bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of a custom designed next generation DNA sequencing gene panel to profile endometrial cancers.
Authors: Miller Eirwen M , Patterson Nicole E , Karabakhtsian Rouzan G , Bejerano-Sagie Michal , Ravi Nivi , Maslov Alexander , Quispe-Tintaya Wilber , Wang Tao , Lin Juan , Smith Harriet Olivia , Kuo Dennis Yi-Shin , Goldberg Gary L. , Montagna Cristina 
Published: September 2018

5593 Background: Using whole genome sequencing (WGS), the Cancer Genome Atlas (TCGA) identified four genomic subtypes of endometrial cancer (EC) with survival differences. Limited clinical data is available in the TCGA dataset restricting correlation of WGS with clinical endpoints. We sought to determine if high depth target sequencing allows for genomic classification of EC and prediction of the tumor biology when clinical variables are known. Methods: Using a custom designed sequencing panel targeting the coding regions of 156 EC genes we analyzed 47 EC samples and matching normal controls. Variants were annotated for pathogenicity. Charts were reviewed for clinicopathologic data. Routine statistical analyses were applied. Results: Endometrioid (EEC) tumors had a significantly higher frequency of total and pathogenic SNVs than serous (USC). Pathogenic PTEN and PIK3CA SNVs were more common in EEC while pathogenic TP53 SNVs were more frequent in USC. The presence of pathogenic TP53 SNVs was significantly associated with disease recurrence/progression. A pathogenic SNV at PTEN locus chr10:89692904 was associated with grade 1 EEC. Six hypermutated specimens were identified with 99-272 SNVs (mean 185.8 v 8.7 in non-hypermutated samples). All 6 were grade 3 EEC, of which 4 patients are alive without clinical evidence of disease (mean follow up 35 months). NTRK3, LRP1B, SLIT2, APC, RAD50, PIK3R1, and JAK2 SNVs were more common in grade 3 EEC than the other histologies. Conclusions: Pathogenic variants in EC associated with PTEN, PIK3CA, and TP53 and the number of somatic variants, as identified by a targeted sequencing, can predict histologic features and clinical behavior. Targeted sequencing panels may be a useful tool to predict the clinical phenotype and guide individualized therapeutic intervention. [Table: see text]
Prognostic importance of p16 status for women with vulvar squamous cell carcinoma (SCC) treated with radiotherapy.
Authors: Lee Larissa Janeen , Howitt Brooke E. , Oliva Esther , Zhang Hongkai , Catalano Paul J. , Crum Christopher , Bu Paula , Cimbak Nicole , Demaria Rebecca , Murphy Rita , Horowitz Neil S. , Matulonis Ursula A. , Russo Andrea Lyn 
Published: September 2018

