Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer

Ming Sound Tsao, Sarit Aviel-Ronen, Keyue Ding, Davina Lau, Ni Liu, Akira Sakurada, Marlo Whitehead, Chang Qi Zhu, Robert B Livingston, David H. Johnson, James Rigas, Lesley Seymour, Timothy Winton, Frances A. Shepherd

Research output: Contribution to journalArticle

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Abstract

Purpose: p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. Methods: p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. Results: Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. Conclusion: p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

Original languageEnglish (US)
Pages (from-to)5240-5247
Number of pages8
JournalJournal of Clinical Oncology
Volume25
Issue number33
DOIs
StatePublished - Nov 20 2007
Externally publishedYes

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Adjuvant Chemotherapy
Non-Small Cell Lung Carcinoma
p53 Genes
Mutation
Survival
Proteins
Neoplasms
Oligonucleotides
DNA Repair
Cisplatin
Genes
Exons
Cell Survival
Cell Cycle
Immunohistochemistry
High Pressure Liquid Chromatography
Observation
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tsao, M. S., Aviel-Ronen, S., Ding, K., Lau, D., Liu, N., Sakurada, A., ... Shepherd, F. A. (2007). Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer. Journal of Clinical Oncology, 25(33), 5240-5247. https://doi.org/10.1200/JCO.2007.12.6953

Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer. / Tsao, Ming Sound; Aviel-Ronen, Sarit; Ding, Keyue; Lau, Davina; Liu, Ni; Sakurada, Akira; Whitehead, Marlo; Zhu, Chang Qi; Livingston, Robert B; Johnson, David H.; Rigas, James; Seymour, Lesley; Winton, Timothy; Shepherd, Frances A.

In: Journal of Clinical Oncology, Vol. 25, No. 33, 20.11.2007, p. 5240-5247.

Research output: Contribution to journalArticle

Tsao, MS, Aviel-Ronen, S, Ding, K, Lau, D, Liu, N, Sakurada, A, Whitehead, M, Zhu, CQ, Livingston, RB, Johnson, DH, Rigas, J, Seymour, L, Winton, T & Shepherd, FA 2007, 'Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer', Journal of Clinical Oncology, vol. 25, no. 33, pp. 5240-5247. https://doi.org/10.1200/JCO.2007.12.6953
Tsao, Ming Sound ; Aviel-Ronen, Sarit ; Ding, Keyue ; Lau, Davina ; Liu, Ni ; Sakurada, Akira ; Whitehead, Marlo ; Zhu, Chang Qi ; Livingston, Robert B ; Johnson, David H. ; Rigas, James ; Seymour, Lesley ; Winton, Timothy ; Shepherd, Frances A. / Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 33. pp. 5240-5247.
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title = "Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer",
abstract = "Purpose: p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. Methods: p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. Results: Of 253 patients, 132 (52{\%}) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95{\%} CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31{\%}) of 397 and 117 (26{\%}) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. Conclusion: p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.",
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T1 - Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer

AU - Tsao, Ming Sound

AU - Aviel-Ronen, Sarit

AU - Ding, Keyue

AU - Lau, Davina

AU - Liu, Ni

AU - Sakurada, Akira

AU - Whitehead, Marlo

AU - Zhu, Chang Qi

AU - Livingston, Robert B

AU - Johnson, David H.

AU - Rigas, James

AU - Seymour, Lesley

AU - Winton, Timothy

AU - Shepherd, Frances A.

PY - 2007/11/20

Y1 - 2007/11/20

N2 - Purpose: p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. Methods: p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. Results: Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. Conclusion: p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

AB - Purpose: p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. Methods: p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. Results: Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. Conclusion: p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

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