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SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors.

ABSTRACT: Background:Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods:We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). Results:34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions:This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.

SUBMITTER: Higham CS

PROVIDER: S-EPMC5613633 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors.

Higham Christine S CS Steinberg Seth M SM Dombi Eva E Perry Arie A Helman Lee J LJ Schuetze Scott M SM Ludwig Joseph A JA Staddon Arthur A Milhem Mohammed M MM Rushing Daniel D Jones Robin L RL Livingston Michael M Goldman Stewart S Moertel Christopher C Wagner Lars L Janhofer David D Annunziata Christina M CM Reinke Denise D Long Lauren L Viskochil David D Baker Larry L Widemann Brigitte C BC

Sarcoma 20170912

<h4>Background</h4>Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported.<h4>Methods</h4>We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target r ...[more]

PMID: 29138631

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Project description:Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers that occur spontaneously (sporadic MPNST) or from pre-existing, benign plexiform neurofibromas in neurofibromatosis type 1 (NF1) patients. MPNSTs metastasize easily, are resistant to therapeutic intervention and are frequently fatal. The molecular changes underlying the transition to malignancy in the NF1 setting are incompletely understood. Here we investigate the involvement of microRNAs in this process. Using an RT-PCR platform microRNA expression profiles were determined from a unique series of archival paired samples of plexiform neurofibroma and MPNST. At least 90 differentially expressed microRNAs (p<0.025; FDR<10%) were identified between the paired samples. Most microRNAs (91%) were found downregulated and 9% of the microRNAs were upregulated in MPNST. Based on the fold changes and statistical significance three downregulated microRNAs (let-7b-5p, miR-143-3p, miR-145-5p) and two upregulated microRNAs (miR135b-5p and miR-889-3p) were selected for further functional characterization. Their expression levels were validated in a relevant cell line panel and a series of unpaired fresh frozen tumor samples containing plexiform neurofibromas, atypical neurofibromas and MPNSTs. As part of the validation process we also determined and analyzed microRNA expression profiles of sporadic MPNSTs observing that microRNA expression discriminates NF1-associated and sporadic MPNSTs emphasizing their different etiologies. The involvement of microRNAs in tumorigenesis and cancer progression was examined in NF1-derived MPNST cell lines through modulating microRNA levels by transient transfection of microRNA mimics or inhibitors. The effects of microRNAs on cellular proliferation, migration, invasion and Wnt/ẞ-catenin signaling were determined. Our findings indicate that, some of the selected microRNAs affect migratory and invasive capabilities and Wnt signaling activity. It was observed that the functional effects upon microRNA modulation are distinct in different cell lines. From our study we conclude that miRNAs play essential regulatory roles in MPNST facilitating tumor progression.

Project description:BACKGROUND: Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by the development of benign nerve-sheath tumors, which transform to malignant peripheral nerve-sheath tumors (MPNST) in about 8 to 13% of patients with NF1. MPNST are invasive sarcomas with extremely poor prognosis, and their development may correlate with internal tumor load of patients with NF1. Because early identification of patients with NF1 at risk for developing MPNST should improve their clinical outcome, the aim of this study was to identify serum biomarkers for tumor progression in NF1, and to analyze their correlation with tumor type and internal tumor load. METHODS: We selected candidate biomarkers for NF1 by manually mining published data sources, and conducted a systematic screen of 56 candidate serum biomarkers using customized antibody arrays. Serum from 104 patients with NF1 with and without MPNST, and from 41 healthy control subjects, was analyzed. Statistical analysis was performed using the non-parametric Mann-Whitney U-test, followed by Bonferroni correction. RESULTS: Our analysis identified four markers (epidermal growth factor receptor, interferon-?, interleukin-6, and tumor necrosis factor-?) for which significantly different serum concentrations were seen in patients with NF1 compared with healthy controls. Two markers (insulin-like growth factor binding protein 1 (IGFBP1) and regulated upon activation, normal T-cell expressed and secreted (RANTES)) showed significantly higher concentrations in patients with NF1 and MPNST compared with patients with NF1 without MPNST. A correlation with internal tumor load was found for IGFBP1. CONCLUSION: Our study identified two serum markers with potential for early detection of patients with NF1 at risk for developing MPNST, and four markers that could distinguish between patients with NF1 and healthy subjects. Such markers may be useful as diagnostic tools to support the diagnosis of NF1 and for timely identification of MPNST. Moreover, the data suggest that there is a systemic increase in inflammatory cytokines independently of tumor load in patients with NF1.

Dataset Information

SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors.

Publications

SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors.

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