5599 Background: To evaluate the association between p16 status and in-field recurrence (IFR), progression-free (PFS) and overall (OS) survival in patients with vulvar SCC treated with radiation (RT) with or without surgical resection. Methods: In a multi-institutional retrospective cohort study, we identified 105 women with vulvar SCC who received RT between 1985-2011. Immunostaining for p16 was performed on archival tumor tissue using the Leica Bond III staining platform. Histopathology and p16 stains were reviewed by pathologists with expertise in gynecologic cancer; the intensity and extent of p16 staining in tumor cells were classified as negative (focal, weak, patchy) or positive (moderate or strong diffuse linear positive). Actuarial estimates of PFS, OS and IFR were calculated using the Kaplan-Meier method and compared by the logrank test. Multivariable analysis (MVA) was performed using the Cox proportional hazards model. Results: Patients with p16-positive disease were significantly younger at diagnosis (median 67 vs. 77 years) and were more likely to be current smokers (51% vs. 0%) and to have received concurrent chemotherapy (68% vs. 47%, all p<0.05). FIGO stage distribution, RT intent and median RT doses were similar by p16 status. With a median follow-up of 61 months, 5-year PFS and OS rates were 35% and 40%, respectively. Women with p16-positive tumors had significantly better 5-year PFS and OS rates than those with p16-negative tumors (61% and 23%, p<0.01 and 64% and 29%, p=0.01, respectively). The 5-year IFR rate was also lower for those with p16-positive disease (17% vs. 65%, p<0.01). On univariate analysis, use of concurrent chemotherapy was not associated with PFS (p=0.5), OS (p=0.3) or IFR (p=0.8). On MVA adjusted for age and stage, p16 positivity was significantly associated with better PFS (HR 0.57, 95% CI 0.33-0.97) and lower IFR (HR 0.24, 95% CI 0.09-0.6). Conclusions: In a multi-institutional setting, women with p16-positive vulvar SCC treated with RT had a lower IFR rate and longer survival than those with p16-negative disease. The magnitude of prognostic importance of p16 status is similar to that seen in oropharyngeal, anal and cervical cancers treated with RT.
Impact in delay of start of chemotherapy and surgery on pCR and survival in breast cancer: A pooled analysis of individual patient data from six prospectively randomized neoadjuvant trials.
Authors: Loibl Sibylle , Werutsky Gustavo , Nekljudova Valentina , Seiler Sabine , Blohmer Jens Uwe , Denkert Carsten , Hanusch Claus , Huober Jens Bodo , Jackisch Christian , Kummel Sherko , Schneeweiss Andreas , Untch Michael , Rhiem Kerstin , Fasching Peter A. , Von Minckwitz Gunter , Furlanetto Jenny 
Published: September 2018

571 Background: Time interval from diagnostic biopsy to neoadjuvant chemotherapy (NACT) start (TBC) and from last chemotherapy application to surgery (TCS) are influenced by many factors. It is unclear whether a delay of systemic therapy or surgery impacts patients (pts) outcome. Methods: 9127 pts with early BC from 6 German neoadjuvant trials receiving an anthracycline-taxane based NACT were included. pCR (ypT0/is ypN0), disease free survival (DFS) and overall survival (OS) were compared according to TBC and TCS length (cut-off of ≤4 vs >4weeks (w)), overall and in subgroups (BC subtypes [luminal, HER2+, triple-negative breast cancer (TNBC)] and pCR [yes vs no] for survival endpoints) adjusted by study. Results: Data on TBC were available for 8072 pts, on TCS for 6420, on follow-up (FU) for 7889. Median age was 49 yrs, 25.6% had cT3-4, 48.6% N+, 44.1% G3, 46.0% luminal, 26.4% TNBC, 27.6% HER2+ tumors. Median (m) FU-time was 65 months [0-201]. mTBC was 23 days [0-228] (67.5% ≤4w vs 32.5% >4w), mTCS was 28d [0-204] (53.7% ≤4w vs 46.3% >4w), with inter-study variability for mTBC ranging from 14 to 32d and for mTCS ranging from 24 to 29d from the oldest to the most recently conducted study. TBC did not influence the pCR rate, neither in all patients nor in subgroups. At multivariable logistic regression analysis TBC length did not independently predict pCR. TBC did not influence DFS or OS, neither in all patients nor in subgroups. TCS<4w was associated with a trend towards a better DFS in all patients (HR=1.11 95%CI (0.99-1.24), p=0.08) and in pts not achieving pCR (HR=1.12, 95%CI (0.99-1.26), p=0.08). No difference was observed within BC subtypes. OS was not impacted by TCS length. At multivariable Cox regression analysis TBC or TCS≤4 vs >4w did not independently influence DFS or OS. Conclusions: A delay in starting NACT does not impact the pCR rate, DFS or OS and results are independent of the subgroup. However, early surgery after NACT in pts without pCR seems to influence outcome. Our analysis is explorative, but indicates for the first time, that time interval of starting NACT and undergoing surgery might be uncritical. Further research is ongoing.
Results of multicenter phase II WSG Neo-Predict trial: Predictive markers for evaluation of response to neoadjuvant paclitaxel+trastuzumab+lapatinib in HER2-positive early breast cancer.
Authors: Eichler Christian , Gluz Oleg , Nitz Ulrike , Christgen Matthias , Krabisch Petra , Hackenberg Reinhard , Skrobol Markus , Möbus Volker , Kates Ronald , Schumacher Johannes , Kreipe Hans Heinrich , Harbeck Nadia , Warm Mathias 
Published: September 2018

