEAR1─/─:K-ras+/LA1 mice were similar (180 vs 153 days, p=0.38) and qPCR and IHC analyses suggested loss of the wild-type DEAR1 allele. The survival of DEAR1-deficient K-rasLA1 mice was also shorter than that of control p53+/─:K-ras+/LA1 mice (240 days; p=0.01). The metastasis incompetent K-rasLA1–positive LKR13 cell line after shRNA DEAR1 knock-down and cell lines derived from DEAR1-deficient K-rasLA1 tumors recapitulated an invasive phenotype in transwell migration and 3D culture assays and a metastatic phenotype on SC or IV injection into immunocompetent wild-type littermates. The latter was associated with epithelial-mesenchymal transition involving loss of E-cadherin and DEAR1 expression and upregulation of vimentin, Twist, and CD44. DEAR1 downregulation was very prevalent in a non-small cell lung cancer (NSCLC) tissue array with 214 samples. Patients with early stage NSCLC and loss of DEAR1 expression had a markedly shorter time to relapse compared to those retaining DEAR1 expression (5.1 vs 2.87 years, p=0.049) and worse 5-year relapse-free and overall survival rates. Conclusions: DEAR1 is a novel tumor suppressor that negatively regulates EMT and promotes lung cancer metastasis. DEAR1 loss is a poor prognostic factor in NSCLC.