Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Authors

Alissa Greenbaum, Division of Surgical Oncology, Department of Surgery, University of New Mexico, Albuquerque, NM.
David R. Martin, Department of Pathology, University of New Mexico, Albuquerque, NM
Thèrése Bocklage, Department of Pathology and Laboratory Medicine, University of Kentucky Albert B. Chandler Hospital, Lexington, KY
Ji-Hyun Lee, Department of Biostatistics, College of Public Health and Health Professions College of Medicine, University of Florida, Gainesville, FL
Scott A. Ness, Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, NM; University of New Mexico Comprehensive Cancer Center, Albuquerque, NM
Ashwani Rajput, Division of Surgical Oncology, Department of Surgery, University of New Mexico, Albuquerque, NM; University of New Mexico Comprehensive Cancer Center, Albuquerque, NM

Document Type

Article

Publication Date

6-1-2019

Abstract

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays.

PATIENTS AND METHODS: DNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2 disease) who received nCRT. High read-depth sequencing of > 400 cancer-relevant genes was performed. Tumor mutations and variant allele frequencies were used to calculate mutant-allele tumor heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection.

RESULTS: Biopsy samples from 21 patient tumors were analyzed. Eight patients had disease noted to have complete response, 2 moderate, 4 minimal, and 7 poor. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to complete response (P = .039).

CONCLUSION: The application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer.

Recommended Citation

Greenbaum A, Martin DR, Bocklage T, Lee JH, Ness SA, Rajput A. Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer. Clin Colorectal Cancer. 2019 Jun;18(2):102-109. doi: 10.1016/j.clcc.2019.02.003. Epub 2019 Feb 13. PMID: 30935775; PMCID: PMC6556409.