[Show abstract][Hide abstract] ABSTRACT: Background
Adjuvant Online (AOL) is web-accessible risk-assessment model that predicts the mortality and the benefits of adjuvant therapy (http://www.newadjuvantonline.com). AOL has never been validated for Asian colon cancer patients.
Using the Yonsei Tumor Registry database, patients who were treated within the Yonsei University Health System between 1990 and 2005 for T1-4, N0-2, and M0 colon cancer were included in the calculations for survival. Observed and predicted 5-year overall survival was compared for each patient.
The median age of the study population of 1431 patients was 60 years (range, 15–87 years), and the median follow-up duration was 7.9 years (range, 0.06–19.8 years). The predicted 5-year overall survival rate (77.7%) and observed survival (79.5%) was not statistically different (95% Confidential interval, 76.3–81.5) in all patients. Predicted outcomes were within 95% confidential interval of observed survival in both stage II and III disease, including most demographic and pathologic subgroups. Moreover, AOL more accurately predicted OS for patients with stage II than stage III.
AOL tended to offer reliable prediction for 5-year overall survival and could be used as a decision making tool for adjuvant treatment in Korean colon cancer patients whose prognosis is similar to other Asian patients.
[Show abstract][Hide abstract] ABSTRACT: Through this study, we aimed to validate several biomarkers that have been known to possibly predict the outcomes of the trastuzumab and paclitaxel (TP). Human epidermal growth factor 2 (HER2) positive metastatic breast cancer (MBC) patients who had been treated with TP in single institute from 2006 to 2009 were included in this study. For procured formalin fixed paraffin embedded tumor tissues, HER2 amplification index (AI) and polymorphisms of the immunoglobulin G fragment C receptors (FCGR) were assessed as biomarkers to the trastuzumab and expression of class III beta tubulin (bTubIII) was evaluated as a predictive factor to the paclitaxel. Of 46 patients treated with TP, 27 patients could be evaluated for HER2 AI, 31 for bTubIII, and 26 for FCGR gene polymorphism. The median of the HER2 AI was 5.0 (range, 1.4-15.5) and a higher HER2 AI (≥5.0) was significantly correlated with better response rate (RR) (80% vs. 42%, P = 0.049) and longer progression-free survival (PFS) (13.6 vs. 6.9 months, P = 0.023). High bTubIII expression showed higher RRs than did low expression (81% vs. 40%, P = 0.040) in addition to longer PFS (16.2 months vs. 8.8 months, P = 0.04). However, polymorphisms in FCGR 2A-H131R or FCGR 3A-V158F were not predictive of RR or PFS. Our results suggest that a high HER2 AI and high bTubIII expression could be predictive of the outcomes to TP therapy but no evidence was found in terms of FCGR polymorphisms.
[Show abstract][Hide abstract] ABSTRACT: Sorafenib, an orally available multikinase inhibitor, combined with radiation has shown potential as an anticancer treatment in an in vitro and in vivo colon cancer model. In this study, we investigated the mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer. The effects of sorafenib on radiation-induced cytotoxicity of DLD-1 and HT-29 were evaluated via clonogenic assay. The impact of sorafenib on radiation-induced cell cycle kinetics and on apoptosis was analyzed using flow cytometry. Cyclin B1 was examined by western blot. As a measure of DNA damage after treatment, γ-H2AX foci and nuclear fragmentation were determined as a function of time after irradiation plus sorafenib combination. Tumor growth delay was used to evaluate the effects of sorafenib on in vivo radiation-induced cytotoxicity. Exposure of each cell line to sorafenib combined with irradiation resulted in an increased radiation-induced cytotoxicity with dose enhancement factors at a surviving fraction of 0.37 ranging from 1.13 to 1.76. Sorafenib strengthened radiation-induced accumulation of tumor cells in the G2-M phase with attenuated expression of cyclin B1, but had no effect on radiation-induced apoptosis. Exposure to sorafenib and radiation resulted in a greater number of remaining γ-H2AX foci and fragmented nuclei than radiation alone. In vivo tumor xenograft study confirmed that administration of sorafenib results in significant tumor growth inhibition when combined with radiation. These results indicate that sorafenib enhances radiation-induced cytotoxicity in colorectal cancer and suggest that the mechanism is associated with delaying repair of radiation-induced DNA damage and down-regulation of cyclin B1.
Preview · Article · Aug 2012 · Journal of Radiation Research
[Show abstract][Hide abstract] ABSTRACT: In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related signaling pathways, four different microarray experiments were reanalyzed before radiotherapy.
Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1) was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2). Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM) and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway.
Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that integrin signaling via adhesion molecules could be a target for radiosensitization.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to develop predictive/prognostic markers for liver metastasis and recurrence following liver resection, investigating not only clinical parameters but also molecular markers that are known to be involved in the process of liver metastasis. Seventy colon cancer patients with either no distant metastasis (group A) or with resectable synchronous liver metastasis only (group B) were prospectively enrolled. All 70 patients received curative resection of the primary tumor. Group B patients underwent additional liver resection. Clinical parameters as well as serum levels of molecular markers [carcinoembryonic antigen (CEA), osteopontin, matrix metalloproteinase-7 (MMP-7), tissue inhibitor of metalloproteinase-1 (TIMP-1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and E-selectin] from both tumor drainage (DV) and peripheral veins (PV) were analyzed. Results showed the clinical parameters were not significantly different between groups A and B. Nonetheless, the levels of VEGF and TIMP-1 from both DV and PV were significantly higher in group B compared to group A. In group A, 10 out of 33 (27.0%) patients developed metachronous liver metastasis. High levels of VEGF and TIMP-1 from DV were found to be significantly correlated with metachronous liver metastasis. In group B, 20 out of 33 (60.6%) patients had intrahepatic recurrence following resection of synchronous liver metastasis. The levels of VEGF from DV and the levels of TIMP-1 both from PV and DV were found to be significantly correlated with intrahepatic recurrence. Forty patients (7 from group A and 33 from group B) had liver resection and their 5-year disease-free survival rate was 15.9%. Univariate and multivariate analyses of prognostic factors revealed that the levels of VEGF and TIMP-1 from DV as well as the presence of lymph node metastasis from the primary tumor, synchronous metastasis and R1 resection were significantly associated with worse prognosis. The colon cancer patients with high levels of VEGF and TIMP-1 detected from the DV at the time of their initial surgery were found to have a high risk of metachronous liver metastasis and hepatic recurrence following the resection of synchronous liver metastasis. The high levels of VEGF and TIMP-1 were found to be significant predictive factors for poor prognosis following liver resection. These results require validation but pave the way for future transitional or clinical studies that may provide a greater understanding of colon cancer liver metastasis.
[Show abstract][Hide abstract] ABSTRACT: Objective
The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has received considerable attention as a first-line treatment of advanced colorectal cancers. Difficulties associated with effectively monitoring the activity of this drug have prompted us to seek a pharmacodynamic marker suitable for defining the optimum biological dose and schedule of bevacizumab administration against colon cancer in early clinical trials.
We evaluated inhibitory effects of bevacizumab on VEGF signaling and tumor growth in vitro and in vivo, and assessed phosphorylation of VEGF receptor 2 (VEGFR2) and downstream signaling in endothelial cells as pharmacodynamic markers using phospho-flow cytometry. We also validated markers in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy.
In in vitro studies, bevacizumab inhibited proliferation of human umbilical vein endothelial cells in association with reduced VEGF signaling. Notably, bevacizumab inhibited VEGF-induced phosphorylation of VEGFR-2, Akt, and extracellular signal-regulated kinase (ERK). In vivo, treatment with bevacizumab inhibited growth of xenografted tumors and attenuated VEGF-induced phosphorylation of Akt and ERK. The median percentages of VEGFR2 + pAkt + and VEGFR2 + pERK + cells, determined by phospho-flow cytometry, were approximately 3-fold higher in mCRC patients than in healthy controls. Bevacizumab treatment decreased VEGFR2 + pAkt + cells in 18 of 24 patients on day 3.
Bevacizumab combined with chemotherapy decreased the number of VEGFR2 + pAkt + cells, reflecting impaired VEGFR2 signaling. Together, these data suggest that changes in the proportion of circulating VEGFR2 + pAkt + cells may be a potential pharmacodynamic marker of the efficacy of antiangiogenic agents, and could prove valuable in determining drug dosage and administration schedule.
No preview · Article · Apr 2012 · Investigational New Drugs
[Show abstract][Hide abstract] ABSTRACT: Cancer patients, who have to adapt to a long treatment process with multiple stressful events, show various stress responses. Genetic components may contribute to individual differences in stress response and risk for development of stress-related psychiatric problems. The present study aimed to investigate the influence of FK506 binding protein 5 (FKBP5) gene polymorphisms regulating the hypothalamic-pituitary-adrenal (HPA) axis on individual distress levels in cancer patients faced with similar stressful situation. The present study used a prospective design to elucidate predictors of distress. A total of 130 patients (90 males, 40 females) who were newly diagnosed with advanced gastric cancer and supposed to receive first-line chemotherapy were initially assessed, and a six-week follow-up assessment occurred for 93 patients (63 males, 30 females) after two cycles of chemotherapy. Distress levels and coping patterns were measured by the Hospital Anxiety and Depression Scale (HADS) and Mini-Mental Adjustment to Cancer (Mini-MAC) scale. For genetic factors, three single nucleotide polymorphisms of FKBP5 rs1360780, rs9296158 and rs9470080 were genotyped. For HADS-anxiety, FKBP5 rs9296158 had a significant group-by-time interaction (p=0.015), and rs9470080 and rs1360780 had a marginally significant interaction (p=0.023, p=0.038, respectively). For HADS-depression, rs9470080 and rs9296158 had a marginally significant group-by-time interaction (p=0.026, p=0.032, respectively). In addition, a step-wise linear regression analysis showed that FKBP5 rs9470080 and rs9296158 were significant predictors of anxiety and depression after prolonged stress exposure in cancer patients. Our findings indicate that the genetic factors regulating the HPA axis such as FKBP5 gene polymorphisms may play a crucial role in anxiety and depression following prolonged stress exposure.
No preview · Article · Mar 2012 · Psychoneuroendocrinology
[Show abstract][Hide abstract] ABSTRACT: Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and miRNAs). A multilayer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations, and key differentially expressed miRNAs. Through this approach, we identified the central metabolic regulator AMP-activated protein kinase (AMPK)α as a potential functional target in Asian gastric cancer. Furthermore, we experimentally showed the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets.
[Show abstract][Hide abstract] ABSTRACT: S-1 or capecitabine plus oxaliplatin are considered active and tolerable in gastric cancer patients. We conducted a randomized phase II trial in gastric cancer patients to compare the activity and safety of these combinations.
The patients received S-1 at 80 mg/m2 for 14 days, followed by a 7-day rest period within a 3-week schedule in the S-1/oxaliplatin (SOX) arm, and capecitabine at 2000 mg/m2 for 14 days, followed by a 7-day rest period within a 3-week schedule in the capecitabine/oxaliplatin (CAPOX) arm. Oxaliplatin 130 mg/m2 was administered every 3 weeks in both arms.
One hundred twenty-nine patients were randomly assigned to SOX (N=65) or CAPOX (N=64). The median time to progression and the overall survival were 6.2 and 12.4 months with SOX, respectively; and 7.2 and 13.3 months with CAPOX, respectively. The overall response rates were 40% and 44% for SOX and CAPOX, respectively. The most frequent grade 3 or 4 toxicities were thrombocytopenia (15.4%) for SOX and neutropenia (18.8%) for CAPOX. The median time to 10% deteriorations in global health scores was similar in both arms (SOX, 4.3 months, CAPOX, 4.9 months).
Both the SOX and CAPOX regimens were equally active and well tolerated in advanced gastric cancer patients.
No preview · Article · Mar 2012 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Although its efficacy is unproven, 5-fluorouracil plus cisplatin (FP) is used to prevent postoperative relapse in gastric cancer. We investigated the safety and feasibility of S-1 plus cisplatin (SP) vs. FP for stage IIIB-IV (M0) gastric cancer.
Following curative resection, 41 stage IIIB-IV (M0) gastric cancer patients were assigned to SP (eight 14-day cycles of S-1 [40 mg/m(2) twice daily] plus cisplatin [60 mg/m(2) day 1] administered every 3 weeks) or FP (six 3-day cycles of FU [1 g/m(2) per day] plus cisplatin [80 mg/m(2) day 1] every 4 weeks). Doses were reduced based on predefined criteria.
Patient characteristics were balanced between the two arms. In total, 124 cycles of SP (N = 20, median = 7, range 1-8) and 113 cycles of FP (N = 21, median 6, range 1-6) were administered. The median relative dose intensity per patient was 75% (49.99-100%) for S-1, 100% (75-100%) for cisplatin in SP, and 100% (64-100%) for 5-FU, 100% (60-100%) for cisplatin in FP. The relative dose intensity of FP was stable, while that of SP decreased during treatment. After median follow-up of 7.9 months (3.8-14.55), the median RFS was not reached. Relapse occurred in two (10%) patients on SP and five (23.8%) in the FP arm (P = 0.24). The incidence of grade 3-4 granulocytopenia was 36.8% with SP and 14.3% with FP. Grade 3-4 non-hematologic toxicities included fatigue (5.2% with SP vs. 4.8% with FP), vomiting (10.5% with SP vs. 0% with FP), and infection (5.2% with SP vs. 0% FP).
S-1 plus cisplatin was feasible and tolerable as adjuvant treatment for stage IIIB-IV (M0) gastric cancer. However, because of decreased relative dose intensity during treatment, further study is warranted to determine optimal dosage and combination.
Preview · Article · Feb 2012 · Investigational New Drugs
[Show abstract][Hide abstract] ABSTRACT: D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer.
The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229).
1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294).
Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer.
F Hoffmann-La Roche and Sanofi-Aventis.
[Show abstract][Hide abstract] ABSTRACT: Nearly 50% of women with breast cancer show depressive symptoms after diagnosis and treatment. The purpose of this study was to clarify how psychosocial factors (body image, sexuality, and social relationships) and genetic factors (functional polymorphism of the serotonin transporter-linked promoter region) influence depression.
The participants were categorized by DSM-IV diagnoses; scored according to their depressive symptoms, body image and social and sexual function (BIRS), self-esteem, and quality of life; and genotyped by functional polymorphism of the serotonin transporter promoter.
Patients with depressive symptoms showed low self-esteem, poor body image, relationship problems, and low quality of life. Genotype frequencies did not differ between two groups categorized by the presence or absence of depressive symptoms. However, the patients with the short allele of the 5-HTTLPR had significantly higher HAM-D scores (F = 7.59, p = 0.047).
The results suggest that psychosocial factors related to breast cancer treatment such as body image, self-esteem, and interpersonal relationship influence the development of depressive symptoms. The 5-HTTLPR may be associated with the severity of depressive symptoms rather than susceptibility to the development of depressive symptoms.
No preview · Article · Dec 2011 · Supportive Care in Cancer