[Show abstract][Hide abstract] ABSTRACT: Objective Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. Conclusions Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology. INTRODUCTION
[Show abstract][Hide abstract] ABSTRACT: Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial.
World Journal of Gastroenterology 10/2014; 20(38):13637-13647. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel.
The Lancet Oncology 09/2014; · 24.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with esophageal carcinoma (EC) who are treated with definitive chemoradiotherapy (bimodality therapy [BMT]) experience frequent relapses. In a large cohort, we assessed the timing, frequency, and types of relapses during an aggressive surveillance program and the value of the salvage strategies.
Journal of Clinical Oncology 09/2014; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The purpose of this study was to examine the significance of signet ring cell histology to predict response to preoperative chemoradiotherapy in patients with esophageal adenocarcinoma.
Two groups of patients with locoregional esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery were studied: those with signet ring cell adenocarcinoma (n = 85) and a reference group (n = 638) with usual and other types of adenocarcinoma. Surgical specimens were reviewed for degree of pathologic response and pathologic stage. Cox regression models were used to assess the effects of clinicopathologic variables on survival.
Tumors from patients in the signet ring cell group had a lower rate of complete pathologic response (9% versus 26%, p < 0.001) and more frequent positive margins (24% versus 10%, p < 0.001) compared with tumors from the reference group. Median overall survival (22 versus 48 months, p = 0.003) and disease-free survival (16 versus 35 months, p = 0.007) were shorter in the signet ring cell group than in the reference group. Signet ring cell histology and high pathologic stage were significant predictors of decreased overall survival and disease-free survival. Survival durations for patients whose resected specimens showed downstaging after neoadjuvant chemoradiation did not significantly differ from survival durations of patients whose specimens did not show downstaging in the signet ring cell group, unlike the reference group.
Signet ring cell histology on pretreatment biopsy predicts a decreased likelihood of complete pathologic response and survival for patients with esophageal adenocarcinoma treated with preoperative chemoradiation and surgery.
The Annals of Thoracic Surgery 09/2014; · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current algorithms for surveillance of patients with esophageal adenocarcinoma (EAC) after chemoradiation and surgery (trimodality therapy [TMT]) remain empiric. The authors hypothesized that the frequency, type, and timing of relapses after TMT would be highly associated with surgical pathology stage (SPS), and therefore SPS could be used to individualize the surveillance strategy. Between 2000 and 2010, 518 patients with EAC were identified who underwent TMT at The University of Texas MD Anderson Cancer Center and were frequently surveyed. Frequency, type, and timing of the first relapse (locoregional and/or distant) were tabulated according to SPS. Standard statistical approaches were used. The median follow-up time after esophageal surgery was 55.4 months (range, 1.0-149.2 months). Disease relapse occurred in 215 patients (41.5%). Higher SPS was associated with a higher rate of relapse (0/I vs II/III, P≤.001; 0/I vs II, P=.002; SPS 0/I vs III, P≤.001; and SPS II vs III, P=.005) and with shorter time to relapse (P<.001). Irrespective of the SPS, approximately 95% of all relapses occurred within 36 months of surgery. The 3- and 5-year overall survival rates were shorter for patients with a higher SPS than those with a lower SPS (0/I vs II/III, P≤.001; 0/I vs II, P≤.001; 0/I vs III, P≤.001; and II vs III, P=.014). The compelling data show an excellent association between SPS and frequency/type/timing of relapses after TMT in patients with EAC. Thus, the surveillance strategy can potentially be customized based on SPS. These data can inform a future evidence-based surveillance strategy that can be efficient and cost-effective.
Journal of the National Comprehensive Cancer Network: JNCCN 08/2014; 12(8):1139-44. · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal carcinoma is a significant worldwide health problem and the incidence is increasing faster than that of any other malignancy. 18F-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography (PET/CT) is important in the management of patients with potentially resectable esophageal cancer and is useful in initial staging of locally advanced cancer and after neoadjuvant therapy. The purpose of this study is to determine the utility of FDG-PET/CT in the clinical staging of early-stage esophageal cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2014; 9(8):1202-1206. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Radiation Therapy Oncology Group 98-11 clinical trial demonstrated the superiority of standard 5-fluorouracil/mitomycin-C over 5-fluorouracil/cisplatin in combination with radiation in the treatment of anal squamous cell cancer. Tumor size (>5 cm) and lymph node metastases are associated with disease progression. There may be key molecular differences (eg, DNA methylation changes) in tumors at high risk for progression.
Diseases of the Colon & Rectum 08/2014; 57(8):941-957. · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional genetic variants of DNA repair genes may alter the host DNA repair capacity, and thus influence efficiency of therapies. We genotyped eight potentially functional SNPs in genes (i.e., ERCC1, XPA, XPC, XPD and XPG) involved in the nucleotide excision repair pathway in 496 Japanese gastric cancer patients, and assessed overall survival and recurrence-free survival. The combined effects of risk genotypes of these eight SNPs in Japanese patients were further replicated in 356 North-American gastric cancer patients. In Japanese patients, we found that the XPC rs2228000 TT genotype was associated with shorter overall survival (HR=1.75, 95% CI = 1.07-2.86) and recurrence-free survival (HR = 2.17, 95% CI=1.19-3.95), compared with CC/CT genotypes, and the XPG rs17655 CC genotype was associated with shorter overall survival (HR=1.60, 95% CI =1.08-2.36), compared with GG/CG genotypes. The number of observed risk genotypes in the combined analysis was associated with shorter overall survival and recurrence-free survival in a dose-response manner (Ptrend=0.006 and Ptrend<0.000) in Japanese patients; specifically, compared with those with ≤ 1 risk genotypes, those with ≥ 2 risk genotypes showed markedly shorter overall survival (HR=1.79, 95% CI=1.18-2.70) and recurrence-free survival (HR=2.80, 95% CI=1.66-4.73). The association between ≥ 2 risk genotypes and shorter overall survival was not significant (HR=1.26, 95% CI=0.82-1.94) in North-American patients, but the trends were similar in these two groups of patients. These data show that functional SNPs in NER core genes may impact survival in Japanese gastric cancer patients.
