bluuebunny/crossref_metadata_2025_split huggingface dataset:
Classifying circulating, mutation bearing tumor cells from breast cancer patients.
Authors: Strauss William , Dempsey Paul W. , Winer-Jones Jessamine , Bingham Catherine , Alpaugh R. Katherine , Cristofanilli Massimo 
Published: March 2020

580 Background: The treatment of advanced breast cancer demands systemic therapies that can address disease heterogeneity and the development of treatment resistance without a “real-time” molecular window into disease biology. New technologies have focused on increased capture and molecular analysis of circulating tumor cells (CTCs) including cells undergoing epithelial mesenchymal transition (EMT). We conducted a pilot experiment to test the efficiency of capture and cytokeratin (CK) detection and the presence of single point variants (SNV) to determine the best utility of scoring alternatives for CTC. Methods: EpCAM expressing CTC were recovered from breast cancer patients using CellSearch (Veridex) and LiquidBiopsy (Cynvenio Biosystems). EpCAM recovery and CK scoring were indexed in spiked samples and in 12 inflammatory breast cancer (IBC) patient samples using antibodies against CKs 7, 8 or CKs 1-8, 10, 13-16, 18, 19. Additionally, LiquidBiopsy template was analyzed using an Ampliseq 1.0 panel on the IonTorrent PGM. SNV present in the CTC but not white blood cell (WBC) negative controls were identified and where possible, compared to tissue biopsy SNV analyzed using Foundation One (Foundation Medicine). Results: CTCs were detected using CellSearch 10/12 (83%) (range 0-2502 CTC/7.5ml) and LiquidBiopsy 12/12 (100%) (range 6-2800 CTC/7.5mL). More CK positive events were scored using CKs 1-8, 10, 13-16, 18, 19 than CKs 7, 8 in patient samples. Upon sequencing, shared germline polymorphisms were observed in CTC and WBC. Conversely, 1 or 2 SNV were detected in the Epcam selected population but not WBC controls from 6/12 patients (frequency 1.1%-2.1% with 520-5160x coverage) with SNV observed in TP53, MPL, PIK3ca, MET and IDH1. All but one of the PIK3ca mutations were absent in evaluable tissue biopsy. Conclusions: CTC recovery and scoring are two separate events. Altered CK detection emphasized the need to tailor CTC classification to specific disease settings. Sequence analysis showed one correlated SNV among 6 evaluable comparisons to tissue reflecting variable analysis as well as the biologic disparity of metastatic disease. This pilot demonstrates the feasibility of using CTC for molecular analysis.
Sym004, a novel strategy to target EGFR with an antibody mixture, in patients with advanced SCCHN progressing after anti-EGFR monoclonal antibody: A proof of concept study.
Authors: Machiels Jean-Pascal H. , Specenier Pol M. , Krauss Jürgen , Dietz Andreas , Kaminsky Marie-Christine , Lalami Yassine , Henke Michael , Keilholz Ulrich , Knecht Rainald , Skartved Niels Jorgen Ostergaard , Horak Ivan David , Flensburg Mimi F , Gauler Thomas Christoph 
Published: March 2020

6002 Background: Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR. In preclinical models, Sym004 exhibited more pronounced EGFR internalization, degradation and tumor growth inhibition than cetuximab. Sym004 was investigated as monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN) patients (pts). Methods: SCCHN pts progressing after anti-EGFR mAbs for palliation were eligible. Documented clinical benefit (PR, CR or SD for at least 8 weeks according to RECIST) on an anti-EGFR mAb-containing regimen followed by disease progression during or within 12 weeks after treatment cessation was required. The primary endpoint of this multicentre single arm trial was centrally evaluated progression-free survival (PFS), estimated by median PFS and 24 week progression free rate. Secondary endpoints included objective tumor response, safety, biomarkers and pharmacokinetics. Pts received weekly iv infusions of 12 mg/kg Sym004 until disease progression. Tumor evaluation was performed week 6, 12 and every 8 weeks thereafter. Results: Based on the statistical hypothesis, 26 pts were included, of whom 23 had progressed while on anti-EGFR mAb treatment. One of 19 evaluable pts was HPV positive and no EGFRvIII mutation was detected in 21 evaluable pts. No anti-drug antibodies were detected. Independent central review of CT/MRI scans from 20 evaluable pts showed tumor shrinkage in 8 pts (% decrease in sum of the largest diameters: 6.5, 7.1, 9.6, 10.2, 11.3, 13.6, 16.7, 27.1) and 14 pts had SD as best overall response. Median PFS was 82 days (95% CI: 41, 140) and 24 week progression free rate was 12% (95% CI: 1, 39). During treatment 25/26 (96%) pts developed skin rash with ≥ grade 3 reported in 11/26 (42%) pts. Hypomagnesemia ≥ grade 3 was reported in 10/26 (38%) pts. Sym004 treatment resulted in a marked down regulation of EGFR in centrally reviewed biopsies from skin and tumors. Conclusions: Sym004 demonstrated clinical activity in heavily pretreated, predominately HPV negative pts with advanced SCCHN previously progressing on or after anti-EGFR mAbs. No unexpected toxicities were reported. Clinical trial information: NCT01417936.
A phase II-III study comparing concomitant chemoradiotherapy (CRT) versus cetuximab/RT (CET/RT) with or without induction docetaxel/cisplatin/5-fluorouracil (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN): Efficacy results (NCT01086826).
Authors: Ghi Maria Grazia , Paccagnella Adriano , Ferrari Daris , Foa Paolo , Cossu Rocca Maria , Verri Elena , Maiello Evaristo , Azzarello Giuseppe , D'Ambrosio Consuelo , Casanova Claudia , Guaraldi Monica , Mantovani Giovanni , Rossetto Ciro , Bonetti Andrea , Cipani Tiziana , Crino Lucio , Koussis Haralabos , Pieri Gabriella , Gava Alessandro , Floriani Irene ,   for the GSTTC Italian Study Group
Published: March 2020

