bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-institutional phase II trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.
Authors: Bible Keith Christopher , Suman VeraJean , Menefee Michael E. , Smallridge Robert C. , Molina Julian R. , Maples William James , Karlin Nina J. , Traynor Anne M. , Kumar Priya , Goh Boon C. , Lim Wan-Teck , Bossou Ayoko R , Isham Crescent R , Webster Kevin P. , Kukla Andrea K. , Bieber Carolyn , Burton Jill K. , Harris Pamela Jo , Erlichman Charles 
Published: March 2020

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.
Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC).
Authors: Cabanillas Maria E. , Brose Marcia S. , Ramies David A. , Lee Yihua , Miles Dale , Sherman Steven I. 
Published: March 2020

5547 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET, VEGFR2, and RET that is currently undergoing evaluation in several oncology indications. Differentiated thyroid cancer (DTC) pts were included in this study based on involvement of the MET, VEGFR, and RET signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity and safety were also evaluated. Methods: Metastatic DTC pts who were enrolled to this study were required to be RAI-refractory, have progressed on standard therapies and have measurable disease. Cabo was given daily at a dose of 140 mg free base (equivalent to 175mg salt form) starting at Day 2. Rosi (4mg) was given Day 1 and Day 22 to complete PK assessment for drug-drug interaction (DDI). Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: 15 DTC pts were enrolled. Median number of prior regimens was 2 (11/15 pts had at least 1 prior VEGFR inhibitor). 8/15 pts (53%) had confirmed PRs including 1 pt with marked improvement of a bone infiltrating lesion; 6 (40%) had best response of SD; all 14 pts with ≥1 post-baseline scan experienced tumor regression (range: -9 to -55%). Disease control rate (PR + SD): 80% at 16 weeks; 10/15 (67%) remain on cabo with a median follow-up of 7.3 months. Median PFS and OS have not been reached. Most common Gr 3/4 AEs were: diarrhea (20%), lipase increased (20%), hypertension (13%) and palmar-plantar erythrodyesthesia (13%); one related Gr 5 event reported: hemoptysis due to aorto-trachael fistula in a pt with history of prior mediastinal XRT and extensive neck surgeries. PK data suggest that clinically relevant doses of cabo do not alter the Cmax or AUC0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: In pts with DTC, cabo treatment resulted in substantial anti-tumor activity. The safety profile of cabo was comparable to that seen with other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).
Response of chemoradiation therapy after induction chemotherapy failure in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Lim Yoojoo , Keam Bhumsuk , Koh Youngil , Lee Kyung-Hun , Kim Tae Min , Lee Se-Hoon , Hah Jeong-Hun , Kwon Tack-Kyun , Kim Dong-Wan , Wu Hong-Gyun , Sung Myung-Whun , Heo Dae Seog , Kim Kwang Hyun 
Published: March 2020

