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Chao J, Bedell V, Lee J, et al. Association Between Spatial Heterogeneity Within Nonmetastatic Gastroesophageal Adenocarcinomas and Survival. JAMA Netw Open. 2020;3(4):e203652. doi:10.1001/jamanetworkopen.2020.3652
Is there an association between tumor cell heterogeneity at time of diagnosis in nonmetastatic gastroesophageal adenocarcinoma and prognosis?
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.
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.
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.
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.
Among the 41 patients included in the analysis (22 men [54%]; mean [SD] age, 63  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.
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