bluuebunny/crossref_metadata_2025_split huggingface dataset:
High level analysis of genomic data reveals complex predictors of response to trastuzumab (T) and chemotherapy for early stage breast cancer
Authors: Harris L. N. , Carter S. , You F. , Eklund A. , Hilsenbeck S. , Szallasi Z. , Chang J. 
Published: March 2020

544 Background: Trastuzumab (T) with chemotherapy has been shown to improve survival in breast cancer patients but de novo resistance is common. Identifying predictors of response to T in primary cancers may lead to an understanding of mechanisms of resistance. We investigated whether combined microarray datasets from patients with early breast cancer treated with preoperative T and chemotherapy could predict for response to therapy. Methods: Two cohorts of patients with HER2 3+/FISH+, stage II-III breast cancer were included in this analysis: trial 1- T and docetaxel (n=38), trial 2 -T and vinorelbine (n=48), both for 12 weeks. Frozen tissue core biopsies were available and successfully amplified in 41 patients (trial 1: 20, trial 2: 21 patients), with standard sample processing, RNA extraction, amplification and hybridization to Affymetrix U133 chips. Differential expression of genes and chromosomal regions, (defined as >10 genes in a given chromosomal cytoband), between patients with pathologic complete response (pCR) vs. those with residual invasive disease were examined. A measure of total functional aneuploidy (tFA) was calculated by summing net deviation in expression of all chromosomal regions and a gene expression signature of genomic instability (CIN) was derived by the identification of genes showing a high level of correlation with tFA . Results: By unsupervised hierarchical analysis, both datasets interdigitated suggesting no inherent bias. Gene expression patterns of individual genes showed weak associations with pCR. However, distinct statistically significant chromosomal regions, Chr2p23 Chr6q24 Chr7q33 Chr2p2 Chr12q21.31 Chr14q32.2 Chr1p34.2 Chr8q21.3, were associated with pCR to T therapy (p<0.005), and were confirmed in more than 50% samples by SNP analysis. In addition, resistant tumors showed higher levels of the CIN signature (p<0.005). Conclusions: We have shown that gene expression data can be merged and used for discovery predictive chromosomal regions associated T response. In addition, chromosomal instability was associated with T resistance. If validated, these distinct dysregulated chromosomal regions may serve as predictive markers of response to trastuzumab therapy. [Table: see text]
A concerted cell and serum proteomic approach for the identification of oral squamous cell carcinoma biomarkers
Authors: Mlynarek A. M. , Balys R. , Jie S. , Xu Y. , Hier M. P. , Black M. J. , Alaoui-Jamali M. A. 
Published: March 2020

5512 Background: Head and neck squamous cell carcinoma is the sixth most common cause of cancer deaths in the world. Despite extensive research, the 5-year survival rates have not changed significantly over the last decade. Presently, the lack of serum biomarkers for head and neck carcinoma limits early diagnosis and treatment monitoring of advanced disease. In this study, we used a proteomic approach on serum from mice bearing human oral squamous cell carcinoma xenografts and from conditioned cell culture medium from matched cell lines. Methods: Oral squamous cell carcinomas, with distinct invasive phenotypes, and adjacent normal tissue were obtained from human patients, and were transplanted orthotopicaly into tongues of RAG-2/γ(c) mice. After a 20% weight loss, the mice were sacrificed by exsanguinations. Two distinct proteomic protocols were used to analyze the mouse serum. The first involved albumin depletion followed by two-dimensional gel electrophoresis and MALDI. The second arm utilized the same albumin depletion followed by multidimensional-protein-information-technology (ESI-LC and MS/MS). The top candidate proteins, which were differentially expressed in the cancer bearing mice compared to matched controls were then validated by Western blot, immunoprecipitation, immunofluorescence, and/or immunohistochemistry analyses using mouse serum and conditioned medium from matched cell lines. Results: Orthotopic implantation of human tumor tissues in mouse tongue was successful in 100% of the mice tested. The human origin of these tumors was confirmed pathologically. A correlation between disease stages and invasiveness was observed. We identified over one hundred proteins as being differentially expressed between control and cancer-bearing mice (p < 0.05), including proteins involved in cell cytoskeleton signaling. The expression of these proteins was then validated in mouse serum, tissue xenografts, and conditioned medium from oral cancer matched established cell lines. Conclusion: We report the first proteomic in-vivo model of oral cancer for the identification of low molecular weight serum biomarkers. We identified candidates that can be exploited as potential markers for diagnosis of human oral squamous cell carcinoma. No significant financial relationships to disclose.