5552 Background: Although induction chemotherapy (IC) for LA-HNSCC has shown high response rates, some patients do not respond to IC. Surgery has been the usual choice for the non-responding patients, but practically, not all of these patients are eligible for operation. The purpose of this study was to evaluate the efficacy of definitive radiation therapy (RT) for the HNSCC patients who failed IC. Methods: We have retrospectively analyzed the outcome of patients with LA-HNSCC who were initially treated with IC at Seoul National University Hospital between Jan. 2006 and Dec. 2010. Chemotherapeutic regimens used were 5-FU/cisplatin, docetaxel/5-FU/cisplatin, and docetaxel/cisplatin with or without cetuximab. After IC, patients were treated with RT, concurrent chemoradiation (CCRT), or surgery, either alone or with postoperative RT. Treatment modality was chosen on multi-disciplinary basis of our institution. Response was evaluated using RECIST criteria. Results: A total of 225 LA-HNSCC patients treated with IC were analyzed. Median age was 54 (range 24-77). Primary tumor locations were oral cavity (39.5%), nasal cavity/paranasal sinus (13.1%), oropharynx (13.1%), nasopharynx (13.1%), larynx (7.9%) and hypopharynx (13.1%). Among the 225 patients, 38 (16.9%) patients did not respond to IC [stable diseases (SD) = 23 (10.2%), progressive disease (PD) = 15 (6.7%)], and their median overall survival was 14.5 months. Among the 38 non-responders, 14 (36.8%) patients were undertaken surgery and 22 (57.8%) unresectable or inoperable patients were treated with either definitive RT or CCRT. Responses to subsequent definitive RT or CCRT for 20 evaluable patients were as follows: complete response = 6 (30.0%), partial response = 7 (35.0%), SD = 3 (15.0%), PD = 4 (20.0%) Overall response rate to definitive RT or CCRT in non-responder to IC was 65.0% (95%CI: 44.1%- 85.9%). Nine out of 15 patients who showed PD to IC received definitive RT or CCRT and interestingly, 3 (33.3%) patients responded to definitive RT or CCRT. Conclusions: A significant portion of HNSCC patients who failed to IC can benefit from subsequent definitive RT or CCRT. Further prospective study is warranted.
Everolimus (RAD) as treatment in breast cancer patients with bone metastases only: Results of the phase II RADAR study.
Authors: Maass Nicolai , Harbeck Nadia , Mundhenke Christoph , Lerchenmuller Christian A. , Barinoff Jana , Lueck Hans-Joachim , Ettl Johannes , Aktas Bahriye , Kuemmel Sherko , Roesel Siegfried , Wagner Steffen , Müller Lothar , Bischoff Joachim , Luebbe Kristina , Schwedler Kathrin , Schmidt Marcus , Bauerschlag Dirk , Nekljudova Valentina , Loibl Sibylle , Von Minckwitz Gunter ,   German Breast Group
Published: March 2020

556 Background: RAD001 is an orally bioavailable rapamycin ester analogue, which acts by selectively inhibiting mTOR (mammalian target of rapamycin), a key player in downstream signaling of different pathways. In vitro, RAD stops formation and activity of osteoclasts. Treating progressive bone metastases in breast cancer (bc) with RAD seems reasonable. Methods: We evaluated RAD in a placebo-controlled, phase II, randomized discontinuation study in bc patients (pts) with bone metastases only. Pts were eligible if they had HER2-negative, hormone-receptor (HR)-positive or –negative bc, with a maximum of 2 previous lines of endocrine therapy (ET) and 1 previous line of chemotherapy (CT). All pts received zoledronate and pts with HR-positive bc could receive ET. All pts started with RAD during a run-in phase of 8 weeks. Pts with stable disease were randomized to RAD or placebo; pts with response continued with RAD and pts with progression went off study. Primary outcome was time to progression (TTP) in pts being stable on 8 weeks of RAD. It was assumed that placebo would obtain a median TTP of 8 weeks which would be increased to 16 weeks, thus requiring 76 randomized pts. It was expected that 70% of all pts would have stable disease after the run-in phase. Overall, 110 pts were needed. Due to slow recruitment and dysbalance between randomized and discontinued pts, recruitment stopped in 12/ 2010. Results: From 11/06 until 12/10, 89 pts were enrolled. Median age was 59.5 years. 93% had HR-positive disease. 15% had prior chemotherapy; 58% had prior ET for metastases. 1/3 received concomitant ET. Three pts did not start therapy, 41 discontinued during run-in phase, 32 due to progression. Six continued as responder. 39 pts with SD after run in phase were randomized to RAD or placebo. Twenty-seven stopped due to progression; 9 discontinued due to AE, 4 are still on treatment. 15 pts had 20 serious adverse events; 1 hyperglycemia and one alveolitis. The TTP in patients with RAD was 8.5 months vs. 2.9 months with placebo (HR: 0.559; 95% CI [0.284-1.10] p=0.092. Conclusions: Pts with bone metastases only had a longer TTP on RAD compared to pts on placebo. Overall 7/89 showed a sustained response on RAD + zoledronate ± ET.
Head and neck cancer in Fanconi anemia and dyskeratosis congenita.
Authors: Alter Blanche P , Giri Neelam , Savage Sharon H 
Published: March 2020

