bluuebunny/crossref_metadata_2025_split huggingface dataset:
CXCR4-CXCL12 axis: Pivotal role as a metastatic mediator in small cell sarcoma
Authors: Dumont S. N. , Aslam M. I. , McAuliffe J. C. , Yang D. , Nolden L. K. , Oyedeji C. O. , Trent J. C. 
Published: August 2020

10569 Background: The chemokine CXCL12, and its receptor CXCR4, are expressed in over 23 different types of cancers, and have been associated with the metastatic phenotype and inferior clinical outcomes. Given the poor prognosis after failure of front-line therapy for patients with metastatic Ewing's sarcoma (EWS) and rhabdomyosarcoma (RMS), we examined the functional role of CXCR4 in these small cell sarcoma in vitro. Methods: Human EWS and RMS cell lines and tissue were used to study CXCR4 expression and activation. Immunoblotting techniques were used to evaluate CXCR4 activation and inhibition. Cell viability, cell cycle, apoptosis, chemosensitivity, migration, and invasion assays were utilized to assess the effects of the small peptide CXCR4 antagonist, CTCE-9908 (Chemokine Therapeutics) on cultured cells. Results: CXCR4 was highly expressed on 46 % of human RMS tumor samples. CXCR4 underwent phosphorylation after stimulation with CXCL12 in EWS and RMS cell lines with downstream activation of Akt, p42/44 MAPK, JAK2 and PLCγ1 in select cell lines. CTCE-9908 was able to specifically inhibit downstream signaling of Akt, p42/44 MAPK and JAK2. Decrease in cell proliferation (20–30%, p < .05), increase in cell apoptosis (20–40 %, p < .05) and cell cycle arrest was also observed with CXCR4 blockade. CTCE-9908 significantly inhibited migration and invasion (68–93 %, p < .05) in our cell lines. Conclusions: CXCR4-CXCL12 axis may be important in EWS and RMS metastasis. These results provide evidence that CTCE-9908 may be a novel therapy for these sarcomas. No significant financial relationships to disclose.
Prognostic factors in adolescents and young adults (AYA) with high-risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on two pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials
Authors: Kasper B. , Ouali M. , Van Glabbeke M. , Blay J. , Bramwell V. H. , Woll P. J. , Schöffski P. 
Published: August 2020

10573 Background: We conducted a retrospective study pooling data from two clinical trials in high risk STS patients with the objective to compare two different age groups: 15 - 29 years (AYA population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population. Methods: Patients selected for analysis were treated in two randomized trials of adjuvant chemotherapy in STS (EORTC 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n = 161, median FU 9.46 years; patients ≥ 30 years: n = 632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumor size and localization (limb vs. other), absence or presence of local recurrence and treatment (control arm vs. adjuvant chemotherapy). Results: Patients’ characteristics were globally similar with two exceptions, histological subtype (p = 0.0043) and tumor size (p < .0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29 %), whereas leiomyosarcoma (18 %), malignant fibrous histiocytoma (MFH, 16 %) and liposarcoma (15 %) were more frequent in patients ≥ 30 years. For OS, independent favorable prognostic factors were low grade and small tumor size for both groups; radical resection and MFH or liposarcoma subtype were factors of favorable prognosis for patients ≥ 30 years only. For RFS, favorable prognostic factors were small tumor size and low grade for both groups; tumor location in the extremities was a factor of favorable prognosis for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favorable factors for patients ≥ 30 years only. Conclusions: On the basis of these data, significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications on the treatment of STS patients in different age groups as well as the design of future clinical trials. No significant financial relationships to disclose.
A phase I study of palifosfamide in combination with doxorubicin: Safety and preliminary efficacy
Authors: Camacho L. H. , Chawla S. P. , Chua V. , Abbadessa G. , Komarnitsky P. B. , Lewis J. 
Published: August 2020