Induction chemotherapy (CT) with weekly paclitaxel, carboplatin, and cetuximab for squamous cell carcinoma of the head and neck (HN)
Authors: Kies M. S. , Garden A. S. , Holsinger C. , Papadimitrakopoulou V. , El-Naggar A. K. , Gillaspy K. , Lewin J. , Lu C. , Villalobos S. , Glisson B. S. 
Published: March 2020

5520 Background: To further determine the potential efficacy of combining cetuximab with chemotherapy, we conducted a phase II trial with induction CT consisting of 6 weekly cycles of paclitaxel 135 mg/m2, carboplatin auc 2 and cetuximab 400 mg/m2 week 1 then 250 mg/m2 weekly. Methods: Patients (pts) were treatment-naïve with staging T0–4, N2b/c/3, M0; PS 0/1; with any HN primary site; and evaluated for clinico-radiographic complete response (CR). Pathway signaling biomarkers and genomic profiling are planned. Following CT, patients underwent “risk-based” local therapy. Choice of surgery ± postoperative radiotherapy (RT), RT, or concomitant chemoRT was based upon tumor stage and site at diagnosis. Results: Patient entry (2/05–11/05) has concluded with 47 patients (33 m, 14 f), median age 53 years and range 21–78. Two patients are too early for response analysis. Oropharynx was the dominant primary site, N = 42, with staging: Tx N2b - 4, Tx N3 - 1; T1 N2b - 5, T1 N2c - 6, T1 N3 - 3; T2 Nx - 1, T2 N2b - 10, T2 N3 - 3; T3 N2b - 5, T3 N2c - 3, T3 N3 - 1; T4 N2b - 2 and T4 N2c - 3. Toxicity was acceptable. Sixteen (34%) pts had grade 3/4 leukopenia; 22 (47%) grade 3 folliculitis (median 5 cycles of cetuximab administered); and 2 (4%) serious hypersensitivity. All 41 evaluable pts achieved a response in the primary site, 7 (17%) PR and 34 (83%) CR. Forty-three of 44 evaluable patients achieved a nodal response, 31 (70%) PR and 12 (27%) CR. Overall, 11 of 45 (24%) pts were disease-free after CT. At this early point, 3 pts have had 4 tumor recurrences, 2 local and 2 distant. Conclusions: CT administered over 6 wks, with cetuximab, was feasible and highly active with all patients achieving a tumor response. Severe skin rash affected nearly 50% of pts. Preliminary survival data, and correlation of surrogate biomarkers with tumor response are to be presented. Supported by: Bristol Myers Squibb Oncology and Imclone Systems Grant #CS 2004–00011435 WC. [Table: see text]
Phase II study of combination cisplatin, docetaxel and erlotinib in patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC)
Authors: Kim E. S. , Kies M. S. , Glisson B. S. , Ginsberg L. E. , Holsinger F. C. , Burke B. J. , Truong M. , Tsao A. S. , Hong W. K. , Lippman S. M. 