5563 Background: Fanconi Anemia (FA) and dyskeratosis congenita (DC) are inherited bone marrow failure syndromes (IBMFS) with extraordinarily high risks of cancer, particularly head and neck squamous cell carcinoma (HNSCC). The standardized incidence ratios (SIR) for solid tumors are 40 in FA and 10 in DC, and for HNSCC 700 and 900 respectively. In the general population, cancers of the oropharynx may be associated with human papilloma virus (HPV) more than the oral cavity. The specific locations of HNSCC in FA and DC have not been reviewed, and thus the hypothetical role of HPV in these cancers is unknown. Methods: Literature cases were reviewed through PubMed searches using the terms “Fanconi anemia” and “dyskeratosis congenita”. All papers were reviewed, and details of the specific cancers recorded. FA literature included reports from 1927 through 2011, and DC literature from 1910 through 2011. Participants in the National Cancer Institute (NCI) IBMFS retrospective/prospective protocol (NCI 02-C-0052, opened in 2002) were also analyzed for cancer. The HPV vaccine was not available during most of the time frame of this study. Results: There were 411 cases of cancer among 2190 (19%) cases of FA described individually in the literature, and 21 cancer cases out of 116 (18%) FA patients in the NCI cohort. HNSCC were reported in 112 FA literature cases (5%), and 9 (8%) in the cohort. The oropharynx was the initial site for HNSCC in 31/112 literature cases (28%) and 3/9 NCI cases (33%). With regard to DC, 51/647 (8%) cases in the literature had cancer, as did 9 of 94 (10%) NCI participants. HNSCC were reported in 21/647 (3%) DC literature cases, and in 5/94 (5%) from the NCI cohort. Four of the 21 HNSCC (19%) in the literature were oropharyngeal, and 2/5 (40%) in the NCI cohort. The cumulative incidences of any HNSCC in the NCI FA and DC cohorts were 50% and 21% by 40 years of age (censored at death from other causes). Conclusions: Patients with FA and DC have extremely high risks of HNSCC at substantially younger ages than the general population. Approximately 30% of these cancers occur in the oropharynx. The HPV vaccine could be important in prevention of these cancers. Future studies of the HPV status of oral cavity and oropharynx HNSCC tumors from patients with FA and DC will be informative.
Should age affect our treatment decisions for head and neck cancer?
Authors: Carballido Estrella M. , Burton Jon N , Pelayo Miguel Ricardo , McCaffrey Judith C , Padhya Tapan , McCaffrey Thomas V , Trotti Andy , Rao Nikhil G , Reich Richard , Tanvetyanon Tawee , De Conti Ronald C. , Kish Julie Ann 
Published: March 2020

5564 Background: Current opinion suggests elderly patients (pts) with head and neck cancer, those 65 or older, do not tolerate surgery, chemotherapy, or radiation as well as their younger counterparts. If this holds true, elderly pts may not be offered standard treatments to prevent assumed complications. Methods: A retrospective cohort study at our comprehensive cancer center was conducted of newly diagnosed pts with head and neck squamous cell carcinoma to explore differences in treatment-related complications between older and younger groups. We included data from the first 199 eligible pts (99 younger than 65 year old and 100 older than 65) evaluated between April 2009 and June 2010. Results: 79% of pts receiving treatment were male with a mean age of 54.9 and 71.6 years for the younger and older groups respectively. The older group had significantly more comorbidities (p < 0.001). The majority of older pts presented with oral cavity tumors (46%) while the oropharynx was the predominant site in the younger group (45%). 55% of younger and 49% of older pts presented with stage 4 disease across all sites. A total of 51 pts were p16 positive with no statistical differences between the groups. Surgery was the initial treatment for 57% of older pts (p < 0.008) while 46% of younger pts received concurrent chemotherapy and radiation as the primary treatment (p < 0.008). There was no statistically significant difference in surgical or radiation complications between the groups. Although most pts receiving chemotherapy experienced complications, older pts had slightly more (93% vs. 78%; p<0.031). The mean survival was 24.8 months with no statistical difference between groups. Significantly more pts in the older group, at last follow-up, were disease free (p < 0.012). Conclusions: The treatment of elderly pts with head and neck squamous cell carcinoma in our experience was congruent with that of younger pts. Elderly pts did not suffer more complications with surgery or radiation, however chemotherapy produced somewhat more complications in the elderly pts. Elderly pts did display less evidence of disease on follow-up. Age is always a consideration when treating individuals, but should not preclude the curative standard.
Correlation between PI3K/PTEN/AKT/mTOR pathway genetic variations and clinical outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment.
Authors: Fusi Alberto , Pfisterer Katharina , Klinghammer Konrad Friedrich , Knoedler Maren , Nonnenmacher Anika , Keilholz Ulrich 
Published: March 2020

5572 Background: The PI3K/PTEN/AKT/mTOR pathway is one of the most targeted in human cancers and alterations in the axis are frequent events in squamous cell carcinoma of the head and neck (HNSCC). Specific genetic variations in this pathway have been associated with variation in recurrence, survival and response in lung cancer and esophageal cancer. The aim of this study was to determine whether single nucleotide nucleotide polymorphisms (SNPs) in AKT1, AKT2, FRAP1, PI3KCA and PTEN identified in other cancers were associated with treatment response and clinical outcome in patients with HNSCC. Methods: Genomic DNA was extracted from FFPE tissue specimens of 45 patients with recurrent or initially metastatic HNSCC who received a combined treatment with docetaxel and cetuximab in a phase II study. Eleven single SNPs in the genes AKT1, AKT2, FRAP1 (mTOR), PIK3CA and PTEN were genotyped by means of Real Time PCR system or by direct sequencing and analysed for association with response to therapy and survival. Results: None of the SNPs was related to treatment response. Two SNPs (AKT2:rs8100018 and PTEN:rs12569998) were associated with variation in progression risk. The AKT2:rs8100018 homozygous variant resulted in increased risk, with a HR of 4.83 (95% CI, 1.11-21.03) and the PTEN:rs12569998 homozygous variant in an increased risk, with a HR of 2.36 (95% CI, 1.24-4.50). AKT2:rs8100018 and PTEN:rs12569998 genetic variation had an additive effect on risk of tumor progression. The AKT2:rs8100018 homozygous variant was significantly associated with overall survival (OS) with HR of 3.57 (95% CI, 1.06-12.00) while presence of one of the two variant alleles of AKT1:rs3803304 with a lower risk of death (HR: 0.51; 95% CI, 0.27-0.97). Conclusions: We found significant associations between common genetic variants in the PI3K/PTEN/AKT/mTOR pathway and outcome in patients with HNSCC. Despite the small sample size, patient cohort and treatment were homogeneous. As a consequence, evaluation of SNPs as a host factor may be considered in addition to tumor-specific mutations for personalized treatment development.
Gene expression as a predictor of radiotherapy or chemoradiotherapy response in head and neck squamous cell carcinoma patients: A molecular approach.
Authors: Lopez-Pousa Antonio , Leon Xavier , Quer Miquel , Quintana Ana , Vila Luis , Camacho Mercedes , Sullivan Ivana , Gallego Rubio Oscar , De Vega Josep M. , Farre Nuria , Barnadas Agust ,   Hospital Sant Pau
Published: March 2020