6003 Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1+ 130 Arm B1) and 160 received CET/RT (80 Arm A2+ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. [Table: see text]
Sorafenib in recurrent and/or metastatic salivary gland carcinomas (RMSGCs): An investigator-initiated phase II trial (NCT01703455).
Authors: Locati Laura D. , Bossi Paolo , Civelli Enrico M. , Perrone Federica , Bergamini Cristiana , Cortelazzi Barbara , Quattrone Pasquale , Imbimbo Martina , Mirabile Aurora , Granata Roberta , Resteghini Carlo , Mariani Luigi , Tosarello Davide , Cassani Camilla , Marchiano' Alfonso , Saibene Gabriella , Pilotti Silvana , Licitra Lisa F. 
Published: March 2020

6020 Background: Palliative chemotherapy is the standard of care for RMSGCs. However its activity is usually poor especially in adenoid cystic carcinoma (ACC), while in histotypes other than ACC (non ACC) the response, if any, is of short duration. Some preclinical and clinical evidence suggest a rationale for the employment of anti-angiogenetic agents in RMSGCs, such as sorafenib. Methods: Subjects withproven RMSGC not amenable to surgery and/or radiotherapy were enrolled to receive sorafenib at 400 mg BID q28 days until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was response rate (RR) (CR+PR) according to RECIST; secondary objectives included RR according to CHOI criteria, disease control rate (DCR) and toxicity. 37 subjects were required to test the null hypothesis that RR will be ≤ 5% versus the alternative that RR ≥ 20% within a two stage Simon design. At least 4 responders were necessary to reject the null hypothesis. Results: 19 ACC and 18 non ACC subjects were accrued from September 2010 to September 2012. 21 patients had received at least one chemotherapy regimen for RMSGC. Overall 6 PRs according to RECIST were recorded corresponding to a RR of 16% (95% CI 6,2-32,0) (11% in ACC and 22% in non ACC). PR according to CHOI was observed in 10 cases (of which only 2 were concordant with RECIST); no response was reported in 15 cases while CHOI response was not evaluable in 12 patients. A dramatic necrotic evolution of the disease, which resulted in cavitation of metastatic lesions in one case, was observed in two patients with mucoepidermoid cancer (MEC). SD was 57% lasting a median of 7 months (range 2-15+ months). At a median follow up of 10 months (range 3-28+ months): 5 patients are still receiving sorafenib; 15 are no longer being treated and 17 have died. AEs were generally consistent with previous sorafenib studies, except for one G5 toxicity due to meningitis (probably related to necrosis of a local relapse) and one G3 aspergillus abscess. Conclusions: Sorafenib is the first anti-angiogenetic agent to demonstrate some activity in RMSGCs, particularly in MEC. Molecular analyses, typifying MEC and ACC are ongoing. Clinical trial information: NCT01703455.
Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C.
Authors: Burtness Barbara , Lee Ju-Whei , Yang Donghua , Zhu Fang , Garcia Joaquin J. , Forastiere Arlene A. , Chung Christine H. 
Published: March 2020

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.
Randomized phase II trial of cixutumumab (CIX) alone or with cetuximab (CET) for refractory recurrent/metastatic squamous cancer of head and neck (R/M-SCCHN).
Authors: Glisson Bonnie S. , Tseng Jennifer , Marur Shanthi , Shin Dong M , Murphy Barbara A. , Cohen Ezra E.W. , Thomas Christopher Y. , Willey Richard , Cosaert Jan , William William Nassib , Harun Nusrat , Lee J. Jack , Haddad Robert I. 
Published: March 2020

