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Clin Cancer Res DOI:10.1158/1078-0432.CCR-19-0908

Integrative molecular characterization of resistance to neoadjuvant chemoradiation in rectal cancer.

Publication TypeJournal Article
Year of Publication2019
AuthorsKamran, SC, Lennerz, JK, Margolis, CA, Liu, D, Reardon, B, Wankowicz, SA, Van Seventer, EE, Tracy, A, Wo, JY, Carter, SL, Willers, H, Corcoran, RB, Hong, TS, Van Allen, EM
JournalClin Cancer Res
Date Published2019 Jun 28

PURPOSE: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiation therapy (CRT) are incompletely characterized.

EXPERIMENTAL DESIGN: We performed integrated whole exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients (8 complete/partial responders [R], 9 nonresponders [NR]).

RESULTS: CRT was not associated with increased tumor mutational burden or neoantigen load and did not alter the distribution of established somatic tumor mutations in rectal cancer. Concurrent / mutations (KP) associated with NR tumors and were enriched for an epithelial-mesenchymal transition transcriptional program. Furthermore, NR was associated with reduced CD4/CD8 T-cell infiltrates and a post-CRT M2 macrophage phenotype. Absent any local tumor recurrences, KP/NR status predicted worse progression-free survival, suggesting that local immune escape during or after CRT with specific genomic features contributes to distant progression.

CONCLUSIONS: Overall, while CRT did not impact genomic profiles, CRT impacted the tumor immune microenvironment, particularly in resistant cases.


Alternate JournalClin. Cancer Res.
PubMed ID31253631
Grant ListU01 CA233100 / CA / NCI NIH HHS / United States