Recurrence‐free and overall survival among elderly stage III colon cancer patients treated with CAPOX or capecitabine monotherapy

The aim of this study is to investigate the effects of CAPOX and capecitabine on recurrence‐free survival (RFS) and overall survival (OS) among elderly stage III colon cancer patients and to evaluate the effect of (non‐)completion. Patients aged ≥70 years who underwent resection only or who were subsequently treated with CAPOX or capecitabine in 10 large non‐academic hospitals were included. RFS and OS were analyzed with Kaplan‐Meier curves and multivariable Cox regression adjusted for patient and tumor characteristics. 982 patients were included: 630 underwent surgery only, 191 received CAPOX and 161 received capecitabine. Five‐year RFS and OS did not differ between capecitabine and CAPOX (RFS: 63% vs. 60% (p = 0.91), adjusted HR = 0.99 (95%CI 0.68‐1.44); OS: 66% vs. 66% (p = 0.76), adjusted HR = 0.93 (95%CI 0.64–1.34)). After resection only, RFS was 38% and OS 37%. Completion rates were 48% for CAPOX and 68% for capecitabine. Three‐year RFS and OS did not differ between patients who discontinued CAPOX early and patients who completed treatment with CAPOX (RFS: 61% vs. 69% (p = 0.21), adjusted HR = 1.42 (95%CI 0.85–2.37); OS: 68% vs. 78% (p = 0.41), adjusted HR = 1.17 (95%CI 0.70–1.97)). Three‐year RFS and OS differed between patients who discontinued capecitabine early and patients who completed treatment with capecitabine (RFS: 54% vs. 72% (p = 0.01), adjusted HR = 2.07 (95%CI 1.11–3.84); OS: 65% vs. 80% (p = 0.01), adjusted HR = 2.00 (95%CI 1.12–3.59)). Receipt of CAPOX or capecitabine is associated with improved RFS and OS. The advantage does not differ by regimen. The addition of oxaliplatin might not be justified in elderly stage III colon cancer patients.     

Pathologic complete response in breast cancer patients receiving anthracycline‐ and taxane‐based neoadjuvant chemotherapy

BACKGROUND:

The current study was conducted to evaluate the influence of race/ethnicity and tumor subtype in pathologic complete response (pCR) following treatment with neoadjuvant chemotherapy.

METHODS:

A total of 2074 patients diagnosed with breast cancer between 1994 and 2008 who were treated with neoadjuvant anthracycline‐ and taxane‐based chemotherapy were included. pCR was defined as no residual invasive cancer in the breast and axilla. The Kaplan‐Meier product‐limit was used to calculate survival outcomes. Cox proportional hazards models were fitted to determine the relationship of patient and tumor variables with outcome.

RESULTS:

The median patient age was 50 years; 14.6% of patients were black, were 15.2% Hispanic, 64.3% were white, and 5.9% were of other race. There were no differences in pCR rates among race/ethnicity (12.3% in black, 14.2% in Hispanics, 12.3% in whites, and 11.5% in others, P = .788). Lack of pCR, breast cancer subtype, grade 3 tumors, and lymphovascular invasion were associated with worse recurrence‐free survival (RFS) and overall survival (OS) (P ≤ .0001). Differences in RFS by race/ethnicity were noted in the patients with hormone receptor‐positive disease (P = .007). On multivariate analysis, Hispanics had improved RFS (hazard ratio [HR], 0.69; 95% confidence interval [95% CI], 0.49‐0.97) and OS (HR, 0.63; 95% CI, 0.41‐0.97); blacks had a trend toward worse outcomes (RFS: HR, 1.28 [95% CI, 0.97‐1.68] and OS: HR, 1.32 [95% CI, 0.97‐1.81]) when compared with whites.

CONCLUSIONS:

In this cohort of patients, race/ethnicity was not found to be significantly associated with pCR rates. On a multivariate analysis, improved outcomes were observed in Hispanics and a trend toward worse outcomes in black patients, when compared with white patients. Further research was needed to explore the potential differences in biology and outcomes. Cancer 2010. © 2010 American Cancer Society.     

Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub‐types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial

Breast cancer can be classified into molecular sub‐types that have distinct survival patterns. We evaluated the prognostic significance of breast cancer sub‐types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with ECMF (epirubicin and CMF). Furthermore, we evaluated whether the sub‐types were predictive of the added benefit of epirubicin in these trials. Tumour tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumours into six intrinsic sub‐types. We used Cox regression to compare overall survival (OS), breast cancer‐specific survival (BCSS) and relapse‐free survival (RFS) in the different sub‐groups. We also compared the effect of ECMF with CMF by sub‐group. Immunohistochemistry data were available for 1,725 cases of whom 805 were luminal 1‐basal negative. Median follow‐up time was 7 years. The luminal 1‐basal negative tumours were associated with the best prognosis in five years after surgery and the HER2‐like tumours were associated with the poorest prognosis. There was little evidence for significant heterogeneity of this effect by tumour sub‐type (OS p = 0.40, BCSS p = 0.53 RFS p = 0.50) – the largest additional benefit of epirubicin was in women with tumours of the 5‐negative phenotype (OS HR = 0.39 95% CI: 0.21–0.73) and the smallest was in Luminal 1‐basal negative tumours (OS HR = 0.86 95% CI: 0.64–1.16). We confirmed that breast cancer sub‐types show distinct behaviour with differences in short‐ and long‐term survival. The benefit of ECMF over CMF was statistically similar in all disease sub‐types.     

Targeting slow‐proliferating ovarian cancer cells

Advanced ovarian cancer has a high rate of recurrence and mortality despite relative chemosensitivity at the time of initial treatment. Conventional chemotherapeutic agents typically target rapidly dividing cells. Disease relapse may therefore result from the survival and later emergence of latent slow‐proliferating and/or quiescent cancer cells. We sought to identify drugs that target this cell population and to investigate the influence of these cells on outcome of patients in remission from advanced ovarian cancer. Drugs with increased efficacy against slower proliferating cells were identified using correlation‐based screening of 44,657 compounds tested on the NCI‐60 panel of cancer cell lines. Validation of candidates was performed in comparison with Cisplatin or Paclitaxel and by manipulation of proliferation rates by serum deprivation. Cytostatic and cytocidal effects were evaluated using MTT assays and active caspase‐3 immunocytochemistry. Ki‐67 proliferation indices were determined for tumors from 104 patients in remission. UCN‐01 efficacy was correlated with longer doubling time among the NCI‐60 cell lines (R = 0.54, p < 0.0001) and in a panel of 24 ovarian cancer cell lines (R = 0.42, p = 0.04), whereas this was not the case for Cisplatin (R = ?0.10, p = 0.65) and Paclitaxel efficacy correlated with shorter doubling time (R = ?0.52, p = 0.009). Cytostatic and cytocidal effects of UCN‐01 were increased in serum‐deprived cells. A low proliferation index was associated with presence of persistent disease at second‐look surgery (p = 0.01) and poor survival (disease‐free survival, p = 0.002; overall survival, p = 0.04). These results suggest that targeting quiescent ovarian cancer cells may be a worthwhile therapeutic approach to improving survival of women with ovarian cancer.     

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

Vav3 is a key modulator of GTP‐hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full‐length Vav3‐alpha and N‐terminal truncated Vav3.1 lacking its self‐regulatory domains. The aim of our study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem‐cell like side‐population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT‐PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum‐sensitivity and survival were analyzed and associated with Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (p < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression‐free (HR = 2.820, p = 0.0001) and overall survival (HR = 2.842, p = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in Type‐II but not in Type‐I cancers. Notably, platinum‐refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum‐sensitivity (15.848 vs. 6.653, p = 0.0001). In conclusion, Vav3.1 is over‐expressed in stem‐cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N‐terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi‐drug resistance.     

Overall survival benefits for irinotecan‐containing regimens as first‐line treatment for advanced gastric cancer: An updated meta‐analysis of ten randomized controlled trials

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan‐containing regimen as first‐line treatment for those patients are controversial. We performed a systematic review and meta‐analysis of randomized controlled trials to determine the survival benefits of irinotecan‐containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan‐containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78–0.94, p = 0.002] and progression‐free survival [HR = 0.82, 95% CI = 0.69–0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77–1.04, p = 0.15), 1‐year survival rate [1‐year SR: relative risk (RR) 1.10, 95% CI = 0.97–1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91–1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan‐containing regimens. This updated meta‐analysis provided strong evidence for a survival benefit of irinotecan‐containing regimen as first‐line treatment for AGC. A clear advantage of irinotecan‐containing over nonirinotecan‐containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.     

Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL‐induced apoptotic pathway regulation

Ovarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell‐cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression‐free survival rates of the CBX7‐positive patients were significantly shorter than those of the CBX7‐negative patients (p < 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC‐7C, revealed that cell viability was significantly reduced compared to the control cells (p < 0.001). Expression microarray analysis revealed that apoptosis‐related genes, particularly tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p < 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL‐induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy.     

Preoperative serum tissue polypeptide‐specific antigen is a valuable prognostic marker in breast cancer

Tissue polypeptide‐specific antigen (TPS), a specific epitope structure of a peptide in serum associated with human cytokeratin 18, is linked to the proliferative activity of tumors. Here, we aimed to identify the association between the preoperative serum TPS level and outcome in breast cancer patients. We assayed preoperative serum TPS levels in 1,477 breast cancer patients treated between June 2000 and December 2006. The TPS level was measured with a one‐step solid phase radiometric sandwich assay detecting the M3 epitope on cytokeratin 18 fragments. The cutoff value was 80 U/L. Among the 1,477 breast cancer patients examined, preoperative serum TPS level was elevated (>80 U/L) in 290 patients (19.6%). Age (>45 years), tumor size (>2 cm), nodal metastasis, negative progesterone receptor and human epidermal growth factor receptor 2 were associated with elevated TPS. Evidence of recurrence was observed in 229 patients (15.6%). Elevated TPS was associated with poor disease‐free survival (p < 0.001) and overall survival (p < 0.001). In a multivariate analysis using the Cox proportional regression model, elevated TPS was an independent prognostic factor for disease‐free survival (p = 0.001) and overall survival (p = 0.026). Furthermore, in subgroup analysis based on molecular subtype, the prognostic effect of preoperative TPS on survival (OS: HR 2.614, p = 0.003; DFS: HR 1.895, p = 0.001) was identified only in the luminal A subtype. Elevated preoperative serum TPS level is associated with poor breast cancer outcomes. Based on these findings, we conclude that preoperative TPS is a valuable biomarker for clinical use in predicting outcomes in breast cancer patients.     

Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p < 0.001) and bilateral breast cancer (p = 0.03), they and were significantly more likely to respond to carboplatin-based neoadjuvant chemotherapy compared to anthracycline- or taxane-based regimen in terms of pathologic complete response (50% vs. 0%, p = 0.006). At the median follow-up of 54 months, TP53 mutation was an independent unfavorable factor for recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) (RFS, adjusted hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.15–4.33, p = 0.02; DRFS, adjusted HR: 2.73, 95% CI: 1.41–5.30, p = 0.003; OS, adjusted HR: 4.60, 95% CI: 2.26–9.41, p < 0.001) in multivariate analyses. Our study suggested that TP53 germline mutations occur more frequently in very early onset unselected breast cancer patients; and TP53 germline mutation carriers have a very poor survival and may benefit from carboplatin-based neoadjuvant chemotherapy in unselected breast cancer patients.     

Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5‐FU/LV plus irinotecan or irinotecan plus oxaliplatin as first‐line treatment (FIRE 1‐trial)

Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT‐qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS‐and PIK3CA‐mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5‐fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE‐1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression‐free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC‐analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402–0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476–1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460–0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351–0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS‐ and PIK3CA‐genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first‐line irinotecan‐based chemotherapy.     

First‐line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: Patients' outcome and analysis of prognostic factors

FOLFIRINOX is a standard first‐line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty‐seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19–9.81) and 12 months (95% CI 9.75–14.25), respectively. Response rate was 38.6%, while disease‐control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42–3.59) and neutrophil‐lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38–4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good‐risk (0 factors, 38 pts), intermediate‐risk (1 factor, 49 pts) and poor‐risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.     

Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta‐analysis

Statins have shown antineoplastic properties in preclinical studies with breast cancer cells. They inhibit the enzyme “HMG CoA reductase” and the expression of this enzyme in cancer cells has been implicated as a favorable prognostic factor in patients with breast cancer. After a search of MEDLINE and Embase from inception through November 2015, 817 abstracts were reviewed to identify studies that described an association between statin use and outcomes in breast cancer. A total of 14 studies which included 75,684 women were identified. In a meta‐analysis of 10 studies, statin use was associated with improved recurrence‐free survival (RFS; HR 0.64; 95% CI 0.53–0.79, I² = 44%). Furthermore, this RFS benefit appeared to be confined to use of lipophilic statins (HR 0.72; 95% CI 0.59–0.89) as hydrophilic statin use was not associated with improvement in RFS (HR 0.80; 95% CI 0.44–1.46). Statin users similarly showed improved overall survival in a meta‐analysis with substantial heterogeneity (8 studies, HR 0.66; 95% CI 0.44–0.99, I² = 89%). Statin users also had improved cancer‐specific survival, although this relationship was measured with less precision (six studies, HR 0.70; 95% CI 0.46–1.06, I² = 86%). In conclusion, breast cancer patients who use statins, or specifically, lipophilic statins show improved recurrence‐free survival. Statin users also had improved overall survival and cancer‐specific survival. These findings should be assessed in a prospective randomized cohort and the choice of statin, dose and biomarkers that may predict the efficacy of these drugs should be identified.     

Prognostic role of platelet to lymphocyte ratio in non‐small cell lung cancers: A meta‐analysis including 3,720 patients

Platelet to lymphocyte ratio (PLR) was recently reported as a useful index in predicting the prognosis of lung cancer. However, the prognostic role of PLR in lung cancer remains controversial. The aim of this study was to evaluate the association between PLR and clinical outcome of lung cancer patients through a meta‐analysis. Relevant literatures were retrieved from PubMed, Ovid, the Cochrane Library and Web of Science databases. Meta‐analysis was performed using hazard ratio (HR) and 95% confidence intervals (CIs) as effect measures. A total of 5,314 patients from 13 studies were finally enrolled in the meta‐analysis. The summary results showed that elevated PLR predicted poorer overall survival (OS) (HR: 1.526, 95%CI: 1.268–1.836, p < 0.001) in patients with lung cancer and OS (HR: 1.631, 95%CI: 1.447–1.837, p < 0.001) in patients with nonsmall cell lung cancer (NSCLC). Subgroup analysis revealed that increased PLR was also associated with poor OS in NSCLC treated by surgical resection (HR: 1.884, 95%CI: 1.308‐2.714, P < 0.001) and non‐surgery (HR: 1.570, 95%CI: 1.323‐1.863, P < 0.001). In addition, PLR Cut‐off value ≤ 160 (HR: 1.506, 95%CI: 1.292‐1.756, P < 0.001) and PLR Cut‐off value>160 (HR: 1.842, 95%CI: 1.523‐2.228, P < 0.001). In contrast, elevated PLR was not associated with OS (HR: 1.117, 95%CI: 0.796‐1.569, P > 0.05) in patients with small cell lung cancer (SCLC).This meta‐analysis result suggested that elevated PLR might be a predicative factor of poor prognosis for NSCLC patients.     

Bevacizumab in combination with different platinum‐based doublets in the first‐line treatment for advanced nonsquamous non‐small‐cell lung cancer: A network meta‐analysis

