Prediction of Pathologic Complete Response by Gene Expression Profiling in Esopha

Summary

Principal Investigator: Jaffer Ajani
Affiliation: The University of Texas
Country: USA
Abstract: DESCRIPTION (provided by applicant): Our objective is to develop a PCR-based ~10-gene signature, through gene expression analyses, that can predict all three subtypes of pathologic responses (with high accuracy) following chemoradiation therapy in patients with esophageal cancer who undergo chemoradiation followed by surgery (Tri-modality [TM] therapy). The three pathologic subtypes are: pathologic complete response (pathCR), partial response, and extreme chemoradiation-resistance (exCRTR). One can conceive a therapeutic approach suited for each outcome (e.g., avoid chemoradiation in patients whose cancer has an exCRTR). Today however, there are no tools to optimize therapy for these outcomes since we cannot predict them before therapy. A predictive signature that has a high level (=80%) of specificity and a reasonable level of sensitivity (=45%) would be an advance. Our hypothesis is that a practical molecular signature can be established through gene expression profiling to predict three subgroups prior to TM therapy. In our 19-patient gene expression profiling study, the unsupervised hierarchical cluster analysis segregated cancers into two subtypes. Five of 6 pathCR patients clustered in subtype I and one pathCR patient clustered in subtype II. We discovered that Sonic Hedgehog and NF-kB-related genes appear to mediate chemoradiation-resistance. We were able to independently validate this. In a gene expression analysis of 47 TM patients (Specific Aim 0), we used 17 genes (10% false-discovery rate) to construct a multivariate model to predict response. For each gene g, we first computed the residuals Rg,i from a linear model of the form , where Yg,i is the expression of gene g in sample i, t(i) is the subtype of sample i, and Sg,t(i) is the mean expression of gene g in samples of that subtype. We then used the residuals as predictors in an ordinal regression model to predict the outcome categories. We used the Akaike Information Criterion (AIC) to remove unnecessary variables from the model. The final model involved 7 genes: RiskScore=1.59 TMEM46 + 0.68 THBS1 -1.52 LOC442578 - 2.14 SRM 1.16 CHST4 + 0.83 DES + 1.14 SDS, with a cutoff between pathCR and partial response at -1.56 and a cutoff between partial response and exCRTR at 3.72. Four of these seven genes are related to Sonic Hedgehog pathway and 2 are NF-kB targets. In this proposal, data from 120 TM patients to be analyzed through a funded grant (R21CA127612) will be added to a new cohort of 120 TM patients (Specific Aim 1) to establish a large (n=240) training (discovery) set. We will identify best performing ~100 genes through microfluidic card technology. Specific Aim 2 will validate ~100 best genes and refine the model to select ~10 best performing genes for predicting three outcomes. Specific Aim 3 will prospectively validate the ~10-gene signature. A continuous "risk score" for the outcome will be computed. Specificity and sensitivity will be determined by generating receiver-operating (ROC) curves for optimizing the prediction boundaries. PUBLIC HEALTH RELEVANCE: This proposal is an early attempt to individualize therapy based on molecular biology for patients with esophageal cancer. Our goal is to pave the way for a strategy in the future that will allow administration of effective therapy, improve safety, and preserve the esophagus in some patients.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties
    Shumei Song
    Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Cancer Res 74:4170-82. 2014
  2. pmc ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients
    J A Ajani
    Department of Gastrointestinal Medical Oncology, University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA Electronic address
    Mol Oncol 8:142-9. 2014
  3. pmc Locoregional failure rate after preoperative chemoradiation of esophageal adenocarcinoma and the outcomes of salvage strategies
    Kazuki Sudo
    All authors The University of Texas MD Anderson Cancer Center, Houston, TX
    J Clin Oncol 31:4306-10. 2013
  4. pmc Gastric cancer-molecular and clinical dimensions
    Roopma Wadhwa
    Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard FC10 3022, Houston, TX 77030, USA
    Nat Rev Clin Oncol 10:643-55. 2013
  5. pmc Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma
    Enping Xu
    Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Carcinogenesis 34:2750-6. 2013
  6. pmc Risk assessment of esophageal adenocarcinoma using γ-H2AX assay
    Enping Xu
    Authors Affiliations Departments of Epidemiology and Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas and Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, People s Republic of China
    Cancer Epidemiol Biomarkers Prev 22:1797-804. 2013
  7. pmc MicroRNA expression signatures during malignant progression from Barrett's esophagus to esophageal adenocarcinoma
    Xifeng Wu
    Department of Epidemiology, Unit 1340, The University of Texas MD Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA
    Cancer Prev Res (Phila) 6:196-205. 2013
  8. pmc The role of microRNAs in cancers of the upper gastrointestinal tract
    Shumei Song
    Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Nat Rev Gastroenterol Hepatol 10:109-18. 2013
  9. doi The influence of high body mass index on the prognosis of patients with esophageal cancer after surgery as primary therapy
    Yuki Hayashi
    Department of Gastrointestinal Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas, USA
    Cancer 116:5619-27. 2010
  10. pmc Combined modality therapy of cT2N0M0 esophageal cancer: the University of Texas M. D. Anderson Cancer Center experience
    Panteleimon Kountourakis
    Department of Gastrointestinal Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer 117:925-30. 2011

