Prognosis in human glioblastoma based on expression of ligand growth hormone-releasing hormone, pituitary-type growth hormone-releasing hormone receptor, its splicing variant receptors, EGF receptor and PTEN genes

Purpose G lioblastoma (GB) is the most frequent brain tumor. Despite recent improvement in therapeutic strategies, the prognosis of GB remains poor. Growth hormone-releasing hormone (GHRH) may act as a growth factor; antagonists of GHRH have been successfully applied for experimental treatment of different types of tumors. The expression profile of GHRH receptor, its main splice variant SV1 and GHRH have not been investigated in human GB tissue samples. Methods We examined the expression of GHRH, fulllength pituitary-type GHRH receptor (pGHRHR), its functional splice variant SV1 and non-functional SV2 by RTPCR in 23 human GB specimens. Epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog gene (PTEN) expression levels were also evaluated by quantitative RT-PCR. Correlations between clinico-pathological parameters and gene expressions were analyzed. Results E xpression of GHRH was found to be positive in 61.9 % of samples. pGHRH receptor was not expressed in our sample set, while SV1 could be detected in 17.4 % and SV2 in 8.6 % of the GB tissues. In 65.2 and 78.3 % of samples, significant EGFR over-expression or PTEN under-representation could be detected, respectively. In 47.8 % of cases, EGFR up-regulation and PTEN down-regulation occurred together. Survival was significantly poorer in tumors lacking GHRH expression. This worse prognosis in GHRH negative group remained significant even if SV1 was also expressed. Conclusion Our study shows that GHRH and SV1 genes expressed in human GB samples and their expression patterns are associated with poorer prognosis

Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy

BACKGROUND: Studies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain. METHODS: One hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival). RESULTS: Twenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group. The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS. CONCLUSIONS: NAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker