Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor

PURPOSE: A subgroup of HER2 overexpressing breast tumors co-expresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting EXPERIMENTAL DESIGN: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2 overexpressing breast primary tumors from a first line lapatinib monotherapy study (EGF20009) and a second line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) and progression-free survival using logistic regression and Cox-proportional hazard models. RESULTS: Lapatinib inhibited tumor growth and HER2 downstream signaling of p95HER2 expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2 positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies there was no statistically significant difference in progression-free survival, clinical benefit rate and overall response rate between p95HER2-positive and p95HER2-negative tumors. CONCLUSIONS: Lapatinib as a monotherapy or in combination with capecitabine appears to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors

Prognostic Significance of Combinations of RNA-Dependent Protein Kinase and EphA2 Biomarkers for NSCLC

IntroductionRNA-dependent protein kinase (PKR) is an independent prognostic variable in patients with non–small-cell lung cancer (NSCLC). In the current study, we investigated the correlation between PKR and 25 other biomarkers for NSCLC, identified the markers that could further improve the prognostic significance of PKR and elucidated the mechanisms of interaction between these markers and PKR.MethodsTissue microarray samples obtained from 218 patients with lung cancer were stained with an anti-PKR antibody and antibodies against 25 biomarkers. Immunohistochemical expression was scored and used for Kaplan–Meier survival analysis. The interaction between PKR and EphA2 in NSCLC cell lines was examined.ResultsWe found that PKR was associated with EphA2 and that the prognostic information regarding NSCLC provided by the combination of PKR and EphA2 (P/E) was significantly more accurate than that provided by either marker alone. The 5-year overall survival rate in patients with PKRlow/EphA2high (20%) was significantly lower than that of patients with PKRhigh/EphA2low (74%), patients with PKRhigh/EphA2high (55%), and patients with PKRlow/EphA2low (55%) (p < 0.0001). We also found that the PKR:EphA2 (P/E) ratio was significantly associated with prognosis (p < 0.0001). Univariate and multivariate Cox analyses revealed that this P/E combination or ratio was an independent predictor of overall survival. In addition, induction of PKR expression reduced EphA2 protein expression levels in NSCLC cell lines.ConclusionsPKR/EphA2 is a significant predictor of prognosis for NSCLC. PKR/EphA2 may be a promising approach to improving screening efficiency and predicting prognosis in patients with NSCLC