Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer: Implications for therapy

Martin K H Maus, Philip Mack, Stephanie H. Astrow, Craig L. Stephens, Gary D. Zeger, Peter P. Grimminger, Jack H. Hsiang, Eric Huang, Tianhong Li, Primo N Lara, Kathleen D. Danenberg, David R Gandara

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Abstract

INTRODUCTION: On the basis of the results of recent clinical trials, histology-based decision-making for therapy of non-small-cell lung cancer has been advocated. We hypothesized associations of the biomarkers excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) with histology as a contributing factor to reported differences in chemotherapy outcomes between squamous cell carcinoma (SCCA) and adenocarcinoma (AC) subtypes. Here, we report analysis of the Response Genetics Inc., database and implications for histology-based therapy. METHODS: RNA from microdissected formalin-fixed paraffin-embedded tumors was extracted and analyzed as previously described. Specimens from 2540 individual non-small-cell lung cancer patients were analyzed for one or more biomarkers, of which 1457 were categorized as AC or SCCA. RESULTS: For each biomarker, gene expression was lower in AC compared with SCCA (<0.001), although there was a wide range between individual patients. Gene expression was higher in men versus women: ERCC1: 2.51 versus 2.22 (p = 0.005); RRM1: 1.41 versus 1.24 (p = 0.004); TS: 3.23 versus 2.83 (p < 0.001). However, SCCA was more frequent in men versus women (30%/19%; p < 0.001). When AC and SCCA were assessed separately, the statistical significance between gene expression and sex was lost (in SCCA: ERCC1, p = 0.14; RRM1, p = 0.26; TS, p = 0.11). CONCLUSIONS: This analysis represents the largest data set for gene expression of these biomarkers reported so far. Significant histology-related associations for ERCC1, RRM1, and TS are seen. However, marked heterogeneity exists in individual patient tumor expression levels. Randomized phase III trials assessing the predictive value of these chemotherapy-related biomarkers are warranted.

Original languageEnglish (US)
Pages (from-to)582-586
Number of pages5
JournalJournal of Thoracic Oncology
Volume8
Issue number5
DOIs
StatePublished - May 2013

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Ribonucleotide Reductases
Thymidylate Synthase
Non-Small Cell Lung Carcinoma
DNA Repair
Squamous Cell Carcinoma
Histology
Biomarkers
Adenocarcinoma
Gene Expression
Therapeutics
Genetic Databases
Drug Therapy
Paraffin
Formaldehyde
Neoplasms
Decision Making
Clinical Trials
RNA

Keywords

  • Biomarkers in NSCLC
  • ERCC1
  • Histology
  • Personalized treatment
  • RRM1
  • Sex
  • TS

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer : Implications for therapy. / Maus, Martin K H; Mack, Philip; Astrow, Stephanie H.; Stephens, Craig L.; Zeger, Gary D.; Grimminger, Peter P.; Hsiang, Jack H.; Huang, Eric; Li, Tianhong; Lara, Primo N; Danenberg, Kathleen D.; Gandara, David R.

In: Journal of Thoracic Oncology, Vol. 8, No. 5, 05.2013, p. 582-586.

Research output: Contribution to journalArticle

Maus, Martin K H ; Mack, Philip ; Astrow, Stephanie H. ; Stephens, Craig L. ; Zeger, Gary D. ; Grimminger, Peter P. ; Hsiang, Jack H. ; Huang, Eric ; Li, Tianhong ; Lara, Primo N ; Danenberg, Kathleen D. ; Gandara, David R. / Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer : Implications for therapy. In: Journal of Thoracic Oncology. 2013 ; Vol. 8, No. 5. pp. 582-586.
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abstract = "INTRODUCTION: On the basis of the results of recent clinical trials, histology-based decision-making for therapy of non-small-cell lung cancer has been advocated. We hypothesized associations of the biomarkers excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) with histology as a contributing factor to reported differences in chemotherapy outcomes between squamous cell carcinoma (SCCA) and adenocarcinoma (AC) subtypes. Here, we report analysis of the Response Genetics Inc., database and implications for histology-based therapy. METHODS: RNA from microdissected formalin-fixed paraffin-embedded tumors was extracted and analyzed as previously described. Specimens from 2540 individual non-small-cell lung cancer patients were analyzed for one or more biomarkers, of which 1457 were categorized as AC or SCCA. RESULTS: For each biomarker, gene expression was lower in AC compared with SCCA (<0.001), although there was a wide range between individual patients. Gene expression was higher in men versus women: ERCC1: 2.51 versus 2.22 (p = 0.005); RRM1: 1.41 versus 1.24 (p = 0.004); TS: 3.23 versus 2.83 (p < 0.001). However, SCCA was more frequent in men versus women (30{\%}/19{\%}; p < 0.001). When AC and SCCA were assessed separately, the statistical significance between gene expression and sex was lost (in SCCA: ERCC1, p = 0.14; RRM1, p = 0.26; TS, p = 0.11). CONCLUSIONS: This analysis represents the largest data set for gene expression of these biomarkers reported so far. Significant histology-related associations for ERCC1, RRM1, and TS are seen. However, marked heterogeneity exists in individual patient tumor expression levels. Randomized phase III trials assessing the predictive value of these chemotherapy-related biomarkers are warranted.",
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T1 - Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer

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AU - Maus, Martin K H

AU - Mack, Philip

AU - Astrow, Stephanie H.

AU - Stephens, Craig L.

AU - Zeger, Gary D.

AU - Grimminger, Peter P.

AU - Hsiang, Jack H.

AU - Huang, Eric

AU - Li, Tianhong

AU - Lara, Primo N

AU - Danenberg, Kathleen D.

AU - Gandara, David R

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N2 - INTRODUCTION: On the basis of the results of recent clinical trials, histology-based decision-making for therapy of non-small-cell lung cancer has been advocated. We hypothesized associations of the biomarkers excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) with histology as a contributing factor to reported differences in chemotherapy outcomes between squamous cell carcinoma (SCCA) and adenocarcinoma (AC) subtypes. Here, we report analysis of the Response Genetics Inc., database and implications for histology-based therapy. METHODS: RNA from microdissected formalin-fixed paraffin-embedded tumors was extracted and analyzed as previously described. Specimens from 2540 individual non-small-cell lung cancer patients were analyzed for one or more biomarkers, of which 1457 were categorized as AC or SCCA. RESULTS: For each biomarker, gene expression was lower in AC compared with SCCA (<0.001), although there was a wide range between individual patients. Gene expression was higher in men versus women: ERCC1: 2.51 versus 2.22 (p = 0.005); RRM1: 1.41 versus 1.24 (p = 0.004); TS: 3.23 versus 2.83 (p < 0.001). However, SCCA was more frequent in men versus women (30%/19%; p < 0.001). When AC and SCCA were assessed separately, the statistical significance between gene expression and sex was lost (in SCCA: ERCC1, p = 0.14; RRM1, p = 0.26; TS, p = 0.11). CONCLUSIONS: This analysis represents the largest data set for gene expression of these biomarkers reported so far. Significant histology-related associations for ERCC1, RRM1, and TS are seen. However, marked heterogeneity exists in individual patient tumor expression levels. Randomized phase III trials assessing the predictive value of these chemotherapy-related biomarkers are warranted.

AB - INTRODUCTION: On the basis of the results of recent clinical trials, histology-based decision-making for therapy of non-small-cell lung cancer has been advocated. We hypothesized associations of the biomarkers excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) with histology as a contributing factor to reported differences in chemotherapy outcomes between squamous cell carcinoma (SCCA) and adenocarcinoma (AC) subtypes. Here, we report analysis of the Response Genetics Inc., database and implications for histology-based therapy. METHODS: RNA from microdissected formalin-fixed paraffin-embedded tumors was extracted and analyzed as previously described. Specimens from 2540 individual non-small-cell lung cancer patients were analyzed for one or more biomarkers, of which 1457 were categorized as AC or SCCA. RESULTS: For each biomarker, gene expression was lower in AC compared with SCCA (<0.001), although there was a wide range between individual patients. Gene expression was higher in men versus women: ERCC1: 2.51 versus 2.22 (p = 0.005); RRM1: 1.41 versus 1.24 (p = 0.004); TS: 3.23 versus 2.83 (p < 0.001). However, SCCA was more frequent in men versus women (30%/19%; p < 0.001). When AC and SCCA were assessed separately, the statistical significance between gene expression and sex was lost (in SCCA: ERCC1, p = 0.14; RRM1, p = 0.26; TS, p = 0.11). CONCLUSIONS: This analysis represents the largest data set for gene expression of these biomarkers reported so far. Significant histology-related associations for ERCC1, RRM1, and TS are seen. However, marked heterogeneity exists in individual patient tumor expression levels. Randomized phase III trials assessing the predictive value of these chemotherapy-related biomarkers are warranted.

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