10577 Background: Palifosfamide, a bi-functional DNA alkylator is the active metabolite of ifosfamide (IFOS), that lacks the toxicity associated with non-active IFOS metabolites and does not require activation. Recent phase II data shows single agent activity in advanced refractory sarcoma. Marked preclinical synergistic efficacy of palifosfamide in combination with doxorubicin provides a strong rationale for clinical evaluation of this combination regimen. Methods: Eligible subjects with advanced refractory tumors were included if no standard therapy exists and if doxorubicin treatment is medically acceptable. Palifosfamide was administered on days 1 - 3 of a 21 day cycle, starting dose of 100 mg/m2. Doxorubicin was administered on day 1 of 21 day cycle, starting dose of 60 mg/m2. Dose was escalated up to MTD or palifosfamide 150 mg/mg2, doxorubicin 75 mg/m2. Pharmacokinetics (PK) for palifosfamide were determined and compared to those obtained in murine PK/efficacy studies. Results: 13 patients with advanced tumors (8 with soft tissue sarcoma - STS, 5 with SCLC, neuroendocrine and osteosarcoma) have been treated with 8 patients still on treatment. All had ECOG PS <2, median age was 58, and 3 had received prior IFOS. With 51 cycles administered, the combination has been well tolerated, with no dose-limiting toxicities reported. Pts did not receive Mesna or hydration. Study-related Grade 3/4 adverse events include neutropenia and thrombocytopenia. PK evaluation indicates that palifosfamide exposure and Cmax at clinically well-tolerated doses are comparable with those in murine models resulting in marked synergy with doxorubicin. Efficacy in 12 evaluable pts: 3/12 PRs, (2/8 PRs for STS); PFS median duration 20 weeks and ongoing. Conclusions: Palifosfamide in combination with doxorubicin is easy to administer, and has been very well tolerated with no encephalopathy, no hemorrhagic cystitis and no renal toxicity. Early efficacy data has prompted an ongoing randomized phase II study in STS comparing doxorubicin 75 mg/m2 to palifosfamide 150 mg/m2 + doxorubicin 75 mg/m2. [Table: see text]
Circulating tumor cells and risk of venous thromboembolism in metastatic breast cancer patients
Authors: Mego M. , De Giorgi U. , Hsu L. , Andreopoulou E. , Valero V. , Dawood S. , Handy B. , Reuben J. M. , Cristofanilli M. 
Published: August 2020

1060 Background: Cancer is well-recognized risk factor for venous thromboembolism (VTE), and VTE is associated with a higher risk of death in cancer patients. Coagulation activation by tissue factor (TF) is associated with cancer growth and disease progression. Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer (MBC) patients. The aim of this study was to test the hypothesis that CTCs are associated with the risk of VTE in MBC patients. Methods: This retrospective study included 362 MBC patients treated in M. D. Anderson Cancer Center between January 2004 and December 2007. CTCs were detected and enumerated using the CellSearch system. Patients were assigned to cohorts based on the highest CTC counts during the course of the disease. All venous thrombosis and/or pulmonary embolism in the presence of unequivocal medical documentation were classified as events. Results: At a median follow up of 11.1 months (range 0–38 months) 30 patients (8.3%) experienced VTE. Median survival was 16.3 months vs. 37.2 months (p = 0.003) in patients with and without VTE, respectively. Patients with ≥ 3 CTCs had an elevated risk of VTE in comparison to patients with < 3 CTCs (12.1% vs 3.7%; p = 0.003). In multivariate analysis, the presence of visceral metastasis, increased number of metastatic sites and ≥ 3 CTCs were associated with the risk of VTE. Conclusions: This retrospective study showed that CTCs are associated with increased risk of VTE in MBC. Prospective assessment of coagulation status and its correlation to CTC counts and clinical outcome are warranted. No significant financial relationships to disclose.
cMET expression in HER2+ MBC patients with first-line lapatinib (L) treatment
Authors: Liu Y. , Liu L. , Shi H. , Greger J. G. , Jackson K. D. , Marty-Ethgen P. , Gilmer T. M. , Martin A. 
Published: August 2020

1073 Background: Overexpression of MET correlates with poor prognosis in breast cancer (Garcia et al., 2007) and is a factor associated with decreased sensitivity to L in HER2+ breast tumor cell lines in vitro (Liu et al., submitted). To test whether MET expression was associated with resistance to L in the clinic we evaluated baseline tumor MET expression levels and clinical outcome to L in 64 patients who participated in the EGF20009 trial of monotherapy L as first-line treatment in HER2+ advanced or MBC. Methods: RNA was extracted from FFPE tumors and MET and HER-2 gene expression was measured by qRT-PCR (Response Genetics, Inc., Los Angeles, CA). The correlation between expression levels of MET, HER2, and clinical outcome (overall response and progression free survival) was performed using JMP software. Results: A trend towards an association with increased MET expression and decreased response (p < 0.054) was observed.. Patients with high HER2 and low MET gene expression had the longest PFS (median difference = ∼9 weeks) compared to patients with low HER2 and high MET gene expression (p < 0.0038). Conclusions: These data support investigating a combination study of L and GSK1363089, a multi-kinase MET inhibitor, in HER2+ BC patients with high MET gene expression. [Table: see text]
New biweekly combination of trastuzumab, docetaxel, and gemcitabine for HER2-positive metastatic breast cancer: First early results from a phase II multicentric trial on behalf of Gruppo Oncologico Italia Meridionale
Authors: Cinieri S. , Orlando L. , Lorusso V. , Filippelli G. , Maiello E. , Blasi L. , Verderame F. , Barni S. , Pisconti S. , Colucci G. 
Published: August 2020

