A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies

Bekaii‐Saab, Tanios; Roda, Julie M.; Guenterberg, Kristan; Ramaswamy, B; Young, Donn C.; Ferketich, Amy K.; Lamb, Tammy; Grever, Michael R.; Shapiro, Charles L.; Carson, William E.

doi:10.1158/1535-7163.mct-09-0820

Cited by 101 publications

(76 citation statements)

References 29 publications

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“…30,31 However, the FDA and Health Canada approvals for trastuzumab (Herceptin r ) treatment include all types of oesophagogastric adenocarcinomas; therefore, strict criteria for ErbB2 assessment in oesophageal adenocarcinomas are of the highest clinical relevance for selecting patients for ErbB2-targeted treatment, which may represent an expensive but promising additional therapeutic option for the advanced stages of this disease. [32][33][34][35][36] In summary, in this study, we found that a significant number of oesophageal adenocarcinomas are positive for ErbB2. The assessment of ErbB2 by immunohistochemistry in combination with in situ hybridisation (bright field double in situ hybridisation or fluorescence in situ hybridisation) reveals highly relevant prognostic information and may also serve as a basis for targeted trastuzumab therapy.…”

Section: Discussionmentioning

confidence: 79%

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

et al. 2011

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Amplification and overexpression of ErbB2 (Her2) is a frequent event in oesophageal adenocarcinomas. Assessment of ErbB2 status is crucial for identifying patients who are likely to benefit from treatment with trastuzumab. In this study, we performed a comprehensive analysis of ErbB2 amplification and expression in 142 oesophageal adenocarcinomas by comparing the most commonly used methods for ErbB2 assessment: ErbB2 expression was determined by immunohistochemistry and was scored (0, 1 þ , 2 þ and 3 þ ) according to a recently described modified scoring system for gastric cancer. ErbB2 amplification was evaluated by bright field double in situ hybridisation. The results were compared with pathologic features, patients' survival and previously published data from fluorescence in situ hybridisation analysis. On the basis of immunohistochemistry, which was applicable in 110 cores of the cases, 83 tumours (75%) had a score of 0 or 1 þ (immunohistochemistry negative), 13 tumours (12%) were scored as 2 þ and 14 tumours (13%) were scored as 3 þ . In situ hybridisation data were obtained from 142 cases. There was a highly significant correlation of immunohistochemistry, bright field in situ hybridisation and fluorescent in situ hybridisation (Po0.001 each). In total, 41 tumours (29%) were categorised as ErbB2 positive, which was defined as immunohistochemistry 3 þ and/or an ErbB2/Chr17 quotient of Z2 as assessed by either bright field double in situ hybridisation or fluorescence in situ hybridisation. ErbB2 positivity was observed more frequently in tumours with lower differentiation grades (P ¼ 0.029). Patients with ErbB2-positive tumours had a significantly worse prognosis, both in univariate analysis (P ¼ 0.004) and in multivariate analysis (P ¼ 0.03).In conclusion, we demonstrate that a significant number of oesophageal adenocarcinomas are positive for ErbB2. Assessment of ErbB2 amplification can be equivalently performed by conventional fluorescence in situ hybridisation or other lightmicroscopy-based methods, such as the novel bright field double in situ hybridisation technique. Modern Pathology (2011) 24, 908-916;

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Section: Discussionmentioning

confidence: 79%

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

et al. 2011

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“…Even in patients with metastatic HER2 þ breast cancer, where the combination of IL-12 with paclitaxel and trastuzumab resulted in a 52% rate of clinical benefit in a phase I trial, the combinatorial strategy was not further pursued. 121 More encouraging results, however, were obtained when treating hematological cancers (Table 1). A phase I dose escalation trial with s.c. delivery of IL-12 twice a week for up to 24 weeks resulted in an overall response rate of 56% in cutaneous T-cell lymphoma patients.…”

Section: Il-12 To Treat Human Cancermentioning

confidence: 98%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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“…Also, fibronectin 1 (FN1) and PDGF receptor B (PDGFRB) appeared repeatedly together specifically in DCIS, along with COL1A2, IL-12/IL-12 receptor/TYK2/JAK2/SPHK2, ESR1, and KRT14. Phase I clinical trials have shown that the clinical effect of trastuzumab (Herceptin) is potentiated by the coadministration of IL-12 to patients with HER2-overexpressing tumors, and this effect is mediated by the stimulation of IFN-γ production in the NK cells (19). (Fig.…”

Section: Paradigm Analysis Of Normal Breast Tissue With High and Lowmentioning

confidence: 99%

Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling

Kristensen

Vaske

Ursini‐Siegel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

141

133

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We use an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We demonstrate that combining mRNA expression and DNA copy number classified the patients in groups that provide the best predictive value with respect to prognosis and identified key molecular and stromal signatures. A chronic inflammatory signature, which promotes the development and/or progression of various epithelial tumors, is uniformly present in all breast cancers. We further demonstrate that within the adaptive immune lineage, the strongest predictor of good outcome is the acquisition of a gene signature that favors a high T-helper 1 (Th1)/ cytotoxic T-lymphocyte response at the expense of Th2-driven humoral immunity. Patients who have breast cancer with a basal HER2-negative molecular profile (PDGM2) are characterized by high expression of protumorigenic Th2/humoral-related genes (24-38%) and a low Th1/Th2 ratio. The luminal molecular subtypes are again differentiated by low or high FOXM1 and ERBB4 signaling. We show that the interleukin signaling profiles observed in invasive cancers are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. The most prominent difference between low and high mammographic density in healthy breast tissue by PARADIGM was that of STAT4 signaling. In conclusion, by means of a pathway-based modeling methodology (PARADIGM) integrating different layers of molecular data from whole-tumor samples, we demonstrate that we can stratify immune signatures that predict patient survival.functional genomics | integrated molecular data | omics | perturbated pathway

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A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies

Cited by 101 publications

References 29 publications

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

New insights into IL-12-mediated tumor suppression

Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling

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