Published: March 2020

5521 Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers and preclinical data has demonstrated possible synergy with platinums and taxanes. Treatment options for advanced or recurrent HNSCC are limited. A study of cisplatin and docetaxel showed a response rate of 40% and 9.6 month median survival. Erlotinib, an EGFR tyrosine kinase inhibitor, had a 4.3% response rate in HNSCC. Because of the possible synergy and efficacy, we proposed to study the combination of cisplatin, docetaxel and erlotinib in advanced HNSCC. Methods: Patients (pts) were required to have adequate performance status, measurable disease, no prior EGFR therapy, and may have received one regimen of induction, concomitant or adjuvant chemotherapy, but not for recurrent/metastatic disease. Sites of disease included squamous cell head and neck sites excluding nasopharynx and sinus. Treatment included docetaxel 75mg/m2 and cisplatin 75mg/m2, intravenously every 3 weeks and erlotinib 150 mg by mouth daily. Patients were treated with growth factor support. Results: 37 pts have been enrolled thus far. Median age is 56 years (range 39–72). Median ECOG PS is 1 (range 0–2). 32 pts are evaluable for confirmed response using RECIST criteria. Complete responses have been in observed in 3 pts, partial responses in 18 pts and 8 pts have stable disease for an overall response rate of 66% and disease control rate of 91%. Only 2 pts progressed after 2 cycles of treatment. 5 pts had grade 3/4 neutropenia (2 febrile),1 pt had grade 4 diarrhea, and 2 pts had grade 3 rash. The most common grade 1–2 toxicities were diarrhea, nausea, and rash. Conclusion: The combination of cisplatin, docetaxel and erlotinib is well tolerated and has very encouraging activity in advanced HNSCC. Data collection for response rate, duration of response and survival is ongoing. Trial accrual continues up to 50 patients and biopsies are being collected for correlative markers including downstream EGFR pathway markers (p-akt, mek, k-ras). The full data set will be presented at the annual meeting. [Table: see text]
Impact on quality of life (QoL) of the addition of docetaxel (T) to neoadjuvant cisplatin plus 5-fluorouracil treatment in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN): EORTC study 24971
Authors: Bernier J. , Coens C. , Remenar E. , Van Herpen C. , Germa Lluch J. , Stewart S. , Degardin M. , Spirlet C. , Vermorken J. B. 
Published: March 2020

5522 Background: The EORTC 24971 trial compared the efficacy and safety of two neoadjuvant regimens in the treatment of stage III or IV, M0 SCCHN. Eligible patients (pts) with primary tumor sites in the oral cavity, oropharynx, hypopharynx, and larynx and WHO performance status (PS) ≤1) were randomized to 2–4 cycles of cisplatin (P) 100 mg/m2 day 1, followed by a continuous infusion of 5-fluorouracil (F) 1000 mg/m2/day from days 1- 5 (PF), or T 75 mg/m2 + P 75 mg/m2 day 1 then F 750 mg/m2/day from days 1 - 5 (TPF), followed by locoregional radiation therapy (RT). The impact of the two regimens on QoL was a secondary endpoint. Methods: QoL was assessed at baseline, at cycles 2 and 4, and 6 and 9 months after RT using the EORTC QLQ-C30 questionnaire to obtain the Global Health Status/Quality of Life (GHS/QoL) score, and the Head and Neck Performance Status Scale (PSS-HN) to assesses the normality of diet, eating in public, and understandability of speech on a scale of 0 to 100. The EORTC QLQ-HN35 questionnaire was also administered at those time-points. Results: 358 pts were randomized to PF (181 pts) or TPF (177 pts). Baseline (BL) characteristics of the pts were well balanced between groups. TPF was superior to PF in terms of response rate, progression-free survival (primary endpoint), overall survival, and tolerability. Compliance with the QLQ-C30 questionnaire was good ranging from 96% at BL to 41% at 9 months post RT, and was similar between the treatment arms. GHS/QoL scores were comparable at BL between the two arms (p = 0.54) and improved in both arms on starting treatment. Over time this score remained stable with TPF, but decreased after RT with PF (treatment-time interaction: p = 0.009). Evolution of the PSS-H&N score was better on TPF (normality of diet p= 0.0064; eating in public p = 0.0004; understandability of speech p = 0.0003). Moreover, TPF was associated with a 30% reduction in the risk of WHO PS deterioration (p = 0.0158) Conclusions: The use of docetaxel in neoadjuvant treatment of SCCHN improves efficacy without deleterious effects on QoL and functional outcomes. [Table: see text]
Does positron emission tomography (PET) improve our ability to detect residual neck node (NN) disease in patients with squamous cell head and neck cancer (SCHNC) after definitive chemoradiotherapy?
