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

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.

SUBMITTER: Kamran SC

PROVIDER: S-EPMC6744983 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Kamran Sophia C SC Lennerz Jochen K JK Margolis Claire A CA Liu David D Reardon Brendan B Wankowicz Stephanie A SA Van Seventer Emily E EE Tracy Adam A Wo Jennifer Y JY Carter Scott L SL Willers Henning H Corcoran Ryan B RB Hong Theodore S TS Van Allen Eliezer M EM

Clinical cancer research : an official journal of the American Association for Cancer Research 20190628 18

<h4>Purpose</h4>Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized.<b>Experimental Design:</b> 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)].<h4>Results</h4>CRT was not assoc ...[more]

PMID: 31253631

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Project description:ObjectiveTo identify a biomarker profile associated with tumor response to chemoradiation (CRT) in locally advanced rectal cancer.BackgroundRectal cancer response to neoadjuvant CRT is variable. Whereas some patients have a minimal response, others achieve a pathologic complete response (pCR) and have no viable cancer cells in their surgical specimens. Identifying biomarkers of response will help select patients more likely to benefit from CRT.MethodsThis study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery. Tumor DNA from pretreatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes. Genetic biomarkers were correlated with tumor response to CRT (pCR vs non-pCR), and the association of single or combined biomarkers with tumor response was determined.ResultsThirty-three of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Three individual markers were associated with non-pCR; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation (P = 0.0145), cyclin D1 G870A (AA) polymorphism (P = 0.0138), and methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (P = 0.0120). Analysis of biomarker combinations revealed that none of the 27 patients with both tumor protein p53 (p53) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations had a pCR. Further, in patients with both p53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations or the cyclin D1 G870A (AA) polymorphism or the methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (n = 52) the association with non-pCR was further strengthened; 51 of 52 (98%) of patients were non-pCR. These biomarker combinations had a validity of more than 70% and a positive predictive value of 97% to 100%, predicting that patients harboring these mutation/polymorphism profiles will not achieve a pCR.ConclusionsA specific biomarker profile is strongly associated with non-pCR to CRT and could be used to select optimal oncologic therapy in rectal cancer patients. ClinicalTrials.org Identifier: NCT00335816.

Dataset Information

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

Publications

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

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