Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib

Burris, Howard A.

doi:10.1634/theoncologist.9-suppl_3-10

Cited by 277 publications

(165 citation statements)

References 6 publications

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“…37,38 Numerous clinical trials are currently underway in cohorts of patients with breast carcinoma to investigate strategies that target multiple T1GFR family members by utilizing combinations of T1GFR inhibitors or new agents capable of blocking multiple family members. 39,40 Further evaluation of the relation of T1GFR family expression with specific treatments utilized may potentially improve the predictive value and the clinical applicability of these markers. Thus, the prognostic and potential treatment implications of tumor expression of HER-1, HER-2, and HER-3 are significant, warrant further study, and may ultimately provide insights into disease biology that will benefit women diagnosed with breast carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Coexpression of the type 1 growth factor receptor family members HER‐1, HER‐2, and HER‐3 has a synergistic negative prognostic effect on breast carcinoma survival

Wiseman¹,

Makretsov²,

Nielsen³

et al. 2005

Cancer

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BACKGROUNDThe clinical significance of coexpression of type 1 growth factor receptor (T1GFR) family members remains largely unknown. The objective of the current study was to determine the frequency and the possible prognostic effect of coexpression of HER‐1, HER‐2, HER‐3, and HER‐4 by breast carcinoma.METHODSTissue microarrays were constructed using clinically annotated formalin‐fixed, paraffin‐embedded tumor samples from 242 patients with invasive breast carcinomas with a median 15‐year follow‐up. The levels of TIGFR family members (HER‐1–HER‐4) were measured by immunohistochemistry. K‐means clustering algorithm, as well as univariate (Kaplan–Meier, log‐rank test) and multivariate (Cox regression) survival analyses were applied to the data set.RESULTSUsing univariate analysis, expression of HER‐1, HER‐2, and HER‐3, but not HER‐4, was significantly associated with decreased patient disease‐specific survival (P < 0.05). Kaplan–Meier survival analysis showed that coexpression of ≥ 2 of HER‐1, HER‐2, and HER‐3 in any combination was associated with reduced patient disease‐specific survival compared with single marker expression or no expression (35% vs. 65% vs. 78% 10‐year survival rates, P = 0.001). Using multivariate analysis, expression of ≥ 2 of HER‐1, HER‐2, and HER‐3 was independent of lymph node status and tumor size.CONCLUSIONSIn a cohort of patients with breast carcinoma, the authors observed T1GFR family member coexpression (HER‐1, HER‐2, and HER‐3) to have a negative synergistic effect on patient outcome, independent of tumor size or lymph node status. Thus, coexpression of T1GFR family members identified a subset of patients with a poor disease prognosis who may potentially benefit from therapy simultaneously targeting several T1GFR family members. Cancer 2005. © 2005 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Coexpression of the type 1 growth factor receptor family members HER‐1, HER‐2, and HER‐3 has a synergistic negative prognostic effect on breast carcinoma survival

Wiseman¹,

Makretsov²,

Nielsen³

et al. 2005

Cancer

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“…68 These findings indicate the importance of GDF-15 clinically, especially in ErbB2 (HER2)-positive cancers that are sensitive to small molecular inhibitors, such as lapatinib. 69 GDF-15 is strongly upregulated in hepatocellular carcinoma and other liver diseases, such as fibrosis or cirrhosis induced by hepatitis C virus. 70 GDF-15 autocrine signaling of transformed or infected hepatocytes then induces Akt, GSK-3/b catenin, Raf phosphorylation and other downstream targets, such as cell-cycle regulators (cyclins A2, E1 and D2) or adhesion molecules (E-cadherin).…”

Section: Gdf-15 In Cancer Progression Systemic and Immune Responsementioning

confidence: 99%

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

Vaňhara

Hampl

Kozubı́k

et al. 2012

Prostate Cancer Prostatic Dis

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Deregulation of expression and function of cytokines belonging to the transforming growth factor-b (TGF-b) family is often associated with various pathologies. For example, this cytokine family has been considered a promising target for cancer therapy. However, the detailed functions of several cytokines from the TGF-b family that could have a role in cancer progression and therapy remain unclear. One of these molecules is growth/differentiation factor-15 (GDF-15), a divergent member of the TGF-b family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with cancer progression, including prostate cancer (PCa). However, studies clearly demonstrating the mechanisms for signal transduction and functions in cell interaction, cancer progression and therapy are still lacking. New GDF-15 roles have recently been identified for modulating osteoclast differentiation and for therapy for PCa bone metastases. Moreover, GDF-15 is as an abundant cytokine in seminal plasma with immunosuppressive properties. We discuss studies that focus on the regulation of GDF-15 expression and its role in tissue homeostasis, repair and the immune response with an emphasis on the role in PCa development.

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“…Lapatinib was discontinued in patients with symptomatic cardiac events (CTCAE grade 3 or 4); in asymptomatic patients it was withheld and could be resumed at a dose of 1 000 mg per day if the LVEF 2 to 3 weeks later was at or above the institution's lower limit of the normal range [38]. In another phase I study evaluating the safety and activity of this agent in heavily pretreated patients with metastatic carcinomas, no cardiac toxicity was observed [39]. It is not clear why the monoclonal antibody trastuzumab that targets the same receptor, ERBB2, has considerable rates of cardiotoxicity.…”

Section: Lapatinibmentioning

confidence: 99%