582 Background: Trastuzumab (T) and Lapatinib (L) containing neoadjuvant chemotherapy (NACT) increases pathological complete response (pCR) (vs. T or nihil) in HER2+ early breast cancer (EBC). Early clinical response markers (e.g. Ki67) in a 3-week biopsy or in residual tumor correlate with therapy efficacy and risk of relapse. This WSG Neo-Predict trial aimed to define early predictive markers for therapy response in a dual blockade (T+L) NACT setting. Methods: Patients with cT1c-cT4c HER2+ EBC were treated by paclitaxel (P) (80 mg/m2weekly) with L (750 mg p.o. daily) + T (2 mg/kg) weekly for 12 weeks. Adjuvant treatment with 4 cycles of Epirubicin/Cyclophosphamide (omission allowed in patients with pCR) and T for an additional 40 weeks was recommended. Primary objectives were pCR (ypT0/is/ypN0) and identification of a dynamic predictive test for pCR using a re-biopsy after three weeks of NACT (early response defined as central Ki67 decrease >30% (vs. baseline) and/or low cellularity (<500 invasive tumor cells)). Results: From 2013-2015, 64 patients (n=80 planned) were recruited. Overall pCR was 41% (41% for HER2+/HR+ (n=34) and 45.5% for HER2+//HR- (n=22)). A 0% pCR in the “non-responder” (n=7) group (vs. 50% in the “responder” (n=34) and 42% in the “missing response” (n=20) groups) is intriguing despite methodological limitations. Missing data for early response assessment in a substantial number of patients and negative DFS data from the ALTTO trial did not justify trial continuation. 27% of patients experienced severe adverse events (AE). 11.5% had > grade 3 AEs (including diarrhea, septic shock, leukopenia, and pneumonia). Conclusions: We observed a clinically meaningful pCR with moderate toxicity with only 12 weeks of paclitaxel weekly with dual HER2 blockade (T+L). Effect of additional chemotherapy in patients with pCR after 12 weeks of monochemotherapy remains questionable due to a strong prognostic effect of pCR in HER2+ EBC. In view of 0% pCR (by hypothesis-generating explorative analysis), a different treatment approach should be investigated in patients without “early response” by further prospective trials. Clinical trial information: 2012-003679-21.
Post-operative concurrent chemo-radiotherapy versus post-operative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: A randomized phase III trial (Trans Tasman Radiation Oncology Group 05.01 Trial; POST study).
Authors: Porceddu Sandro Virgilio , Poulsen Michael , Bressel Mathias , Stoneley Adam , Veness Michael , Kenny Lizbeth M. , Wratten Christopher , Corry June , Cooper Stephen , Fogarty Gerald , Collins Marnie , Collins Michael , Macann Andrew , Milross Christopher , Penniment Michael Gordon , Panizza Benedict , Rischin Danny 
Published: September 2018

6008 Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node > 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute & late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- & 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- & 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- & 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.
Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.
Authors: Shah Manisha H. , Wei Lai , Wirth Lori J. , Daniels Gregory A. , De Souza Jonas A. , Timmers Cynthia Dawn , Sexton Jennifer L. , Beshara Mamdouh , Nichols Debra , Snyder Norka , Devine Catherine E , Konda Bhavana , Busaidy Naifa Lamki 
Published: September 2018

