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Ref Type Journal Article
PMID (30926065)
Authors Eze N, Lee JW, Yang DH, Zhu F, Neumeister V, Sandoval-Schaefer T, Mehra R, Ridge JA, Forastiere A, Chung CH, Burtness B
Title PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma.
Journal Oral oncology
Vol 91
Issue
Date 2019 Apr
URL
Abstract Text 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.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.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).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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA wild-type PTEN pos head and neck squamous cell carcinoma predicted - sensitive Cetuximab + Cisplatin Clinical Study - Cohort Actionable In a clinical study, combination of Erbitux (cetuximab) with Platinol (cisplatin) tended to improve progression-free survival compared to placebo in PTEN-expressing, PIK3CA wild-type head and neck squamous cell carcinoma patients (HR=0.54, p=0.0502) by multivariable analysis, but not in PTEN null or PIK3CA mutated patients (HR=0.76, p=0.54) (PMID: 30926065). 30926065
PTEN positive head and neck squamous cell carcinoma predicted - sensitive Cetuximab Clinical Study - Cohort Actionable In a clinical study, high PTEN expression was associated with improved progression-free survival (HR=0.35, p=0.008) in head and neck squamous cell carcinoma patients treated with Erbitux (cetuximab) with or without Nexavar (sorafenib) (PMID: 30926065). 30926065