PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma

Nnamdi Eze, Ju Whei Lee, Dong Hua Yang, Fang Zhu, Veronique Neumeister, Teresa Sandoval-Schaefer, Ranee Mehra, John A. Ridge, Arlene A. Forastiere, Christine H. Chung, Barbara Burtness

Research output: Contribution to journalArticle

Abstract

Introduction: Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab. Methods: Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing. Results: For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008). Conclusion: Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalOral Oncology
Volume91
DOIs
StatePublished - Apr 1 2019

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Phosphatidylinositol 3-Kinases
Epidermal Growth Factor Receptor
Cisplatin
Biomarkers
Placebos
Mutation
Cetuximab
Carcinoma, squamous cell of head and neck
Receptor Protein-Tyrosine Kinases
Therapeutics
Sample Size
Fluorescent Antibody Technique
Neoplasms
Monoclonal Antibodies
Survival

Keywords

  • Biomarkers
  • Cetuximab
  • Head and neck cancer
  • PTEN

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research

Cite this

Eze, N., Lee, J. W., Yang, D. H., Zhu, F., Neumeister, V., Sandoval-Schaefer, T., ... Burtness, B. (2019). PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma. Oral Oncology, 91, 69-78. https://doi.org/10.1016/j.oraloncology.2019.02.026

PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma. / Eze, Nnamdi; Lee, Ju Whei; Yang, Dong Hua; Zhu, Fang; Neumeister, Veronique; Sandoval-Schaefer, Teresa; Mehra, Ranee; Ridge, John A.; Forastiere, Arlene A.; Chung, Christine H.; Burtness, Barbara.

In: Oral Oncology, Vol. 91, 01.04.2019, p. 69-78.

Research output: Contribution to journalArticle

Eze, N, Lee, JW, Yang, DH, Zhu, F, Neumeister, V, Sandoval-Schaefer, T, Mehra, R, Ridge, JA, Forastiere, AA, Chung, CH & Burtness, B 2019, 'PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma', Oral Oncology, vol. 91, pp. 69-78. https://doi.org/10.1016/j.oraloncology.2019.02.026
Eze, Nnamdi ; Lee, Ju Whei ; Yang, Dong Hua ; Zhu, Fang ; Neumeister, Veronique ; Sandoval-Schaefer, Teresa ; Mehra, Ranee ; Ridge, John A. ; Forastiere, Arlene A. ; Chung, Christine H. ; Burtness, Barbara. / PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma. In: Oral Oncology. 2019 ; Vol. 91. pp. 69-78.
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AU - Eze, Nnamdi

AU - Lee, Ju Whei

AU - Yang, Dong Hua

AU - Zhu, Fang

AU - Neumeister, Veronique

AU - Sandoval-Schaefer, Teresa

AU - Mehra, Ranee

AU - Ridge, John A.

AU - Forastiere, Arlene A.

AU - Chung, Christine H.

AU - Burtness, Barbara

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N2 - Introduction: Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab. Methods: Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing. Results: For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008). Conclusion: Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.

AB - Introduction: Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab. Methods: Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing. Results: For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008). Conclusion: Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.

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