Platinum‐based doublet chemotherapy with or without bevacizumab is the standard treatment for untreated advanced nonsquamous non‐small‐cell lung cancer (NS‐NSCLC). However, adding bevacizumab to chemotherapies other than paclitaxel–carboplatin is, though widely applied clinically, largely unjustified due to the lack of head‐to‐head data. We performed a Bayesian network meta‐analysis (NMA) to address this important issue. Data of 8,548 patients from 18 randomized controlled trials (RCTs) receiving six treatments, including taxane–platinum (Taxane–Pt), gemcitabine–platinum (Gem–Pt), pemetrexed–platinum (Pem–Pt), taxane–platinum + bevacizumab (Taxane–Pt + B), gemcitabine–platinum + bevacizumab (Gem–Pt + B) and pemetrexed–platinum + bevacizumab (Pem–Pt + B), were incorporated into the analyses. Direct and indirect evidence of overall survival (OS) and progression‐free survival (PFS) were synthesized at the hazard ratio (HR) scale and evidence of objective response rate (ORR) and serious adverse events (SAE) were synthesized at the odds ratio (OR) scale. Taxane–Pt + B showed significant advantages in OS (HR = 0.79, p < 0.001), PFS (HR = 0.54, p < 0.001) and ORR (OR = 2.7, p < 0.001) over Taxane–Pt with comparable tolerability (OR = 3.1, p = 0.08). Gem–Pt + B showed no OS benefit compared to any other treatment. No significant differences were detected between Pem–Pt + B and Pem–Pt in four outcomes. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B were ranked the first and second, respectively. In conclusion, in the first‐line treatment for advanced NS‐NSCLC, Taxane–Pt and Gem–Pt are the most and least preferable regimens to be used with bevacizumab, respectively. Adding bevacizumab to Pem–Pt remains unjustified because it fails to improve efficacy or tolerability. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B are the best and second‐best treatment for this population.     

Functional significance of VEGFR‐2 on ovarian cancer cells

Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of this study. By protein analysis, A2780‐par and HeyA8 ovarian cancer cell lines expressed VEGFR‐1 and HeyA8 A2774, and SKOV3ip1 expressed VEGFR‐2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR‐2 expression, whereas only 15% showed moderate to high VEGFR‐1 expression. By immunofluorescence, little or no VEGFR‐2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with SKOV3ip1 cells and treated with either human VEGFR‐2 specific antibody (1121B), murine VEGFR‐2 specific antibody (DC101) or the combination. Treatment with 1121B reduced SKOV3ip1 cell migration by 68% (p < 0.01) and invasion by 72% (p < 0.01), but exposure to VEGFR‐1 antibody had no effect. Treatment with 1121B effectively blocked VEGF‐induced phosphorylation of p130Cas. In vivo treatment with either DC101 or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ip1 and A2774 models. Decreased tumor burden after treatment with DC101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p < 0.001). We show functionally active VEGFR‐2 is present on most ovarian cancer cells. The observed anti‐tumor activity of VEGF‐targeted therapies may be mediated by both anti‐angiogenic and direct anti‐tumor effects. © 2008 Wiley‐Liss, Inc.     

Quantitative proteomic analysis of mitochondria from human ovarian cancer cells and their paclitaxel‐resistant sublines

Paclitaxel resistance is a major obstacle for the treatment of ovarian cancer. The chemoresistance mechanisms are partly related to the mitochondria. Identification of the relevant proteins in mitochondria will help in clarifying the possible mechanisms and in selecting effective chemotherapy for patients with paclitaxel resistance. In the present study, mitochondria from two paclitaxel‐sensitive human ovarian cancer cell lines (SKOV3 and A2780) and their corresponding resistant cell lines (SKOV3‐TR and A2780‐TR) were isolated. Guanidine‐modified acetyl‐stable isotope labeling and liquid chromatography‐hybrid linear ion trap Fourier‐transform ion cyclotron resonance mass spectrometry (LC‐FTICR MS) were performed to find the expressed differential proteins. Comparative proteomic analysis revealed eight differentially expressed proteins in the ovarian cancer cells and their paclitaxel‐resistant sublines. Among them, mimitin and 14‐3‐3 ζ/δ were selected for further research. The effects of mimitin and 14‐3‐3 ζ/δ were explored using specific siRNA interference in ovarian cancer cell lines and immunohistochemistry in human tissue specimens. The downregulation of mimitin and 14‐3‐3 ζ/δ using specific siRNA in paclitaxel‐resistant ovarian cancer cells led to an increase in the resistance index to paclitaxel. Multivariate analyses demonstrated that lower expression levels of the mimitin and 14‐3‐3 ζ/δ proteins were positively associated with shorter progression‐free survival (PFS) and overall survival (OS) in patients with primary ovarian cancer (mimitin: PFS: P = 0.041, OS: P = 0.003; 14‐3‐3 ζ/δ: PFS: P = 0.031, OS: P = 0.011). Mimitin and 14‐3‐3 protein ζ/δ are potential markers of paclitaxel resistance and prognostic factors in ovarian cancer.     

