Format

Send to

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

Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer.

Author information

1
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
2
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
3
Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Boston, Massachusetts.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
5
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
6
Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
7
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. eliezerm_vanallen@dfci.harvard.edu tshong1@mgh.harvard.edu.
8
Broad Institute of MIT and Harvard, Cambridge, Massachusetts. eliezerm_vanallen@dfci.harvard.edu tshong1@mgh.harvard.edu.
#
Contributed equally

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.

PMID:
31253631
PMCID:
PMC6744983
[Available on 2020-03-15]
DOI:
10.1158/1078-0432.CCR-19-0908

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center