1096 Background: The clinical activity of the combination of chemotherapy plus trastuzumab in HER-2 overexpressing metastatic breast cancer has been well documentated. We report the first results in terms of efficacy and safety of a phase II trial on biweekly combination of trastuzumab plus docetaxel and gemcitabine as first line therapy in HER-2-positive metastatic breast cancer patients. Methods: Patients at first relapse or with synchronous metastasis, were treated with trastuzumab (4 mg/kg, loading dose 6 mg/kg) plus gemcitabine (1000 mg/m2) plus docetaxel (50 mg/m2) as biweekly schedule. Primary end-point was overall response rate (ORR), secondary end-point time to progression (TTP), clinical benefit rate (CBR; PR+ CR + prolonged SD for ≥ 24 weeks), and tolerability. Based on previous data, an ORR greater than 60% was considered to indicate clinical activity in this two stage design trial. Results: A total of 26 patients with histologically confirmed, measurable MBC, tumors scored as +3 positive for HER-2 by immuno-histochemistry or FISH +, no pretreated with chemotherapy or trastuzumab for metastatic disease have been enrolled, 22 actually evaluable for response and toxicity. Median age was 49 years (range 34–66), visceral metastases were present in most patients (73%). Median number of cycles was 8 (range 3–12). The ORR was 86% (95% CI, 80–91%), with two CR (9 %) and 17 PR (77%). 3 patients had SD, 1 prolonged (14%). The CBR was 91% (95% CI, 87%-94%). No progression of disease was observed. Median TTP was 7 months (range 5- 9+ months). The worst toxicity was WHO grade 2 neutropenia and grade 2 gastric pain. Conclusions: In this phase II study, the biweekly combination of trastuzumab, gemcitabine, and docetaxel in HER-2-positive breast cancer is very active. The toxicity observed was manageable and did not lead to treatment discontinuation. Thus, the patients accrual is ongoing to the preset target of 50 patients. No significant financial relationships to disclose.
Cisplatin chemotherapy in the treatment of BRCA1-positive metastatic breast cancer (MBC)
Authors: Byrski T. , Foszczynska-Kloda M. , Huzarski T. , Dent R. , Gronwald J. , Cybulski C. , Debniak T. , Gorski B. , Lubinski J. , Narod S. 
Published: August 2020

1099 Background: Preclinical data suggest that women with BRCA1 related breast cancers may be particularly sensitive to chemotherapeutic agents that cause DNA damage such as cisplatin chemotherapy. This study was conducted to assess the efficacy and safety of cisplatin chemotherapy in patients with BRCA1 positive MBC. Methods: This was a multicenter, open label, single arm study of cisplatin 75 mg/m2 given intravenously every three weeks until disease progression or toxicity. The primary objective was to assess antitumour activity of cisplatin, as measured by clinical benefit response (CR, PR, or SD ≥ 6 months). Eligible patients had locally recurrent or MBC, had 0–2 prior chemotherapy regimens in the metastatic setting, and had received prior therapy with an anthracycline. Patients were restaged every eight weeks. The study protocol was approved by the institutional review boards of participating institutions. Results: A total of 15 patients were enrolled. Mean age was 48.1 years (range: 32 to 70). ECOG performance status scores were 0 (6 pts), 1 (5 pts), 2 (4 pts). All patients had a confirmed BRCA1 mutation (7 with C61G mutation, 7 with 5382 insC, 1 with 4153delA). Five patients (33%) were ER or PR + and none were HER-2+. Prior history of MBC chemotherapy included 1 regimen (4 pts) and 2 regimens (7 pts). Seven (46%) and 4 (26%) patients had complete and partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, for an overall response rate of 72%. Median duration of response has not yet been reached. In general, cisplatin was well tolerated. Neutropenia was the commonest toxicity with 33% grade 2 (6,7% and 0%, grades 3 and 4 neutropenia). No patients developed febrile neutropenia. Conclusions: Significant activity and favorable toxicity profile provides a basis for considering cisplatin for further evaluation in phase III trials for women with BRCA1 positive MBC. No significant financial relationships to disclose.
Selecting subjects for a therapeutic target in colorectal cancer (CRC): Using a clinical database to enrich for patients harboring the BRAFV600E mutation
Authors: Tie J. , Sieber O. M. , Gibbs P. , Lipton L. , Jorissen R. N. , Langland R. , Kosmider S. , McKay D. , Nolop K. B. , Desai J. 
Published: August 2020

11003 Introduction: The BRAFV600E mutation (BRAF) causes constitutive activation of the RAS-induced MAPK pathway and is found in 10% of colon cancers. B-RAF inhibitors are in early clinical development, but their development in CRC will be challenging unless subsets of patients (pts) with higher rates of BRAF can be defined. The mutation rate in rectal tumors, the concordance between primary and metastases, and the prognostic/predictive significance of BRAF are current gaps in knowledge. Methods: 481 primary tumors and 80 matched primary-metastasis (prim-met) pairs were analysed from a pre-defined cohort of pts with CRC based on age (≥ 70 vs < 70 years), gender, tumor site (right-R, left-L and rectum), stage (A to C vs D) and ≥ 2 years follow-up. BRAF was assessed by routine sequencing of exon 15 and by a mutant-specific PCR assay. KRAS (KRAS-codon 12 and 13) and MSI (Bethesda markers) status were also examined. Results: Overall prevalence of BRAF was 11%. BRAF (see table ) was independently associated with increasing age, female gender and R-sided cancer, but not with stage. Mutations were rare in rectal cancers. BRAF was associated with inferior overall survival in stage D pts (log-rank, p = 0.0003; HR 0.38, 95% CI, 0.10–0.51). Survival analysis will be further stratified by treatment received. No difference in outcome was seen in preliminary analysis of earlier stage cancers. Mutation frequencies in the prim-met pairs were 38% (30/80) and 1.3% (1/80) for KRAS and BRAF, respectively. Overall concordance was 88% (70/80) for KRAS and 100% (80/80) for BRAF status. Conclusions: The development of selective B-Raf inhibitors in CRC is potentially more attractive due to the ability to define patient subsets with a higher prevalence of BRAF mutations. Analysis of the primary tumor reliably predicts the status of metastatic disease in the same patient. The association between BRAFand poor outcome will need to be considered when interpreting the result of studies targeting this mutation. [Table: see text] [Table: see text]
Establishment of human primary non-small cell lung cancer xenograft models for test of cytotoxic and targeted anticancer drugs
Authors: Liu C. , Liu Y. , Chen D. , Tang Z. , Pan W. , Wery J. , Chen Y. 
Published: August 2020

11008 Background: New oncology drug development has moved from general cytotoxic agents to molecular target-directed therapeutics. Consequently, there is a need to identify tumor types and individual patient tumors that express the target and could benefit from more selective therapies in clinical trials. Therefore, the in vivo models used in preclinical development should be“disease-oriented” and target-directed. Recently, we developed non-small cell lung cancer (NSCLC) xenograft models by transplanting human fresh tumor fragments into nude mice, which have been used for test of cytotoxic and targeted anticancer drugs. Methods: The fresh NSCLC tumors were collected from local hospitals. The tumor fragments were subcutaneously implanted into nude mice. The EGFR and K-ras mutation status of the tumors were investigated and compared with the efficacy results. The test drugs included paclitaxel, gemcitabine, and the epidermal growth factor receptor (EGFR) inhibitor erlotinib. Results: A total of 72 NSCLC samples were implanted, and 13 tumor models were established (tumor taking rate 18%) for the first passage. The tumor taking rates were higher in the second and third passages (80–100%). Paclitaxel and gemcitatbine produced tumor growth inhibition rates of 50–53% regardless of the EGFR and K-ras mutation status. While erlotinib demonstrated a significant antitumor activity only in the tumors bearing EGFR mutation with wild-type K-ras, which were consistent with their clinical findings. The tumor xenografts’ architecture, the cell and histopathological morphology from the three generations mirrored the original patient cancers. Conclusions: These results suggest that human primary tumor xenograft models provide a unique renewable source of tumor material for test of novel anticancer agents. They may predict more relevant clinical response rates and higher correlation with clinical findings than use of xenograft models established from long-term cultured cancer cell lines, especially for test of target-oriented therapeutics in new drugs development programs. No significant financial relationships to disclose.
Notch-associated expression profiles in basal-like and claudin-low breast cancer molecular subtypes
Authors: Prat A. , Karginova O. , Fan C. , Perou C. M. 
Published: August 2020