5590 Background: There are not validated markers of radioresistance in patients with a head and neck squamous cell carcinoma (HNSCC). The objective of our study was to explore the relationship between response to radiotherapy and the expression at transcriptional level of a panel of genes related with the HNSCC carcinogenic process. Methods: The study group was 76 consecutive HNSCC patients treated with radiotherapy (n=51) or chemoradiotherapy (n=25) with curative intention, and a minimum follow-up of three years. Thirty-seven patients were T1-T2 tumors and 16 had an advanced tumor (T3-T4). Biopsy specimens were performed from the primary tumor before treatment and conveniently stored until processing. Expression of genes related with cell cycle (cyclin D1), apoptosis (Bcl-XL), angiogenesis (VEGF), inflammation (IL-8), and tissue invasiveness (MMP-2 and MMP-9) were examined using a RT-PCR method. The continuous value of the mRNA expression level was evaluated with a classification and regression tree (CRT) method, considering the local control of the disease achieved with radiotherapy as the dependent variable. Results: During the follow-up 26 patients (33.8%) had a local failure. The CRT method found a significant relationship between VEGF and MMP-9 expression and local control of the disease. According the expression level of VEGF and MMP-9 the patients were classified in three groups: the A group (n=19) defined by a low expression of VEGF, the B group (n=19) defined by a high expression of VEGF and a low expression of MMP-9 and the C group (n=38) defined by a high expression of both VEGF and MMP-9. The 5-year local recurrence free survival was: A group 94.7% (CI 95%: 84.7-100%), B group 83.3% (CI 95%: 66.1-100%), and C group 37.6% (CI 95%: 21.0-54.2%). There were significant differences in the local control of the disease according to the VEGF and MMP-9 expression values (test log rank, P<0.0001). Conclusions: Expression of VEGF and MMP-9 genes may be a radiosensitivity marker for patients with HNSCC treated with radical intention. We didn’t find prognostic significance for other genes explored.
Impact of exogenous female hormone use (EHU) on breast cancer (BC) recurrence as assessed by the 21-gene assay (Oncotype DX).
Authors: Ledesma Wendy M. , Onitilo Adedayo A. , Zhang Chong , Kim KyungMann , Andreason Molly , Charlson John A. , Ridolfi Kimberly , Engel Jessica Marie , Wisinski Kari Braun , Millholland Robert , Dean James T , Tevaarwerk Amye 
Published: March 2020

563 Background: Observational studies suggest that EHU, such as oral contraceptive (OCPs) or postmenopausal hormone replacement therapy (HRT), increases the risk of developing BC. However, the prognosis of women taking EHU compared to nonusers remains controversial. The Oncotype Dx 21-gene assay RS predicts the distant recurrence risk for early stage, HR+ BC. We assessed RS in patients (pts) on EHU at diagnosis (users) vs nonusers. Methods: Retrospective chart review was conducted on BC pts with a RS, diagnosed 2005–2010. Stage, grade, estrogen (ER), progesterone (PR) and HER2 receptor status were abstracted. Manual review of medications, as well as electronic data pull within ≤5yrs of diagnosis, defined users as pts on EHU within 1 yr of diagnosis for ≥1 yr. Nonusers had been on EHU > 5 yrs before diagnosis or never. Comparisons between EHU users and nonusers were made using two-sample tests; chi-square or Fisher’s exact test for discrete data such as stage and ER status and t-test or Wilcoxon rank sum test for continuous data such as RS. All tests were at a two-sided significance level of 0.05. Results: 495 pts had RS. EHU was documentable for 475, 77 were using exogenous hormone at diagnosis. Type of hormone use included systemic HRT (48%), OCPs (36%), other (4%), and unknown (12%). For users vs nonusers, mean RS was 17 vs 19, (p=0.007, t-test). See table for other predictors. Conclusions: Prior study shows21-gene assay predict distant recurrence risk for HR+BC. In our study, an association existed between EHU and lower RS, suggesting that BC developing on EHU may have less risk of recurrence. Prospective evaluation is warranted. [Table: see text]