Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer

Clin Cancer Res. 2019 Sep 15;25(18):5561-5571. doi: 10.1158/1078-0432.CCR-19-0908. Epub 2019 Jun 28.

Abstract

Purpose: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (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, 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 KRAS/TP53 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. Absence of 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / immunology
  • Biomarkers, Tumor*
  • Chemoradiotherapy, Adjuvant
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Radiation Tolerance* / genetics
  • Rectal Neoplasms / etiology*
  • Rectal Neoplasms / metabolism
  • Rectal Neoplasms / therapy
  • Transcriptome
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Whole Exome Sequencing

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • KRAS protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins p21(ras)