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

Alissa Greenbaum; David R. Martin; Thèrése Bocklage; Ji Hyun Lee; Scott A. Ness; Ashwani Rajput

doi:10.1016/j.clcc.2019.02.003

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

Alissa Greenbaum, David R. Martin, Thèrése Bocklage, Ji Hyun Lee, Scott A. Ness, Ashwani Rajput

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Pages (from-to)	102-109
Number of pages	8
Journal	Clinical colorectal cancer
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.clcc.2019.02.003
State	Published - Jun 2019
Externally published	Yes

Keywords

Bioinformatics
Colorectal cancer
Personalized medicine
Targeted sequencing
Translational research

ASJC Scopus subject areas

Oncology
Gastroenterology

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10.1016/j.clcc.2019.02.003

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@article{94cb822bbbf749b2a93c3d46b01907ae,

title = "Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer",

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.",

keywords = "Bioinformatics, Colorectal cancer, Personalized medicine, Targeted sequencing, Translational research",

author = "Alissa Greenbaum and Martin, {David R.} and Th{\`e}r{\'e}se Bocklage and Lee, {Ji Hyun} and Ness, {Scott A.} and Ashwani Rajput",

note = "Funding Information: Supported in part by National Institutes of Health grants 5R01CA170250 , 5R01DE023222 , and 5P30CA118100 (to S.A.N.). The authors acknowledge outstanding technical support from Jennifer Woods, Maggie Cyphery, Jamie Padilla, and Kathryn Brayer at the University of New Mexico. We thank Patricia J. Young in the Division of Surgical Oncology at the University of New Mexico for assistance in document preparation. Some experiments used the facilities or services provided by the Analytical and Translational Genomics Shared Resource, which is supported by the State of New Mexico and the UNM Comprehensive Cancer Center P30CA118100 . Funding Information: Supported in part by National Institutes of Health grants 5R01CA170250, 5R01DE023222, and 5P30CA118100 (to S.A.N.). The authors acknowledge outstanding technical support from Jennifer Woods, Maggie Cyphery, Jamie Padilla, and Kathryn Brayer at the University of New Mexico. We thank Patricia J. Young in the Division of Surgical Oncology at the University of New Mexico for assistance in document preparation. Some experiments used the facilities or services provided by the Analytical and Translational Genomics Shared Resource, which is supported by the State of New Mexico and the UNM Comprehensive Cancer Center P30CA118100. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jun,

doi = "10.1016/j.clcc.2019.02.003",

language = "English (US)",

volume = "18",

pages = "102--109",

journal = "Clinical colorectal cancer",

issn = "1533-0028",

publisher = "Elsevier",

number = "2",

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TY - JOUR

T1 - Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

AU - Greenbaum, Alissa

AU - Martin, David R.

AU - Bocklage, Thèrése

AU - Lee, Ji Hyun

AU - Ness, Scott A.

AU - Rajput, Ashwani

N1 - Funding Information: Supported in part by National Institutes of Health grants 5R01CA170250 , 5R01DE023222 , and 5P30CA118100 (to S.A.N.). The authors acknowledge outstanding technical support from Jennifer Woods, Maggie Cyphery, Jamie Padilla, and Kathryn Brayer at the University of New Mexico. We thank Patricia J. Young in the Division of Surgical Oncology at the University of New Mexico for assistance in document preparation. Some experiments used the facilities or services provided by the Analytical and Translational Genomics Shared Resource, which is supported by the State of New Mexico and the UNM Comprehensive Cancer Center P30CA118100 . Funding Information: Supported in part by National Institutes of Health grants 5R01CA170250, 5R01DE023222, and 5P30CA118100 (to S.A.N.). The authors acknowledge outstanding technical support from Jennifer Woods, Maggie Cyphery, Jamie Padilla, and Kathryn Brayer at the University of New Mexico. We thank Patricia J. Young in the Division of Surgical Oncology at the University of New Mexico for assistance in document preparation. Some experiments used the facilities or services provided by the Analytical and Translational Genomics Shared Resource, which is supported by the State of New Mexico and the UNM Comprehensive Cancer Center P30CA118100. Publisher Copyright: © 2019 The Authors

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - Bioinformatics

KW - Colorectal cancer

KW - Personalized medicine

KW - Targeted sequencing

KW - Translational research

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JO - Clinical colorectal cancer

JF - Clinical colorectal cancer

IS - 2

ER -

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

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Keywords

ASJC Scopus subject areas

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