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    Original Investigation
    April 27, 2020

    Association Between Spatial Heterogeneity Within Nonmetastatic Gastroesophageal Adenocarcinomas and Survival

    Author Affiliations
    • 1Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
    • 2Cytogenetics Core, City of Hope Comprehensive Cancer Center, Duarte, California
    • 3Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
    • 4Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, California
    • 5Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California
    • 6Bioinformatics Core, City of Hope Comprehensive Cancer Center, Duarte, California
    • 7Department of Medicine, Massachusetts General Hospital Cancer Center, Boston
    • 8Harvard Medical School, Boston, Massachusetts
    • 9Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California
    JAMA Netw Open. 2020;3(4):e203652. doi:10.1001/jamanetworkopen.2020.3652
    Key Points español 中文 (chinese)

    Question  Is there an association between tumor cell heterogeneity at time of diagnosis in nonmetastatic gastroesophageal adenocarcinoma and prognosis?

    Findings  In this case series of 41 patients with gastroesophageal adenocarcinoma, a high degree of intratumoral heterogeneity was identified. The presence of clonal populations coexisting at submillimeter distances was associated with worse survival.

    Meaning  These findings suggest that understanding intratumoral heterogeneity is highly relevant for future precision medicine neoadjuvant strategies in gastroesophageal adenocarcinoma, and single-cell analytic approaches are recommended.


    Importance  Intratumoral heterogeneity has been recognized as a significant barrier in successfully developing targetable biomarkers for gastroesophageal adenocarcinoma (GEA) and may affect neoadjuvant precision medicine approaches.

    Objective  To describe intratumoral spatial heterogeneity of tumor cell populations in nonmetastatic GEA and its association with survival.

    Design, Setting, and Participants  This case series retrospectively identified 41 patients with GEA who underwent up-front surgical resection at a tertiary referral cancer center from January 1, 1989, through December 31, 2013. Survival was calculated from date of surgery to date of death through June 1, 2017. Data were analyzed from June 2, 2017, to March 1, 2019.

    Main Outcomes and Measures  Overall survival, intratumoral clonal composition determined by genomic single-nucleotide variation array and bioinformatic analysis, and intercellular tumoral distances determined by multiprobe fluorescence in situ hybridization.

    Results  Among the 41 patients included in the analysis (22 men [54%]; mean [SD] age, 63 [12] years), a high proportion (19 [46%]) presented with tumors possessing high intratumoral heterogeneity. Kaplan-Meier analysis demonstrated that cases with an intratumoral clonal composition count of at least 2 exhibited worse survival compared with cases with a clonal composition count of 0 to 1 (univariate hazard ratio, 3.92; 95% CI, 1.27-12.08; P = .02). This finding remained significant on multivariate analysis controlling for stage, Lauren histologic subtype, receipt of adjuvant therapy, and age (multivariate hazard ratio, 4.55; 95% CI, 1.09-19.04; P = .04). Multiprobe fluorescence in situ hybridization demonstrated intratumoral clonal populations coexisting at submillimeter distances with differing relevant oncogenic copy number alterations, such as EGFR, JAK2, FGFR2, MET, CCND1, KRAS, MYC, PIK3CA, CD274, and PDCD1LG2.

    Conclusions and Relevance  This study found that spatial intratumoral heterogeneity of oncogenic copy number alterations exists before metastatic dissemination, and increased heterogeneity was associated with worse outcomes in resected GEA. Baseline heterogeneity illustrates the challenges in GEA targeted therapy. Further study may offer insight into strategies on combinatorial and/or sequential targeted and immunotherapeutic approaches.