Authors: Tan A. , Adelstein D. J. , Esclamado R. M. , Rybicki L. A. , Saxton J. P. , Wood B. G. , Lorenz R. R. , Strome M. , Carroll M. A. 
Published: March 2020

5526 Background: Management of the neck in patients undergoing non-operative treatment for SCHNC is controversial. This study details our experience using the neck exam, computerized tomography (CT), and PET to clinically evaluate patients for residual NN disease after definitive chemoradiotherapy. Methods: We retrospectively reviewed all patients with SCHNC with NN involvement at presentation, who were treated with definitive concurrent chemoradiotherapy using fluorouracil and cisplatin. Clinical restaging by neck exam, CT, and PET was accomplished 8–12 weeks after completion of treatment. Residual palpable nodes on exam, residual nodes larger than 1 centimeter, or with central necrosis on CT, or any residual hypermetabolic lymph nodes on PET were considered to be clinical evidence of residual NN disease. Persistent NN disease was confirmed only if pathologic involvement was identified at the time of neck dissection, or if regional recurrence developed. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy (Acc) were calculated for all three clinical assessment tools. Results: The study included 43 patients with 64 positive necks at diagnosis, followed for a median of 11.5 (range 3.9–43.3) months. All but two patients are alive. Planned neck dissection was performed in 26 necks after chemoradiotherapy, and was positive in four. Recurrent primary site or NN disease prompted a delayed neck dissection in eight necks, which was positive in three. The utility of these clinical assessment tools and combinations thereof are detailed in the table . Conclusions: Residual NN disease after definitive chemoradiotherapy was infrequent and not well predicted by PET. A positive PET in this setting is of little utility. Although a negative PET was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck exam and the CT. [Table: see text] No significant financial relationships to disclose.
Should early cancers of the oral tongue be kept under surveillance after wide excision alone? A prospective study
Authors: Gupta T. , Agarwal J. , D’Cruz A. , Ghosh-Laskar S. , Malde R. , Gupta M. , Shrivastava S. , Dinshaw K. 
Published: March 2020

5541 Background: The treatment of the clinically N0 neck in early stage oral tongue cancer remains controversial. Several clinico-pathologic criteria that can reliably identify an increased risk of occult metastases in the neck have been proposed. Our aim was to assess the impact of elective neck dissection (END) on outcome and correlate it with clinico-pathologic criteria for patient selection for surveillance. Methods: Patients with early stage cancer of the oral tongue (T1–2, N0) after undergoing wide excision with or without END were prospectively kept under observation. Patients having adverse histological features necessitating adjuvant radiotherapy were excluded. All patients gave informed consent and were closely followed. Relapsers were offered appropriate salvage therapy. The primary end-point for our prospective phase II study was the impact of END on relapse-free survival (RFS) with an estimated sample size of 50 patients. Overall survival (OS) was a secondary endpoint. Results: Fifty three eligible patients were consecutively accrued on the trial after surgery. Forty eight patients underwent per oral wide excision, with only 5 requiring a neck approach. Twenty two patients underwent upfront END. Twenty four patients relapsed (23 of which had some loco-regional component). The risk of neck recurrence in patients whose necks were not dissected electively was significantly higher than in patients treated with END (55% vs 9% respectively, p = 0.0016). The 3-year RFS (69.1% vs 40.9%, p = 0.008) and OS (87.2% vs 42.6%, p = 0.0228) was significantly better for patients treated with END. Conclusions: Regional recurrences are the most important cause of failure after wide excision alone. END which achieves excellent disease control in the neck and significantly improves RFS and OS should be considered routine for early stage oral tongue cancer. No significant financial relationships to disclose.