11017 Background: An attractive candidate target for breast cancer (BC) and BC tumor-initiating cells is the Notch signaling pathway. To better understand the potential dependence of breast cancer upon Notch-signaling, we used a genomic approach to study the activation of this pathway in the different molecular subtypes. Methods: Breast basal-like, luminal and HER2+ cell lines were examined for sensitivity to gamma-secretase inhibition (GSI). Gene expression data from the most sensitive cell line was analyzed during treatment and upon releasing from GSI (4h, 8h and 24h post-treatment). Using an unsupervised analysis, all time points were hierarchically clustered and genes that changed in expression were identified (SAM one-class). This Notch-associated signature identified in vitro was used to classify 2 distinct sporadic breast tumor populations (UNC and NKI, n=495). Each tumor sample was categorized into 6 molecular subtypes (basal-like, claudin-low [submitted], luminal A/B, HER2-enriched and normal-like). Results: In vitro, breast basal-like cell lines SUM102 and SUM149 were more sensitive to GSI (IC50, 0.3 and 1.5μM, respectively) compared to the luminal MCF7 (>10μM) and HER2+ SKBR3 (>5μM) cell lines. Over 340 genes that changed in expression (FDR<0.03%) were identified in SUM102, including known targets of the canonical Notch pathway (Hes1 and Hey2). Selected GO terms overrepresented in this signature were the following (EASE score, p<0.01): Wnt and Hedgehog signaling, embryonic development and cell differentiation. In vivo, 2 distinct gene clusters were evident in both populations, one of which was predictive of poor patient outcome. This Notch-associated poor prognostic signature was highly expressed in >90% of basal-like tumors. The second cluster was highly expressed in the recently identified claudin-low subtype, and was uniquely enriched with genes involved in cell differentiation (Sox7/9, Hey2, Dll1, Fzd5) and cell adhesion. Conclusions: Notch associated expression profiles are associated with basal-like and claudin-low BC subtypes, providing additional biological insight of pathway activation. GSI could represent a novel strategy for both subtypes, which represent the vast majority of the “triple negative” population. No significant financial relationships to disclose.
Reduction of elevated plasma osteopontin levels with resection of non-small cell lung cancer (NSCLC)
Authors: Blasberg J. D. , Pass H. I. , Flores R. M. , Donington J. S. 
Published: August 2020

11019 Background: Plasma osteopontin (OPN) levels in advanced NSCLC correlate with response to therapy and survival but the role plasma OPN in diagnosis or monitoring of early stage NSCLC has not been investigated. We hypothesize that plasma OPN levels are elevated in early stage NSCLC and that resection results in a measurable reduction. Methods: Pre-operative (pre-op) plasma OPN levels (ng/ml) were measured by ELISA (IBL-Japan) in a discovery set of 60 early stage NSCLC patients and compared to 56 current or former smokers. Pre-op OPN was validated in an independent cohort of 78 resectable NSCLC patients. The pre-op OPN level in the latter cohort was compared to matched postoperative (post-op) OPN levels to monitor the impact of surgery on the biomarker. Results: Discovery set pre-op OPN (271+31) was significantly higher than in smokers (40+2)(p=.001). Pre-op OPN was similar in the validation cohort (357+31, p=.055, demographics in Table ). Post-op OPN (189+19) measured at mean of 23 weeks (range 2–105) was significantly lower than pre-op (p<.0001). Time from surgery significantly impacted post-op OPN, with OPN<6 weeks post-op (282+30) higher than OPN>6 weeks post-op (155+18)(p<.0001). After 6 weeks post-op, resected stage I patients (N=45) had a significant decrease in OPN levels from 373+45 to 142+21 (p<.0001). Multivariate analysis ( Table ) noted a significant correlation between age, albumin and pre-op OPN, and between albumin and pre-op OPN and >6 weeks post-op OPN. No correlation was noted between gender, smoking, histology, diabetes or stage and the pre- or >6 weeks post-op OPN. Conclusions: Plasma OPN levels in early stage NSCLC patients are significantly elevated compared to smokers. The elevated pre-op OPN levels were validated in an independent cohort of early stage NSCLC patients. A significant decrease in OPN was noted following resection. Peri-operative reductions in plasma OPN may serve as a marker for response to therapy and warrant investigation into prognostic significance in early stage NSCLC. [Table: see text] [Table: see text]