Phase II Trial of Trastuzumab in Combination With Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma With Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children's Oncology Group

Ebb, David; Meyers, Paul A.; Grier, Holcombe E.; Bernstein, Mark L.; Görlick, Richard; Lipshultz, Steven E.; Krailo, Mark; Devidas, Meenakshi; Barkauskas, Donald A.; Siegal, Gene P.; Ferguson, William S.; Letson, G. Douglas; Marcus, Karen J.; Goorin, Allen M.; Beardsley, Peter; Marina, Neyssa

doi:10.1200/jco.2011.37.4546

Cited by 206 publications

(173 citation statements)

References 38 publications

(8 reference statements)

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…IgG antibodies constitute one of the most important host adaptive immune mechanisms and bridge the interactions between innate immunity such as mediated by NK and phagocytic macrophages with adaptive cellular immunity mediated by T cells (18,19,22). It is well documented that the Fc regions of IgGs play key roles in eliminating target cells, and Fc-mediated effector functions have been shown to contribute to the efficacy of several cancer therapeutic monoclonal antibodies (30)(31)(32). Our recent studies demonstrated that single-strand hinge cleavage of the anti-HER2 IgG1 antibody trastuzumab impaired its antitumor efficacy due to the loss of Fc-mediated effector functions (6,10).…”

Section: Discussionmentioning

confidence: 99%

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity

Zhang

Deng

Fan

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Studies have demonstrated that cancer-associated matrix metalloproteinases (MMP) can generate single peptide bond cleavages in the hinge region of immunoglobulin G 1 (IgG1). This study investigated the cleavage of endogenous IgGs by MMPs in the tumor microenvironment and the consequences of the IgG hinge cleavage for humoral immunity.Experimental Design: We investigated the occurrence of single peptide bond cleaved IgGs (scIgG) in tumor tissues and plasma samples collected from a cohort of breast cancer patients (n ¼ 60). Samples from healthy people (n ¼ 20) were used as the control. Antibody hinge cleavage was detected by multiple assays, including IHC, ELISA, and flow cytometry. A correlation analysis was conducted between scIgG levels and patient clinical parameters.Results: Levels of scIgGs in tumors were significantly higher than in normal tissues. In addition, scIgG levels in tumors were enriched compared with that in the plasma of the same patients. The appearance of scIgGs in tumor tissues was associated with altered host IgG content and decreased IgG1. Increased tumor scIgGs were found to be positively correlated with adverse clinical factors, such as elevated tumor-associated macrophages, increased expression of MMP9 and other MMPs, and local metastasis to axillary lymph nodes.Conclusions: The study contributes to mounting evidence for the presence of hinge-cleaved antibodies with reduced Fc immune effector function in the tumor microenvironment. The results highlight a link between tumor scIgGs and poor patient outcomes, and reveal a component of compromised humoral immunity within tumors that could point to new immunotherapeutic strategies to rescue host immunity. Clin Cancer Res; 21(23); 5380-90.Ó2015 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity

Zhang

Deng

Fan

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…All patients received methotrexate, doxorubicin, and cisplatin, with the possible addition of ifosfamide or trastuzumab. [41][42][43] Patient outcome data through June 2012 were obtained from the COG. A single patient with metastatic disease at initial presentation had only completed 3.4 y of off-treatment follow up.…”

Section: Methodsmentioning

confidence: 99%

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

et al. 2015

Self Cite

View full text Add to dashboard Cite

Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P-value D 1.7 £ 10 ¡6 ), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies.

show abstract

“…However, no statistical difference was found between the study arm and the standard arm 41 . There is a clear need for newer effective agents for patients with osteosarcoma.…”

Section: Chaptermentioning

confidence: 62%

3405 The role of pharmacogenetics in osteosarcoma

Hagleitner¹,

Coenen²,

Gelderblom³

et al. 2015

European Journal of Cancer

View full text Add to dashboard Cite

Prof. dr. F.G.M. RusselThe research described in this thesis was financially supported by Stichting Kinderen Kankervrij (KiKa). 7 Contents CONTENTS Chapter 1 IntroductionChapter 2 Age as prognostic factor in patients with osteosarcoma Bone. 2011;49:1173-1177 Chapter 3 Survival trends and long term toxicity in pediatric patients with osteosarcoma Sarcoma. 2012;636405Chapter 4 Taqman genotyping assays can be used on decalcified and paraffin embedded tissue from patients with osteosarcomaPediatr Blood Cancer. 2011;56:35-38 Chapter 5 A pilot study: Genetic variants may influence methotrexate plasma concentrations in pediatric malignancies Chapter 6The role of the MTHFR 677C>T polymorphism in methotrexate -induced liver toxicity: a meta-analysis in patients with cancer J. 2014;14:115-119 Chapter 6B Is there a role for the MTHFR 677C>T and the 1298 A>C polymorphism methotrexate induced liver toxicity? . 2014;15:1401-1403 . Treatment with bisphosphonates such as pamidronate or zoledronic acid in addition to chemotherapy is only applied to a hand full of patients and the clinical benefit of these agents need to be studied in a prospective randomized trial 21,22 . As the incidence of osteosarcoma is between 3 and 4.5 cases per million, it will take several years to include a large number of patients in a prospective trial to study the efficacy of these new agents. Furthermore, the a priori knowledge of which patients will benefit from new agents will help to define new strategies in order to improve outcome and decrease the burden of late effects. We hypothesized that pharmacogenetics may help to stratify patient into good responders and bad responders. More insight in the genetic determinants involved in drug response may help in designing more effective therapeutic approaches, e.g. targeted cancer therapy for patients not responding on standard therapy ( Figure I). Pharmacogenomics Pharmacogenomics O s t e o s a r c o m aOsteosarcoma is the most common primary tumor of the bone, which may occur at all ages but is seen predominantly in adolescents. Nevertheless, it is still a rare disease with a worldwide incidence rate of 3-4 cases per million per year 1 . Untreated, osteosarcoma is fatal. Aggressive local growth and the tendency to metastasize mark its course. In the 1970s when surgery was the only treatment option, the prognosis for patients with osteosarcoma was poor, with long-term survival rates of less than 20% 2 . Today, therapy is changed to a multi-disciplinary approach, focusing on both local and systemic manifestations of osteosarcoma, incorporating surgery and chemotherapy. The use of this multi-disciplinary approach has resulted in survival rates of 60-65% since the late 1980s Drug related phenotypeThe candidate gene approach is a hypothesis driven method that investigates genetic variants in genes known to be associated with the trait of interest e.g. metabolism of the used medication. However, replication studies often show inconsistent results making it difficult to interpret the clinical v...

show abstract

Phase II Trial of Trastuzumab in Combination With Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma With Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children's Oncology Group

Cited by 206 publications

References 38 publications

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

3405 The role of pharmacogenetics in osteosarcoma

Contact Info

Product

Resources

About