A phase II trial of BAY 43–9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): A Southwest Oncology Group (SWOG) trial
Authors: Williamson S. K. , Moon J. , Huang C. H. , Guaglianone P. , Wolf G. T. , Urba S. G. 
Published: March 2020

5550 Background: Bay 43–9006 (Sorafenib) is a potent Raf-1 and B-Raf kinase inhibitor of the RAS/RAF/MEK/ERK pathway. The compound also inhibits protein tyrosine kinases associated with VEGFR-2 and 3 as well as PDGFR-B. We conducted a phase II trial to evaluate the efficacy of BAY 43–9006 in chemotherapy naive patients with metastatic or recurrent HNSCC. Methods: Chemotherapy naïve patients with histologically proven squamous cell carcinoma of the head and neck either metastatic, persisted or recurred following definitive surgery and/or radiation therapy, and not amenable to salvage surgical resection were eligible. Patients may have received only one induction or adjuvant chemotherapy regimen provided that at least 6 months have elapsed since the last course was administered. Patients must have adequate cardiac, hematologic, renal and hepatic function and a Zubrod Performance Status of ≤ 1. Specimens were obtained from either archival or fresh pre-treatment biopsies and at the time of progression of disease for molecular correlative studies. BAY 43–9006 was administered orally at 400 mg BID on a continuous basis, in 28-day cycles. Responses were evaluated every 8 weeks according to RECIST criteria. Initially 20 patients will be registered. If one or more confirmed responses are observed in the first 20 patients, an additional 20 patients will be registered. Results: Thirty-eight patients (31 males, 7 females, median age 64 years) have been enrolled to date. Twenty-seven patients are evaluable for toxicity. The drug was generally well tolerated. There have been 2 Grade 4 toxic events - one cerebral ischemia and an asymptomatic pulmonary embolus. Grade 3 toxicities include 2 patients with hand/foot syndrome, 4 with stomatitis or oral pain, and one episode each of anorexia, dysphagia, hypertension, and ulceration. The most common grade 2 toxic events were fatigue (8 pts.), anorexia (8 pts.), stomatitis (5 pts.), and hypertension (4 pts.). Complete accrual to 40 patients is anticipated by January 31, 2006. Conclusions: BAY 43–9006 is well tolerated. Updated toxicity data will be reported. Preliminary response, time to progression and survival data will be presented. [Table: see text]
Association of serum level of YKL-40 in patients with squamous cell carcinoma of the head and neck with survival
Authors: Roslind A. , Johansen J. S. , Christensen I. J. , Bentzen J. , Nielsen D. L. , Price P. A. , Andersen E. 
Published: March 2020

5551 Background: High serum YKL-40 is associated with poor prognosis in breast-, colorectal-, ovarian-, prostate-, small cell lung carcinoma and malignant melanoma. YKL-40 is secreted by cancer cells, macrophages and neutrophils. Its function in cancer is unknown. It may be a growth factor, play a role in angiogenesis or protect against apoptosis. The aim was to examine serum YKL-40 in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods: YKL-40 was determined by ELISA (Quidel, Santa Clara, CA) in serum samples from 138 patients with SCCHN (median age 60, range 44–92 years) before surgery and/or fractionated radiotherapy (total dose of 60–68 Gy, 2-Gy fractions). 42 patients had stage 1, 28 stage 2, 22 stage 3, and 46 stage 4 disease. The median follow-up time was 4.0 years (range 15 days–8.5 years). 91 patients had died. Results: Serum YKL-40 was increased (p < 0.001) in patients with SCCHN (median 120 μg/l, range 25–1848 μg/l) compared to healthy controls (43 μg/l, 20–184 μg/l, n = 245). Serum YKL-40 was elevated in 52% of the patients. Patients with stage 1 disease had lower, but non-significant, serum YKL-40 compared to patients with stage 2–4 disease (median 113 μg/l, range 25–1000 μg/l vs. 139 μg/l, 29–1848 μg/l, p = 0.06). Patients with high serum YKL-40 had significantly shorter survival than patients with normal serum YKL-40 (33 months vs. 74 months, p = 0.01 logrank test). Univariate analysis of serum YKL-40 (log transformed and treated as a continuous covariate) showed significant association with overall survival after start of therapy (HR = 1.4, 95% CI: 1.2–1.7, p = 0.0004). Multivariate Cox analysis including age, stage and serum YKL-40 (log transformed and treated as a continuous variable) showed that stage (stage 3–4 vs. stage 1–2, HR = 3.0, 95% CI: 1.9–4.6, p < 0.0001) and serum YKL-40 (HR = 1.5, 95% CI: 1.2–1.8, p = 0.0003) were independent prognostic variables of overall survival. Conclusions: Serum YKL-40 is a prognostic biomarker of overall survival in SCCHN patients. No significant financial relationships to disclose.
A phase II study of single agent depsipeptide (DEP) in patients (pts) with radioactive iodine (RAI)-refractory, metastatic, thyroid carcinoma: Preliminary toxicity and efficacy experience
Authors: Su Y. B. , Tuttle R. M. , Fury M. , Ghossein R. , Singh B. , Herman K. , Venkatraman E. S. , Stambuk H. , Robbins R. , Pfister D. G. 
Published: March 2020

5554 Background: RAI-refractory thyroid cancer carries a poor prognosis, and no effective systemic therapy exists. DEP is a potent histone deacetylase inhibitor with broad in vitro and phase I anti-tumor activity, and has restored sodium-iodide symporter expression and RAI avidity in thyroid cancer cell lines. Methods: Eligible pts have confirmed papillary, follicular, or Hürthle cell carcinoma, progressive measurable disease, and adequate hepatic/renal function. All pts are RAI-refractory by diagnostic RAI whole body scan (WBS). Prior chemotherapy in the recurrent/metastatic setting, and history of significant cardiac disease are exclusions. DEP 13 mg/m2 IV is given on day 1, 8, and 15, every 28 days. A novel Simon 2-stage design specifies an initial accrual of 21 pts, with expansion to 41 total pts if 2 RECIST responses or 6 pts with PFS at 6 months are observed. Primary outcome is RECIST response rate. Change in RAI avidity (by diagnostic RAI WBS) is a secondary outcome. Results: To date, 14 pts have been enrolled: female 50%, median age 62 (42–78), median Karnofsky 90 (70–100), papillary/follicular/Hürthle histology (7/1/6). Grade 3–5 toxicities possibly related to drug: grade 5 sudden death (1); no grade 4 toxicity; grade 3 toxicity - fatigue (1), dysphagia (1), dyspnea (1). No grade 3 thrombocytopenia (phase I DLT) has been observed. Grade 1 (6) and grade 2 (4) fatigue have been common. As a result of the grade 5 event, protocol accrual and treatment were suspended temporarily. After NCI-CTEP review, more restrictive cardiac exclusions were added and protocol accrual was resumed. Response at 2 months: stable disease (4); progression (2); inevaluable (6, due to protocol suspension); withdrew consent (1); too early (1). In a proof-of-principle event, clinically significant restoration of RAI avidity was observed in a 78 year-old woman with papillary carcinoma. Per protocol, she was taken off study and given treatment-dose RAI; post-therapy WBS confirmed dramatic RAI avidity. Conclusions: Preliminary signs of in vivo reversal of RAI resistance have been observed. Accrual continues with more restrictive cardiac exclusions, and close surveillance for cardiac events. No significant financial relationships to disclose.