Detail Information

Publications13

  1. pmc Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties
    Shumei Song
    Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Cancer Res 74:4170-82. 2014
    ..Cancer Res; 74(15); 4170-82. ©2014 AACR. ..
  2. pmc ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients
    J A Ajani
    Department of Gastrointestinal Medical Oncology, University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA Electronic address
    Mol Oncol 8:142-9. 2014
    ..We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response...
  3. pmc Locoregional failure rate after preoperative chemoradiation of esophageal adenocarcinoma and the outcomes of salvage strategies
    Kazuki Sudo
    All authors The University of Texas MD Anderson Cancer Center, Houston, TX
    J Clin Oncol 31:4306-10. 2013
    ..However, the benefits of surveillance are not well understood. We report on LRFs and salvage strategies in a large cohort...
  4. pmc Gastric cancer-molecular and clinical dimensions
    Roopma Wadhwa
    Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard FC10 3022, Houston, TX 77030, USA
    Nat Rev Clin Oncol 10:643-55. 2013
    ..However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer. ..
  5. pmc Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma
    Enping Xu
    Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Carcinogenesis 34:2750-6. 2013
    ..8 for each validated gene). The differentially methylated genes and pathways may provide biological insights into the development and progression of BE and become potential biomarkers for the prediction and early detection of EAC. ..
  6. pmc Risk assessment of esophageal adenocarcinoma using γ-H2AX assay
    Enping Xu
    Authors Affiliations Departments of Epidemiology and Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas and Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, People s Republic of China
    Cancer Epidemiol Biomarkers Prev 22:1797-804. 2013
    ..The formation of γ-H2AX is an early cellular response to DNA double-strand breaks (DSB). We hypothesize that higher level of radiation-induced γ-H2AX in PBLs may be associated with an increased risk of esophageal adenocarcinoma...
  7. pmc MicroRNA expression signatures during malignant progression from Barrett's esophagus to esophageal adenocarcinoma
    Xifeng Wu
    Department of Epidemiology, Unit 1340, The University of Texas MD Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA
    Cancer Prev Res (Phila) 6:196-205. 2013
    ....
  8. pmc The role of microRNAs in cancers of the upper gastrointestinal tract
    Shumei Song
    Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Nat Rev Gastroenterol Hepatol 10:109-18. 2013
    ..In-depth studies of miRNAs in UGICs might yield novel insights and potential novel therapeutic strategies...
  9. doi The influence of high body mass index on the prognosis of patients with esophageal cancer after surgery as primary therapy
    Yuki Hayashi
    Department of Gastrointestinal Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas, USA
    Cancer 116:5619-27. 2010
    ..Its influence on a patient's outcome remains unclear. In the current study, the authors examined the impact of BMI on survival and complications in patients with esophageal cancer (EC) who underwent surgery as their primary therapy...
  10. pmc Combined modality therapy of cT2N0M0 esophageal cancer: the University of Texas M. D. Anderson Cancer Center experience
    Panteleimon Kountourakis
    Department of Gastrointestinal Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer 117:925-30. 2011
    ..This study analyzed the largest series of consecutive cT2N0M0 esophageal cancer patients treated with preoperative chemoradiotherapy...
  11. pmc Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy
    Akihiro Suzuki
    Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    Cancer 117:4823-33. 2011
    ..The authors hypothesized that initial SUV would correlate with patient outcome...
  12. pmc Gene expression signature-based prognostic risk score in gastric cancer
    Jae Yong Cho
    Department of Systems Biology, Division of Cancer Medicine, The University of Texas M D Anderson Cancer Center, Houston, Texas 77054, USA
    Clin Cancer Res 17:1850-7. 2011
    ..We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment...