Matrix metalloproteinase 9 expression and prognosis in colorectal cancer: a meta-analysis

Matrix metalloproteinase-9 (MMP-9) is an important member of the matrix metalloproteinase family and is considered to be involved in the invasion and metastasis of cancer cells. Many studies were published to assess the prognostic role of MMP-9 overexpression in patients with colorectal cancer, but the findings from those studies were inconsistent. We searched eligible studies in Pubmed, Embase, and Web of Science databases. Thirteen studies with a total of 2, 390 CRC patients were finally included into the meta-analysis. The pooled hazard ratios (HRs) with the corresponding 95 % confidence interval (95 % CIs) for overall and progression-free survival were calculated by using meta-analysis. There were nine studies with a total of 1,674 colorectal cancer patients relating the progression-free survival, and eight studies with a total of 1,379 colorectal cancer patients relating the overall survival. Overall, MMP-9 overexpression was associated with poorer progression-free survival in patients with colorectal cancer (fixed-effects HR 1.81, 95 % CI 1.48–2.20, P?<?0.001; random-effects HR 1.92, 95 % CI 1.46–2.53, P?<?0.001). In addition, MMP-9 overexpression was also associated with poorer overall survival in patients with colorectal cancer (fixed-effects HR 1.74, 95 % CI 1.39–2.19, P?<?0.001; random-effects HR 1.78, 95 % CI 1.31–2.41, P?<?0.001). MMP-9 expression is associated with the prognosis of patients with colorectal cancer, and patients with higher MMP-9 expression have poorer survival.     

Assessment of Folate Receptor-α and Epidermal Growth Factor Receptor Expression in Pemetrexed-Treated Non–Small-Cell Lung Cancer Patients

IntroductionFolate receptor-α regulates cellular uptake of folates and antifolates (eg, pemetrexed) and is frequently expressed in pulmonary adenocarcinoma. EGFR is an established therapeutic target in NSCLC. Therapies targeting FRA or EGFR are available. The association between FRA and EGFR expression in advanced NSCLC has not been explored. Combining therapeutic FRA antibodies with an EGFR inhibitor might be beneficial, if both of the targets are significantly coexpressed.Patients and MethodsSpecimens from 160 advanced NSCLC patients receiving pemetrexed-based chemotherapy were assessed for membranous FRA and EGFR protein expression using immunohistochemistry and the Hybrid (H)-score. EGFR (exons 18-21) and Kirsten RNA-associated rat sarcoma 2 virus (exon 2) mutations were determined. Results were correlated to patients' clinicopathological data, progression-free survival (PFS), and overall survival (OS).ResultsForty-seven patients (29%) had tumors with strong FRA and EGFR expression, but no statistically significant correlation was seen between protein levels of FRA and EGFR. High membranous FRA expression (H-score ≥ 20) was associated with prolonged PFS (5.5 vs. 3.4 months; hazard ratio [HR], 0.6060; P = .0254) and improved OS (12.1 vs. 6.4 months; HR, 0.5726; P = .0076).ConclusionSurvival times are improved in NSCLC patients whose tumors show strong membranous FRA expression. No statistical correlation between membranous FRA and EGFR expression was demonstrated in advanced NSCLC, but 47 patients (29%) had higher expression of both of the receptors and could be suitable for combined targeted therapies.     

The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters

The prognostic role of HER-2 has been established in breast cancer but remains controversial in colorectal cancer. In this study, 170 archival specimens of Dukes' B and C colorectal cancer were analysed immunohisto-chemically, using an anti-HER-2 monoclonal antibody HM64.13. Immunostaining was classified as cytoplasmic or membranous, and the intensity of the immunostaining was graded negative, weak or strong. The association between these scores and survival was estimated using Cox survival analyses. Overall, 87% of cases showed cytoplasmic HER-2 staining, with 54% exhibiting strong intensity cytoplasmic immunostaining. Membranous HER-2 was seen in 41% of cases, with most of these being of strong intensity. No correlation with clinical outcome was seen with membranous HER-2. Positive cytoplasmic immunostaining was found to be associated with a significantly better overall survival (HR 0.46, CI95 0.24-0.87) in the Dukes C cancers, but no survival benefit was seen in the Dukes' B cancers. Tumour grade, depth of tumour invasion and positive apical node were also found to be independent prognostic factors in Dukes' C cancers. We conclude that HER-2 over-expression occurs in a significant number of colorectal cancers. Since cytoplasmic HER-2 is incapable of transmitting the strong mitogenic signal via heterodimerization with other members of the Epidermal Growth Factor Receptor (EGFR) family, this may partly explain the correlation between cytoplasmic HER-2 over-expression and a better prognosis in the Dukes' C colorectal cancers. In addition, high levels of membraneous HER-2 in colorectal cancer could make HER-2 a good target for monoclonal antibody-based immunotherapy.     

SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential

The S-phase kinase-associated protein 2 (SKP2) oncoprotein is an E3 ubiquitin ligase. Overexpression of SKP2 was found in various human cancers, including colorectal cancers, but its potential role as a prognostic marker after neoadjuvant chemoradiotherapy (CRT) and for therapeutic intervention in rectal cancers is unknown. This study examined the correlation of SKP2 expression in the prognosis of rectal cancer patients and the viability of colorectal cancer cells treated with CRT. SKP2 immunoexpression was retrospectively assessed in pretreatment biopsies of 172 rectal cancer patients treated with neoadjuvant CRT followed by surgery. Results were correlated with clinicopathological features, therapeutic responses, and patient survival. Pharmacologic assays were used to evaluate the therapeutic relevance of Bortezomib in two colorectal cancer cell lines (HT-29 and SW480). High expression of SKP2 was correlated with the advanced Post-Tx nodal status (p?=?0.002), Post-Tx International Union for Cancer Control stage (p?=?0.002), and a lower-degree tumor regression grade (p?<?0.001). Moreover, high expression of SKP2 (p?=?0.027, hazard ratio 3.21) was an independent prognostic factor for local recurrence-free survival. In vitro, Bortezomib downregulated SKP2 expression, induced caspase activation, and decreased the viability of colorectal cancer cells with or without a combination with fluorouracil. Bortezomib also promoted caspase activation and gamma-H2AX formation in colorectal cancer cells concurrently treated with CRT. High expression of SKP2 was associated with a poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CRT. In the presence of chemotherapy with or without radiotherapy, the promoted sensitivity of colorectal cancer cells to Bortezomib with an SKP2-repressing effect indicated that it is a potential therapeutic target.     

Prognostic value of Ki-67 expression in conversion therapy for colorectal liver-limited metastases

Introduction: The objective of this study was to examine the prognostic value of Ki-67 expression in conversion therapy for colorectal liver-confined metastases. Methods: We enrolled a total of 96 patients including 54 patients who received oxaliplatin- or irinotecan-based chemotherapy and curative hepatectomy for initially unresectable metastases (conversion group) and 42 patients with initially resectable liver metastases (straight hepatectomy group). Ki-67 expression was examined in 96 resected specimens but excluded the 2 specimens that revealed no residual cancer cells in conversion group. Results: Conversion therapy leads to greater survival that is equivalent to that straight hepatectomy group. In conversion group, high Ki-67 expression (> 30%) levels were detectable in 33 patients (64%) after chemotherapy prior to conversion therapy. High Ki-67 expression was significantly associated with shorter disease-free survival and worse overall survival (P < 0.01 in both), and was an independent worse prognostic factor of disease-free survival and overall survival (hazard ratio [HR] and P-values were 5.608, 0.001 and 5.366, 0.04, respectively) in patients with conversion therapy. Interestingly, even in the patients with RECIST PR (n = 32), high Ki-67 expression was significantly shorter disease-free survival compared to low Ki-67 expression (P < 0.001). In contrast to conversion group, there was no significant difference in disease free survival and overall survival between low (n = 14, 33%) and high (n = 28, 67%) Ki-67 expressions in patients with straight hepatectomy (P = 0.14 and 0.74, respectively). Conclusions: Residual Ki-67 expression is a useful biomarker for worse prognostic outcomes after conversion therapy. High Ki-67 expression may be a biomarker of micrometastases containing aggressive cancer cells.     