6030 Background: Preclinical evidence supports clinical investigation of IGF-1R inhibitors alone, or combined with EGFR inhibitors, in SCCHN patients (pts). CIX and CET monoclonal antibodies block ligand binding to IGF-1R and EGFR, respectively. CIX mono and CIX+CET combo were studied in pts with chemotherapy-refractory R/M-SCCHN. Methods: This open-label phase II trial randomized 97 pts with R/M-SCCHN, ECOG PS 0-2 and disease progression following (<90 days) platinum-based chemotherapy, to CIX 10 mg/kg alone (Arm A) or with CET 500 mg/m2 (Arm B) every 2 wks. Time to recurrence from last anti-EGFR exposure had to be >90 days; pts were stratified by prior CET exposure. Primary endpoint was median PFS (RECIST assessments every 8 wks). Efficacy endpoints in the CET-naïve patients, immunohistochemical analysis of 10 relevant markers on tumor specimens, and cytokine/angiogenic factor profiling of blood samples obtained serially through treatment were also examined. Results: 47 Arm A and 44 arm B pts were treated: median age: 60.0 y (35 - 81), PS 0/1/2: 17.6%/62.6%/19.8%, male (80.2%), tumors originating mainly from oropharynx (67.1%), supraglottic (9.9%) and oral cavity (13.2%), with 33% moderately and 36.3% poorly differentiated tumors, previous therapy: 98.9% chemotherapy and 82.4% radiotherapy indicating no baseline differences. Most common tx-emergent AEs were fatigue (55.3 vs. 61.4%), dermatitis acneiform (6.4 vs 63.6%), nausea (29.8 vs. 34.1%), weight decreased (25.5 vs. 29.5%), hyperglycemia (25.5% vs. 29.5%), vomiting (21.3 vs. 20.5%), and headache (17 vs. 25%). Efficacy: See Table. Conclusions: Targeting IGF-1R alone with CIX or co-targeting IGF-1R and EGFR with CIX and CET did not result in improved PFS compared to historical data with CET alone in patients with chemotherapy-refractory R/M-SCCHN. The results of this study do not support CIX single-agent activity in this patient population. Therapy on both arms was feasible. There was no apparent exacerbation of CET toxicity by concurrent CIX exposure. Clinical trial information: NCT00617734. [Table: see text]
A phase III randomized trial of two cisplatin-based concurrent chemoradiation (CCRT) regimens for locally advanced head and neck squamous cell carcinoma (LAHNSCC).
Authors: Rodriguez Cristina P. , Adelstein David J. , Rybicki Lisa A. , Savvides Panayiotis , Saxton Jerrold P. , Koyfman Shlomo A. , Greskovich John , Yao Min , Scharpf Joseph , Lavertu Pierre , Wood Benjamin J. , Burkey Brian , Lorenz Robert , Rezaee Rod , Zender Chad , Ives Denise I. 
Published: March 2020

6035 Background: Excellent outcomes have been reported using both single and multiagent CCRT in LAHNSCC. This trial compares a 5FU/cisplatin regimen to single agent cisplatin CCRT. Methods: Patients (pts) with previously untreated stage III-IV, M0, LAHNSCC of the larynx, oropharynx (OP), oral cavity or hypopharynx received definitive once or twice daily radiation (70-74.4 Gy) and were randomized between concurrent chemotherapy with either Arm A: cisplatin 100mg/m2 on days 1, 22 and 43 or Arm B: cisplatin (20mg/m2/day) and 5-FU (1000mg/m2/day) as continuous 96 hour infusions weeks 1 and 4. ECOG performance status ≤ 1, and adequate renal, liver and marrow function were required for entry. The primary endpoint was recurrence free survival (RFS). Results: Between 2/2008 and 10/2011, 69 pts were enrolled. An accrual of 126 pts was planned in order to demonstrate an improvement in 2-year RFS from 55% to 75%. The study was closed prematurely when a scheduled interim analysis confirmed markedly better outcomes in both arms and the futility of further comparison. Pt and tumor characteristics were well balanced in both arms. OP cancer was diagnosed in 83% of pts; 86% of the OP cancers were HPV/p16+. With a median follow up of 29.4 months, 2 yr Kaplan-Meier outcome estimates were similar between arms (Table). Pts on Arm A experienced more nephrotoxicity (26% vs. 3%; p=0.007) and ototoxicity (11% vs. 0%; p=0.042), but less Grade ≥2 radiation dermatitis (43% vs. 68%; p=0.038), neutropenia <1000/mm3 (34% vs. 65%; p=0.012), and unplanned hospitalization (43% vs. 68% p=0.038). Treatment outcomes were inferior and feeding tube requirements greater in the HPV/p16 negative and actively smoking pts. Conclusions: Although these CCRT regimens produced similar outcomes, their toxicity profiles proved different and may serve to inform individual pt treatment. Tobacco use and HPV status had far greater impact on treatment outcomes than did the CCRT regimen. Clinical trial information: NCT00608205. [Table: see text]
Impact of obesity on survival in patients (pts) with early-stage squamous cell carcinoma (SCC) of the oral tongue.
Authors: Iyengar Neil M. , Kochhar Amit , Morris Patrick Glyn , Morris Luc G. , Zhou Xi Kathy , Pino Alejandro , Fury Matthew G. , Pfister David G. , Patel Snehal G. , Boyle Jay , Hudis Clifford , Dannenberg Andrew J. 
Published: March 2020

6048 Background: Obesity is a risk factor for several malignancies and an independent predictor of worse outcomes. In contrast, low body mass index (BMI) has been associated with increased risk of oropharyngeal cancers and poorer prognosis. In tongue SCC, impaired nutrition, smoking, and alcohol use impact BMI, and pre-diagnosis weight (wgt) loss negatively affects survival. The prognostic effect of obesity in tongue cancer is unknown. Methods: We conducted a single-institution, retrospective study of pts who underwent resection of T1/T2 SCC of the oral tongue. All pts underwent nutritional assessment prior to surgery. BMI was calculated from measured height and wgt at surgery and categorized as obese (≥30), overwgt (25-29.9), or normal (18.5-24.9). The association between BMI and the primary endpoint, disease specific survival (DSS), was evaluated by Cox regression. The effect of BMI on the secondary endpoints, recurrence free survival (RFS) and overall survival (OS), was also assessed. Results: From 2000 to 2005, 155 pts (90 men, 65 women) of median age 57 (range 18-86) were included. Clinicopathologic characteristics were similar by BMI group. Obesity was significantly associated with adverse DSS compared with normal wgt in univariable (Table) and multivariable analyses (HR 2.87; 95% CI, 1.08-7.67; p=0.04). Obesity was also significantly associated with adverse RFS (HR 2.53; 95% CI, 1.12-5.74; p=0.03). Overwgt subjects may also have worse RFS (HR 1.74; 95% CI, 0.85-3.55; p=0.13). In pts without pre-diagnosis wgt loss (n=94), obesity was significantly associated with adverse OS (HR 2.70; 95% CI, 1.12-6.54; p=0.03). Conclusions: These data suggest that obesity is associated with a worse prognosis in tongue cancer, which may not have previously been appreciated due to confounding by pre-diagnosis wgt loss. [Table: see text]
Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).
Authors: Datko Farrah Mikhail , D'Andrea Gabriella , Dickler Maura N. , Goldfarb Shari Beth , Theodoulou Maria , Lake Diana , Fornier Monica Nancy , Modi Shanu , Fasano Julie , Comen Elizabeth Anne , Gajria Devika , Moynahan Mary Ellen , Traina Tiffany A. , Chen Melanie , Hamilton Nicola , Patil Sujata , Chandarlapaty Sarat , Hudis Clifford , Dang Chau T. 
Published: March 2020

606 Background: Pertuzumab is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab, disrupting HER2 dimerization and signaling. Pertuzumab improves progression-free survival (PFS) and overall survival when combined with docetaxel/trastuzumab. We report results of a phase II study to evaluate the efficacy and safety of pertuzumab, trastuzumab and weekly paclitaxel. Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) were eligible. Rx is weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → 420mg). The primary endpoint is PFS at 6 months (mo). Evaluable pts are those who started study Rx and are assessed at 6 mo for PFS, including pts who progressed prior to 6mo. Secondary endpoints include response, safety (including cardiac events), and tolerability. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 1-18-13, 53 pts are enrolled; 36 are evaluable at 6 mo. At 6 mo, 29/36 pts (81%) are progression-free (4 CR, 14 PR and 11 SD); 7 pts progressed. The 6 mo PFS results for all patients will be updated. Median LVEF is 64% at baseline (range 50-72%), 63% at 3 mo (range 50-73%), and 62% at 6 mo (range 49-69%). There are no cardiac events to date. Of the 36 pts, grade 3/4 toxicities include fatigue (3 pts, 8%), peripheral neuropathy (2 pts, 6%), sepsis (1pt, 3%), cellulitis (1pt, 3%), neutropenia (1pt, 3%), and skin ulceration (1pt, 3%). There are no grade 3 diarrhea or febrile neutropenic events in the evaluable pts to date. Conclusions: The preliminary 6-month PFS is 81% (95% CI 67-91%) in evaluable patients. The study is closing to accrual. Treatment is ongoing, with few grade 3/4 toxicities and no signal of increased cardiac toxicity to date. This phase II study demonstrates efficacy and safety for pertuzumab with trastuzumab and weekly paclitaxel in HER2+ MBC. Clinical trial information: NCT01276041.