[Show abstract][Hide abstract] ABSTRACT: Hispanics are the largest nonwhite ethnic group in the US population, and they have higher incidence and mortality rates for gastric cancer (GC) than whites and Asians. Studies have identified several genetic susceptibility loci and intermediate phenotypic biomarkers for GC in whites and Asians. No studies have evaluated genetic susceptibility and intermediate phenotypic biomarkers in Hispanics.
[Show abstract][Hide abstract] ABSTRACT: Our clinical study indicates esophageal adenocarcinoma patients on metformin had a better treatment response than those without metformin. However, the effects of metformin and the mechanisms of its action in esophageal cancer (EC) are unclear. EC cell lines were used to assess the effects of metformin alone or in combination with 5-fluorouracil on survival and apoptosis. RPPA proteomic array and immunoblots were used to identify signaling affected by metformin. Standard descriptive statistical methods were used. Reduction in cell survival and induction of apoptosis by metformin were observed in several EC cell lines. The use of metformin in combination with 5-FU significantly sensitized EC cells to the cytotoxic effect of 5-FU. RPPA array demonstrated that metformin decreased various oncogenes including PI3K/mTORsignaling and survival/cancer stem cell-related genes in cells treated with metformin compared with its control. Immunoblots and transcriptional analyses further confirm that metformin downregulated these CSC-related genes and the components of the mTOR pathway in a dose?dependent manner. Sorted ALDH-1+ cell tumor sphere forming capacity was preferentially reduced by metformin. Finally, metformin reduced tumor growth in vivo and when combined with FU, there was synergistic reduction in tumor growth. Metformin inhibits EC cell growth and sensitizes EC cells to 5-FU cytotoxic effects by targeting CSCs and the components of mTOR. The present study supports our previous clinical observations that the use of metformin is beneficial to EC patients. Metformin can complement other therapeutic combinations to effectively treat EC patients.
International Journal of Oncology 05/2014; · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ramucirumab (IMC-1121B) targets VEGFR-2. Ramucirumab is being investigated in many malignancies including gastric cancer. The Phase III trial in patients with advanced breast cancer failed to improve the primary end point The REGARD trial, a Phase III study, in patients with advanced gastric cancer in the second line setting, had a marginal improvement in overall survival but did not achieve the expected hazard ratio target (of 0.69) and the median duration of therapy with ramucirumab was meager 8 weeks (only 2 weeks longer than the placebo's). Other notable agents in the second line setting are docetaxel and irinotecan. Preliminary results of the RAINBOW trial suggest that ramucirumab may be providing more than marginal advantage. In this review, we briefly summarize the process of angiogenesis and address the emerging cost-benefit issues that surround all newly developed agents including ramucirumab.
Expert Review of Anti-infective Therapy 03/2014; · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Chemoradiation represents the standard of care for most patients with localized squamous cell carcinoma of the anal canal. In this article, randomized trials and studies on chemoradiation for localized anal cancer are reviewed.
Areas covered: Herein the major Phase III randomized controlled trials published on the treatment of anal carcinoma are discussed. A recent randomized trial (Anal Cancer Trial II), after a total follow-up of 5.1 years, demonstrated that there was no difference in the complete response rate or 3-year progression-free survival when 5-fluorouracil (5-FU) with cisplatin chemoradiation was compared with 5-FU plus mitomycin C chemoradiation. Maintenance chemotherapy using 5-FU and cisplatin did not improve 3-year progression-free survival – 74 versus 73%. Recent studies have continued to evaluate intensity-modulated radiation therapy for anal cancer in an effort to reduce acute and long-term toxicity from radiotherapy, but no clear answers have emerged.
Expert opinion: Studies on tumor biology, patient genetics and predictive marker are warranted to identify patients that are most likely to benefit from newer locoregional and systemic therapies. Intensity-modulated radiation therapy appears to be a promising approach for reducing treatment-related toxicity in anal cancer patients, but its role still remains to be completely defined.
[Show abstract][Hide abstract] ABSTRACT: Cancer stem cells are proposed to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of cancer stem cells (CSCs); however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional co-activator YAP1 is a major determinant of CSC properties in non-transformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSCs properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenecity in vivo. The small molecule inhibitor of YAP1, Verteporfin (VP) significantly blocks CSCs properties in cells with high YAP1 and a high proportion of ALDH1+. Our findings identify YAP1 driven SOX9 expression is a critical event in acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.
Cancer Research 01/2014; 74:4170-4182. · 9.28 Impact Factor