Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811

Corinne M. Doll, Jennifer Moughan, Alexander Klimowicz, Clement K. Ho, Elizabeth N. Kornaga, Susan P. Lees-Miller, Jaffer A. Ajani, Christopher H. Crane, Lisa A. Kachnic, Gordon S. Okawara, Lawrence B. Berk, Kevin S. Roof, Mark J. Becker, David L. Grisell, Robert J. Ellis, Paul W. Sperduto, Gerald W. Marsa, Chandan Guha, Anthony M. Magliocco

Research output: Contribution to journalArticle

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Abstract

Purpose To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. Methods and Materials EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. Results A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.

Original languageEnglish (US)
Pages (from-to)554-562
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume97
Issue number3
DOIs
StatePublished - Mar 1 2017

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Anus Neoplasms
Chemoradiotherapy
Epidermal Growth Factor Receptor
cancer
tumors
Neoplasms
Fluorouracil
pretreatment
hazards
confidence
radiation therapy
Radiotherapy
adjusting
quartiles
Confidence Intervals
intervals
Colostomy
biomarkers
Mitomycin
metastasis

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy : An Analysis of NRG Oncology RTOG 9811. / Doll, Corinne M.; Moughan, Jennifer; Klimowicz, Alexander; Ho, Clement K.; Kornaga, Elizabeth N.; Lees-Miller, Susan P.; Ajani, Jaffer A.; Crane, Christopher H.; Kachnic, Lisa A.; Okawara, Gordon S.; Berk, Lawrence B.; Roof, Kevin S.; Becker, Mark J.; Grisell, David L.; Ellis, Robert J.; Sperduto, Paul W.; Marsa, Gerald W.; Guha, Chandan; Magliocco, Anthony M.

In: International Journal of Radiation Oncology Biology Physics, Vol. 97, No. 3, 01.03.2017, p. 554-562.

Research output: Contribution to journalArticle

Doll, CM, Moughan, J, Klimowicz, A, Ho, CK, Kornaga, EN, Lees-Miller, SP, Ajani, JA, Crane, CH, Kachnic, LA, Okawara, GS, Berk, LB, Roof, KS, Becker, MJ, Grisell, DL, Ellis, RJ, Sperduto, PW, Marsa, GW, Guha, C & Magliocco, AM 2017, 'Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811', International Journal of Radiation Oncology Biology Physics, vol. 97, no. 3, pp. 554-562. https://doi.org/10.1016/j.ijrobp.2016.11.021
Doll, Corinne M. ; Moughan, Jennifer ; Klimowicz, Alexander ; Ho, Clement K. ; Kornaga, Elizabeth N. ; Lees-Miller, Susan P. ; Ajani, Jaffer A. ; Crane, Christopher H. ; Kachnic, Lisa A. ; Okawara, Gordon S. ; Berk, Lawrence B. ; Roof, Kevin S. ; Becker, Mark J. ; Grisell, David L. ; Ellis, Robert J. ; Sperduto, Paul W. ; Marsa, Gerald W. ; Guha, Chandan ; Magliocco, Anthony M. / Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy : An Analysis of NRG Oncology RTOG 9811. In: International Journal of Radiation Oncology Biology Physics. 2017 ; Vol. 97, No. 3. pp. 554-562.
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abstract = "Purpose To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. Methods and Materials EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. Results A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65{\%}, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95{\%} confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95{\%} confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.",
author = "Doll, {Corinne M.} and Jennifer Moughan and Alexander Klimowicz and Ho, {Clement K.} and Kornaga, {Elizabeth N.} and Lees-Miller, {Susan P.} and Ajani, {Jaffer A.} and Crane, {Christopher H.} and Kachnic, {Lisa A.} and Okawara, {Gordon S.} and Berk, {Lawrence B.} and Roof, {Kevin S.} and Becker, {Mark J.} and Grisell, {David L.} and Ellis, {Robert J.} and Sperduto, {Paul W.} and Marsa, {Gerald W.} and Chandan Guha and Magliocco, {Anthony M.}",
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T1 - Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy

T2 - An Analysis of NRG Oncology RTOG 9811

AU - Doll, Corinne M.

AU - Moughan, Jennifer

AU - Klimowicz, Alexander

AU - Ho, Clement K.

AU - Kornaga, Elizabeth N.

AU - Lees-Miller, Susan P.

AU - Ajani, Jaffer A.

AU - Crane, Christopher H.

AU - Kachnic, Lisa A.

AU - Okawara, Gordon S.

AU - Berk, Lawrence B.

AU - Roof, Kevin S.

AU - Becker, Mark J.

AU - Grisell, David L.

AU - Ellis, Robert J.

AU - Sperduto, Paul W.

AU - Marsa, Gerald W.

AU - Guha, Chandan

AU - Magliocco, Anthony M.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Purpose To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. Methods and Materials EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. Results A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.

AB - Purpose To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. Methods and Materials EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. Results A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.

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