Ataxia‐telangiectasia‐mutated protein expression with microsatellite instability in gastric cancer as prognostic marker

The prognostic significance of ataxia‐telangiectasia‐mutated (ATM) expression in gastric cancer remains unclear. The functional loss of ATM gene exhibits a biologic correlation with microsatellite instability (MSI). In this study, we investigated the significance of ATM expression with MSI by evaluating gastric cancer patients who had underwent curative resection. ATM expression was classified into low ATM expression (?, ±, +) and high ATM expression (++, +++) using immunohistochemistry analysis. MSI status was classified as MSI‐negative (MSS, MSI‐low) and MSI‐positive (MSI‐high). Of 321 patients, 205 (63.9%) exhibited low ATM expression and 116 (36.1%) exhibited high ATM expression. Low ATM expression was more frequently identified in patients of older age, more advanced stage and with MSI‐positive tumor (p = 0.025, p = 0.001 and p = 0.014, respectively). The probability of 5‐year disease‐free survival (DFS) and overall survival (OS) was lower in low ATM expression group compared with the high ATM expression group (DFS: 62.5%, 76.4%, p = 0.017, OS: 65.9%, 78.5%, p = 0.027, respectively). According to MSI status, a subgroup of MSI‐negative and low ATM expression cases exhibited the worst prognosis for DFS and OS; this subgroup also exhibited poorer DFS according to multivariable analysis (hazard radio = 1.8, 95% confidence interval, 1.2–2.8, p = 0.010), although prognostic value of ATM expression alone did not remain in the multivariable analysis. Taken together, these findings indicate that ATM expression with MSI status is an independent factor for gastric cancer prognosis in gastric cancer patients who received curative surgery.     

Neuropilin‐2 and its ligand VEGF‐C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients

The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder‐sparing therapy can be performed by transurethral resection (TURBT) and radio‐chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin‐2 (NRP2)/VEGF‐C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF‐C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n = 198) or RT (n = 49) and a follow‐up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 – 7.86; p = 0.004) and was associated with a 3.85‐fold increased risk of an early cancer specific death (95% CI: 0.91 – 16.24; p = 0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p = 0.037). Patients with high VEGF‐C expression have a 2.29‐fold increased risk of shorter CSS (95% CI: 1.03–5.35; p = 0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF‐C expression (p = 0.041). Additionally, NRP2 and VEGF‐C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57–36.23; p = 0.012). Stratification for muscle invasiveness (T1 vs. T2‐T4) confirmed the prognostic role of NRP2 and NRP2/VEGF‐C co‐expression in patients with T2‐T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF‐C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.     

Body mass index and survival in patients with renal cell carcinoma: A clinical‐based cohort and meta‐analysis

Growing evidence suggests that obesity, an established cause of renal cell cancer (RCC), may also be associated with a better prognosis. To evaluate the association between RCC survival and obesity, we analyzed a large cohort of patients with RCC and undertook a meta‐analysis of the published evidence. We collected clinical and pathologic data from 1,543 patients who underwent nephrectomy for RCC between 1994 and 2008 with complete follow‐up through 2008. Patients were grouped according to BMI (kg/m²): underweight <18.5, normal weight 18.5 to <23, overweight 23 to <25 and obese ≥25. We estimated survival using the Kaplan–Meier method and Cox proportional hazard models to examine the impact of BMI on overall survival (OS) and cancer‐specific survival (CSS) with adjustment for covariates. We performed a meta‐analysis of BMI and OS, CSS and recurrence‐free survival (RFS) from all relevant studies using a random‐effects model. The 5‐year CSS increased from 76.1% in the lowest to 92.7% in the highest BMI category. A multivariate analysis showed higher OS [hazard ratio (HR) = 0.45; 95% CI: 0.29–0.68) and CSS (HR = 0.47; 95% CI: 0.29–0.77] in obese patients than in normal weight patients. The meta‐analysis further corroborated that high BMI significantly improved OS (HR = 0.57; 95% CI: 0.43–0.76), CSS (HR = 0.59; 95% CI: 0.48–0.74) and RFS (HR = 0.49; 95% CI: 0.30–0.81). Our study shows that preoperative BMI is an independent prognostic indicator for survival among patients with RCC.