6022 Background: BRAF mutations are present in ~44% of papillary thyroid carcinoma (PTC) and its role in development of PTC is well established. We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in BRAF mutated PTC and that combining it with trametinib (MEK inhibitor) would result in greater clinical efficacy than dabrafenib alone, through vertical inhibition of the RAF/MAP/ERK pathway and mitigation of potential mechanisms of resistance. Methods: Patients (pts) with BRAF mutated radioiodine refractory PTC who had evidence of disease progression within 13 months prior were randomized to Arm A (dabrafenib 150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO qd). Cross-over to Arm B was allowed at time of progression. Responses were assessed by modified RECISTv1.1 every 2 months. Primary endpoint was objective response rate (ORR) (complete-, partial- and minor-response). With assumed true ORR of 15% vs 35%; and 90% power to identify the correct regimen as most promising, 26 pts were to be accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts (median age 63 years, 38 females) were enrolled; 25% of pts had 1-3 prior therapy with multi-kinase inhibitors. Median follow up was 13 months. Preliminary efficacy results are outlined in Table. The treatment-related adverse events were similar to previously reported phase III clinical trial of these drugs in melanoma. Conclusions: Single agent dabrafenib, as well as combination of dabrafenib/trametinib are well tolerated therapies that result in similar high objective response rates with durable responses in pts with progressive BRAF-mutated PTC. BRAF-pathway targeted therapies provide novel treatment options. Clinical trial information: NCT01723202. [Table: see text]
Notch pathway inhibition with LY3039478 in adenoid cystic carcinoma (ACC).
Authors: Even Caroline , Lassen Ulrik Niels , Merchan Jaime R. , Le Tourneau Christophe , Soria Jean-Charles , Ferte Charles , Diener Jon Thomas , Yuen Eunice , Smith Claire , Oakley Gerard Joseph , Benhadji Karim A. , Massard Christophe 
Published: September 2018

6024 Background: ACCs have high levels of Notch-1 receptor expression and activation. LY3039478 (LY) is an orally bioavailable selective Notch inhibitor (Notch 1-4). Here we report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of LY in patients (pts) with ACC. Methods: Ongoing, multi-part, phase I trial enrolled pts with advanced or metastatic ACC, measurable disease, ECOG ≤1, and baseline tumor tissue. Eligible pts received LY 50 mg three times per week (TIW), on a 28-day cycle until disease progression. Safety assessments were based on CTCAE V4.0. Tumor responses were assessed using RECIST 1.1. Primary objectives are to confirm the recommended phase II dose of LY and document antitumor activity. Secondary objectives are safety and toxicity, PK and progression-free survival (PFS). Exploratory objectives include assessment for PET metabolic responses. Results: 22 pts have been enrolled and received LY 50mg TIW (13 men, 9 women; median age 60, range 41-82). All pts had metastatic disease; median treatment duration was 3 cycles (range 1-10) with 6 pts continuing on treatment. One pt had an unconfirmed partial response. Disease control rate (DCR) was 16/22 (73%), of which 4 pts had stable disease ≥ 6 months. In the overall group (n = 22) median PFS (mPFS) was 5.3 months (95% CI: 2.4, NE). mPFS was 7.7 (95% CI: 4.0, NE) for pts in second line (n = 7), while mPFS was 2.4 (95% CI: 1.1, NE) for pts in third line or more (n = 9). In pts without prior systemic therapy (n = 6) mPFS could not be estimated since 4 of those patients were censored. In preliminary analysis, 14 pts were assessed by PET, with 2 (14%) achieving partial metabolic response. Most frequent related adverse events (all grades) occurring in ≥20% of pts included diarrhea (55%), fatigue (45%), vomiting (36%), decreased appetite (27%), dry mouth (27%), and dry skin (23%). Grade 3/4 related treatment-emergent adverse events observed in more than one pt were diarrhea (n = 3) and squamous cell carcinoma of skin (n = 2). PK was assessed in 17 pts, with peak concentrations occurring approximately 2 hours post-dose. Biomarker and histologic analyses of pre and post treatment biopsies will be presented. Conclusions: LY showed activity (73% DCR) in ACC with a manageable safety profile. Clinical trial information: NCT01695005.
Long-term survival in oligometastatic head and neck cancer patients.
Authors: Leeman Jonathan Eric , Patel Suchit H. , Anderson Erik Steven , Tsai C. Jillian , McBride Sean Matthew , Dunn Lara , Sherman Eric Jeffrey , Lee Nancy Y. , Riaz Nadeem 
Published: September 2018

6029 Background: Aggressive therapies for patients with oligometastatic disease are increasingly being administered with definitive intent in the context of clinical trials. However, outcomes in oligometastatic head and neck squamous cell carcinoma (HNSCC) patients have not been well characterized. Methods: We reviewed outcomes from 1147 patients who received intensity modulated radiotherapy (IMRT) as part of definitive management for stage I-IVB HNSCC from 2001-2013 at our institution. The primary sites included oropharynx (n=735), oral cavity (OCC, n=182), larynx (n=180) and hypopharynx (n=50). Among patients who developed distant metastasis (DM), the the number of clinically or radiographically apparent tumors was assessed. Survival estimates following DM were generated using the Kaplan-Meier method and compared using log-rank testing. Cox proportional hazards models were used for univariate (UVA) and multivariate analyses (MVA). Results: A total of 148 (13%) patients developed DM at a median time of 10.7 months (range 0.3-81.2) after IMRT. The median follow-up time following DM was 48 months. 5-year survival following DM was significantly longer in patients with a solitary metastatic lesion compared to multiple lesions (table 1, p=0.001). Of the 19 patients with solitary metastasis, the 14 who received definitive local therapy with either surgery or radiation survived longer than those who did not (5-year survival 55.7% vs 0%, p=0.001), though patients who did not receive local therapy were of poorer performance status. On UVA and MVA, longer survival after DM was associated with presence of a solitary metastatic tumor (MVA hazard ratio 0.31, 95% CI 0.16-0.59, p=0.001). Conclusions: An oligometastatic phenotype characterizes HNSCC patients with solitary metastasis, especially when amenable to definitive local therapy. These findings have important implications regarding clinical trial design for HNSCC in the recurrent and oligometastatic setting. [Table: see text]
Treatment patterns in recurrent/metastatic head and neck squamous cell carcinoma in the US.
Authors: Nadler Eric S. , Joo Seongjung , Black-Shinn Jenny , Boyd Marley , Zhuo Joseph , Chirovsky Diana Romana 
Published: September 2018

6033 Background: Given the most recent FDA approval of cetuximab in 2008 for treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), the objective was to assess utilization of cetuximab and other treatments for R/M HNSCC in real world setting. Methods: Adult patients (pts) with R/M HNSCC who initiated systemic therapy between 9/1/2011-12/31/2014 were identified from iKnowMedelectronic health records database (McKesson Specialty Health) supplemented with chart abstraction. Pts were followed through 12/31/2015 to collect data on clinical characteristics, treatments and survival outcomes. Results: Among 325 pts with R/M HNSCC, median age was 62 yrs; 82% were male, and 67% had oropharyngeal cancer. The most common first line (1L) regimen consisted of platinum-based combinations (76%; Table 1); 63% received platinum+taxane +/-5FU and only 8% received platinum+cetuximab +/- 5FU. Median overall survival was 13.6 months (range 11.7-16.6). Following 1L therapy, 171 pts (53%) received a 2L regimen; 57 pts (18%) received platinum monotherapy and 8% received 2L platinum+taxane +/- 5FU, while only 12% received cetuximab mono- or platinum+cetuximab + /- 5FU. Among pts receiving 1L platinum combination, 32% were re-treated with platinum based therapy of which platinum monotherapy (23%) and platinum+taxane +/- 5FU (7%) were most common. Conclusions: Despite FDA approval and NCCN guidelines recommending use of cetuximab for palliative treatment of R/M HNSCC, our study demonstrates underutilization in both 1L and 2L settings, underscoring the need to understand reasons for underutilization and the need for newer efficacious treatments. [Table: see text]