Gastroesophageal adenocarcinoma (GEC) remains a challenging problem in oncology. GEC remains the fourth most common malignancy and the second most common cause of death worldwide. Gastroesophageal junction (GEJ) adenocarcinomas have an estimated 350% increase in incidence in the US in the last two to three decades for unclear reasons. GEC is a molecularly heterogeneous disease both between patients (inter-patient) and within an individual patient (intra-patient). Intra-patient heterogenety manifests through space (primary tumor to metastatic lymph nodes to distant metastases, and even across different metastases) and time (natural selection of genomic aberrations conferring growth/metastatic advantage, as well as evolution of treatment resistant clones over time). Inter- and intra-patient tumor heterogeneity has likely contributed to negative results in a number of recent clinical trials testing novel molecularly targeted therapeutics using a 'one-size-fits-all' approach. Tumor heterogeneity poses a significant hurdle to achieving personalized treatment, particularly when using standard/accepted clinical trial designs. This proposal seeks to address inter-patient tumor heterogeneity by assigning treatment based on predefined predictive molecular 'oncogenic driver' categories, namely, HER2, MET, FGFR2, EGFR/HER3, and KRAS/PI3K-like. These are the most frequently observed molecular categories within GEC cell lines and tumor tissues. A comprehensive molecular profiling of the tumor at diagnosis will be done on the primary tumor and a metastatic disease site (liver, lung, or peritoneum) at enrollment, and all patients will be assigned to one of five specific treatments based on their metastatic tumor molecular profile as assessed via a novel treatment assignment algorithm. [This treatment algorithm is a compromise between the vast number of potential treatment groups and the feasibility of conducting such a trial and acquiring the many investigational agents necessary.] Metastatic disease will be uniformly used to profile the tumor in order to address intra-patient tumor heterogeneity through space, which can account for an approximate 10-15% discordant rate, resulting in subset misclassification. Additionally, patients will have planned serial biopsies at each progression point to determine molecular evolution over time and treatment. The correlative science incorporated into this study design will greatly improve our understanding of the disease with respect to inter-patient and intra-patient heterogeneity, and also will help to shed light on how to best address these hurdles in order to truly treat with molecular therapies for specific molecular targets, despite each molecular category occurring relatively infrequently. The feasibility and safety endpoints of this novel [pilot trial] are accompanied by a preliminary efficacy endpoint of overall survival [for the HER2+ and MET+ subgroups (N=68)], as compared to recent historical controls of approximately 12 months as seen in these GEC patients. [Secondary endpoints will include analysis of overall survival and other clinical endpoints amongst all five subgroups, anticipated to be approximately 104 patients]. This clinical trial design is innovative with its biostastistical approach and in its atempt to improve our understanding of the molecular biology of the disease, address inter- and intra-patient tissue heterogeneity within the disease, and to achieve our ultimate goal of molecularly personalized cancer care in order to significantly improve clinical outcomes.

Public Health Relevance

Gastroesophageal adenocarcinoma (GEC) remains the fourth most common malignancy worldwide and the second most common cause of death worldwide, with some types having an estimated 350% increase in incidence in the United States in the last two to three decades for unclear reasons. Five molecular subsets of the disease have been defined, and the key oncoprotein of each subset has a number of pharmaceutical agents developed to specifically inhibit its function. Evaluating each of these subsets independently has proven difficult, given the small proportion of each within the total GEC patient population, and the consequent difficulties with slow trial accrual; therefore, a novel clinical trial design which assigns each patient screened to one of the five arms with a paired assigned treatment, within this one single pilot trial, is proposed. Ultimately, if this strategy proves feasible and early efficacy endpoints are promising, subsequent randomized placebo controlled trials are planned, which may prove to be practice changing for the treatment of cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
Application #
Study Section
Subcommittee J - Career Development (NCI-J)
Program Officer
Radaev, Sergei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wong, Gabrielle S; Zhou, Jin; Liu, Jie Bin et al. (2018) Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med 24:968-977
Pectasides, Eirini; Stachler, Matthew D; Derks, Sarah et al. (2018) Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov 8:37-48
de W Marsh, Robert; Talamonti, Mark S; Baker, Marshall S et al. (2018) Primary systemic therapy in resectable pancreatic ductal adenocarcinoma using mFOLFIRINOX: A pilot study. J Surg Oncol 117:354-362
Joshi, Smita S; Maron, Steven B; Catenacci, Daniel V (2018) Pembrolizumab for treatment of advanced gastric and gastroesophageal junction adenocarcinoma. Future Oncol 14:417-430
Fuchs, Charles S; Doi, Toshihiko; Jang, Raymond W et al. (2018) Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol 4:e180013
Maron, Steven B; Alpert, Lindsay; Kwak, Heewon A et al. (2018) Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma. Cancer Discov 8:696-713
An, E; Ock, C-Y; Kim, T-Y et al. (2017) Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment. Ann Oncol 28:110-115
Catenacci, Daniel V T; Ang, Agnes; Liao, Wei-Li et al. (2017) MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma. Cancer 123:1061-1070
Guo, Wentian; Ji, Yuan; Catenacci, Daniel V T (2017) A subgroup cluster-based Bayesian adaptive design for precision medicine. Biometrics 73:367-377
Maron, Steven B; Catenacci, Daniel V T (2017) Novel Targeted Therapies for Esophagogastric Cancer. Surg Oncol Clin N Am 26:293-312

Showing the most recent 10 out of 22 publications