Prognostic Value of microRNA-9 in Various Cancers: a Meta-analysis

Recently, there are more and more evidences from studies have revealed the association between microRNA-9 (miR-9) expression and outcome in multiple cancers, but inconsistent results have also been reported. It is necessary to rationalize a meta analysis of all available data to clarify the prognostic role of miR-9. Eligible studies were selected through multiple search strategies and the quality was assessed by MOOSE. Data was extracted from studies according to the key statistics index. All analyses were performed using STATA software. Twenty studies were selected in the meta-analysis to evaluate the prognostic role of miR-9 in multiple tumors. MiR-9 expression level was an independent prognostic biomarker for OS in tumor patients using multivariate and univariate analyses. High expression levels of miR-9 was demonstrated to associated with poor overall survival (OS) (HR?=?2.23, 95 % CI: 1.56–3.17, P?<?0.05) and recurrence free survival/progress free survival (RFS/PFS) (HR?=?2.08, 95 % CI: 1.33–3.27, P?<?0.05). Subgroup analysis showed that residence region (China and Japan), sample size, cancer type (solid or leukemia), follow-up months and analysis method (qPCR) did not alter the predictive value of miR-9 on OS in various cancers. Furthermore, no significant associations were detected for miR-9 expression and lymph node metastasis or distant metastasis. The present results suggest that promoted miR-9 expression is associated with poor OS in patients with general cancers.     

A shift from membranous and stromal syndecan‐1 (CD138) expression to cytoplasmic CD138 expression is associated with poor prognosis in breast cancer

Syndecan‐1 (CD138) is a transmembrane proteoglycan expressed in normal and malignant tissues. It is of interest because of a possible prognostic effect in tumors and as a target for Indatuximab, a monoclonal antibody coupled to a cytotoxic agent. To assess the prognostic role of CD138 expression in breast cancer (BCa), a tissue microarray containing 1535 BCa specimens was analyzed by immunohistochemistry. Cytoplasmic, membranous, and stromal CD138 staining was separately analyzed. In normal breast tissue, CD138 staining was limited to epithelial cell membranes. In cancers, membranous staining tended to become weaker or even disappeared (38.3% of cancers with absence of membranous staining) but cytoplasmic and stromal staining newly appeared in 29.7% and 58.1% of cancers. Loss of membranous epithelial CD138 staining as well as presence of cytoplasmic and stromal CD138 positivity were—to a variable degree—associated with high pT, high grade, nodal metastasis, estrogen receptor‐negative, progesterone receptor‐negative, human epidermal growth factor receptor 2+, and poor overall patient survival. A combined analysis of epithelial and stromal CD138 expression revealed a link to overall patient survival (P < .0001) with best prognosis for patients with stromal positivity and absence of cytoplasmic staining, the worst prognosis for cancers with cytoplasmic staining and stromal negativity and intermediate prognosis for patients having either cytoplasmic staining or stromal negativity. In multivariate analyses, CD138 was not independent of established prognostic features. In summary, these data reveal a compartment depending prognostic effect of CD138 expression in BCa with cytoplasmic positivity being linked to aggressive cancer and stromal CD138 being linked to a more favorable prognosis.     

Overabundant FANCD2, alone and combined with NQO1, is a sensitive marker of adverse prognosis in breast cancer

BackgroundDefective DNA repair is central to the progression and treatment of breast cancer. Immunohistochemically detected DNA repair markers may be good candidates for novel prognostic and predictive factors that could guide the selection of individualized treatment strategies.Patients and methodsWe have analyzed nuclear immunohistochemical staining of BRCA1, FANCD2, RAD51, XPF, and PAR in relation to clinicopathological and survival data among 1240 paraffin-embedded breast tumors, and additional gene expression microarray data from 76 tumors. The antioxidant enzyme NQO1 was analyzed as a potential modifier of prognostic DNA repair markers.ResultsRAD51 [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70–0.94, P = 0.0050] and FANCD2 expression (HR 1.50, 95% CI 1.28–1.76, P = 1.50 × 10^-7) were associated with breast cancer survival. High FANCD2 expression correlated with markers of adverse prognosis but remained independently prognostic in multivariate analysis (HR 1.27, 95% CI 1.08–1.49, P = 0.0043). The FANCD2-associated survival effect was most pronounced in hormone receptor positive, HER2-negative tumors, and in tumors with above-median NQO1 expression. In the NQO1-high subset, patients belonging to the highest quartile of FANCD2 immunohistochemical scores had a threefold increased risk of metastasis or death (HR 3.10, 95% CI 1.96–4.92). Global gene expression analysis indicated that FANCD protein overabundance is associated with the upregulation of proliferation-related genes and a downregulated nucleotide excision repair pathway.ConclusionFANCD2 immunohistochemistry is a sensitive, independent prognostic factor in breast cancer, particularly when standard markers indicate relatively favorable prognosis. Taken together, our results suggest that the prognostic effect is linked to proliferation, DNA damage, and oxidative stress; simultaneous detection of FANCD2 and NQO1 provides additional prognostic value.     

Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers.

PURPOSE: Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival. EXPERIMENTAL DESIGN: Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates. RESULTS: High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004). CONCLUSION: Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.     

Primary Tumor Location and Survival in the General Population With Metastatic Colorectal Cancer

Background

Recent evidence from clinical trials suggests that primary tumor location in patients with metastatic colorectal cancer correlates with differential outcomes, and patients with tumors originating in the right side of the colon have inferior survival. We conducted a large population-based cohort study using individual patient data to confirm the prognostic importance of primary tumor location in the general population with metastatic colorectal cancer.

Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status

Background:

Evidence suggests that epidermal growth factor receptor (EGFR)-activation status may better predict the clinical behaviour of colon cancers than does EGFR expression. However, the prognostic effect of phospho-EGFR in primary colon cancer remains undefined.

Methods:

Phospho-EGFR (Tyr-1173) and EGFR expression were analysed by immunohistochemistry (IHC) in tissue microarrays of TNM stage II and III colon cancers from completed adjuvant therapy trials (n=388). Staining intensity was scored and correlated with clinicopathological variables, DNA mismatch repair (MMR) status, rates of cell proliferation (Ki-67), apoptosis (caspase-3), and patient survival.

Results:

Phospho-EGFR expression was detected in 157 of 388 (40%) tumours, whereas EGFR was found in 214 of 361 (59%). Although phospho-EGFR was unrelated to clinicopathological variables, strong EGFR intensity was associated with higher tumour stage (P=0.03). Tumours overexpressing EGFR (P=0.0002) or phospho-EGFR (P=0.015) showed increased Ki-67, but not caspase-3 expression. Phospho-EGFR was not prognostic. EGFR intensity was associated with worse disease-free survival (DFS) (hazard ratio (HR): 1.21 (1.03, 1.41); P=0.019) and overall survival (OS) (HR: 1.19 (1.02, 1.39); P=0.028). Tumours expressing both EGFR and phospho-EGFR had similar survival as EGFR alone. Stage and lymph node number were prognostic for DFS and OS, and histological grade for OS. EGFR was an independent predictor of DFS (P=0.042) after adjustment for stage, histological grade, age, and MMR status.

Conclusion:

Phospho-EGFR and EGFR expression were associated with tumour cell hyperproliferation. Phospho-EGFR was not prognostic, whereas increased EGFR intensity was independently associated with poor DFS.     

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: A dual-institutional follow-up with the RTOG 9704 trial

Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47–0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33–0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR’s regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.     

Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival.

PURPOSE: CD24 is a cell adhesion molecule that has been implicated in metastatic tumor progression of various solid tumors. We aimed to clarify the expression patterns of CD24 in colorectal cancer and to correlate these to clinicopathologic variables including patient survival. EXPERIMENTAL DESIGN: 147 colorectal carcinomas and two colon carcinoma cell lines were immunostained for CD24. Cytoplasmic and membranous immunoreactivity were semiquantitatively scored. Fisher's exact test, chi(2) test for trends, Kaplan-Meier analysis, and Cox's regression were applied. RESULTS: The cell line CX-2 showed only a minimal membranous CD24 immunoreactivity, in contrast to HT29, which stained strongly in the cytoplasm. In colorectal cancer, 68.7% of the tumors showed membranous CD24 staining, whereas 84.4% showed cytoplasmic staining. In 10% of cases, an exceptionally strong cytoplasmic CD24 expression was observed. The latter significantly correlated to higher tumor stages (Dukes and pT), nodal or systemic metastasis, and higher tumor grade. In survival analysis, strong cytoplasmic CD24 expression correlated significantly (Cox's regression: P = 0.012, relative risk = 3.7) to shortened patient survival in the group of cases without distant metastases. CONCLUSIONS: CD24 is commonly up-regulated in colorectal cancer and is a new independent prognostic marker which corroborates the importance of CD24 in tumor progression of this disease.     

PD-1 and PD-L1 Protein Expression Predict Survival in Completely Resected Lung Adenocarcinoma

Background

We assessed the prognostic value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in patients with completely resected lung adenocarcinoma.

Prognostic role of microRNA-100 in various carcinomas: evidence from six studies

Recent studies have shown that microRNAs (miRNA) exhibit altered expression levels in cancers, and they may be considered as valuable prognostic biomarkers for patients with cancers. We performed this meta-analysis to provide a comprehensive evaluation of the role of miRNA-100 expression on the overall survival rate by calculating the pooled hazard ratio (HR) for overall survival (OS), which compared the high and low expression levels of miR-100 in patients of the available studies. Finally, a total of six studies dealing with various carcinomas were involved for this meta-analysis. The results indicated that lower expression of miR-100 in cancerous tissue could significantly predict poorer survival in various carcinomas with the pooled HR of 2.19 (95 % CI 1.49–3.24, P?=?0.0007). In conclusion, the findings from this present meta-analysis suggest that miR-100 expression is associated with OS in cancer patients and could be a useful clinical prognostic factor for those patients.     

Overexpression of NUAK1 is associated with disease-free survival and overall survival in patients with gastric cancer

Transient receptor potential vanilloid 2 (TRPV2) was proved to play a crucial role in the tumor progression of various cancers. The association between the expression of TRPV2 and clinical outcome in cancer patients has not been studied yet. We aim to elucidate the role of TRPV2 in predicting prognosis of patients with esophageal squamous cell carcinoma (ESCC). Fresh frozen samples were collected immediately from 170 patients with ESCC after surgical resection from 2003 to 2008, including 45 pairs of tumor tissues and non-tumor tissues. TRPV2 expression was measured by quantitative real-time PCR. TRPV2 mRNA was over-expressed in ESCC tissues and cell lines. High expression of TRPV2 was observed more frequently in patients with advanced pT stage (P < 0.001), lymph node metastasis (P = 0.010) and advanced pathological stage (P = 0.001). Patients with high expression of TRPV2 (>44.40, n = 83) had worse 5-year disease-specific survival (40.0 vs 62.6 %, P < 0.001) and disease-free survival (38.4 vs 61.5 %, P < 0.001) than that with low expression (≤44.40, n = 87). Multivariate analysis found that the expression of TRPV2 mRNA (HR 2.19, 95 % CI 1.39–3.46, P = 0.031) and pN category (HR 2.13, 95 % CI 1.36–3.33, P = 0.001) were independent prognostic factors. Overexpression of TRPV2 mRNA was associated with poor prognosis and might serve as a novel prognostic biomarker for resected ESCC patients in early stage.     

Prognostic significance of cyclooxygenase-2 in osteosarcoma: a meta-analysis

Published studies researching the prognostic significance of cyclooxygenase-2 (COX-2) expression in patients with osteosarcoma are inconclusive and heterogeneous. We conducted a meta-analysis to assess its prognostic value more precisely. The pooled odds ratios (ORs) or hazard ratios (HRs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the effects. Fourteen studies with 735 osteosarcoma patients were included to estimate the relationship between COX-2 and metastasis of tumor, clinical stage, and 3-year overall survival. High expressions of COX-2 predicted neoplasm metastasis (OR?=?1.891, 95 % CI 1.276–2.803, P?=?0.002), advanced clinical stage (OR?=?1.801, 95 % CI 1.257–2.581, P?=?0.001). In addition, high COX-2 expression tended to be associated with a poor 3-year survival (HR?=?1.741, 95 % CI 0.762–3.979, P?=?0.188), but the difference was not significant. Therefore, this meta-analysis demonstrated that high COX-2 expression might be an unfavorable prognostic effect in osteosarcoma.