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

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.

Predictive Value of EGFR-PI3K-AKT-mTOR-Pathway Inhibitor Biomarkers for Head and Neck Squamous Cell Carcinoma: A Systematic Review

“…Four biomarkers were described in clinical studies that correlate positively with cetuximab response: (1) the possession of a germline mutation in a microRNA-binding site in KRAS [ 63 ], (2) phosphatase and tensin homolog (PTEN) protein expression [ 36 , 59 , 64 ] supported by a study where PTEN knock down correlates with cetuximab resistance [ 65 ], although no correlation was found in two studies [ 37 , 66 ]; (3) VEGF protein/Interleukin(IL)-6 expression [ 67 ]; and (4) expression of IL-1 ligands [ 68 ]. Four clinical studies describe biomarkers that correlate negatively with cetuximab response: (1) KRAS/HRAS mutations [ 57 ], (2) presence of the EGFR-variant EGFRvIII [ 35 ], (3) phosphorylated AKT levels [ 69 ] and (4) the presence of a long noncoding RNA transcript fusion [ 70 ].…”

Head and neck cancer: the role of anti-EGFR agents in the era of immunotherapy

“… 90 Loss of PTEN expression in tumor samples correlates with longer PFS on Cx therapy, while patients with PTEN high-expressing tumors had improved PFS. 91 …”

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

“…Activation of downstream signaling effectors, such as STAT3 (signal transducer and activator of transcription 3) (77, 84, 101-106), Src Kinases (64,107,108), RAS/MAPK pathways (86,96,(109)(110)(111)(112)(113)(114)(115), and PI3K/Akt/mTOR pathway (102,105,(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127) could induce CTX resistance independently of the EGFRligand activation.…”

“…Moreover, Eze et al. recently reported the analysis of PTEN and PIK3CA expression in samples from patients with recurrent or metastatic HNSCC enrolled in two trials of cetuximab-based therapy ( n =48 patients in the E5397 trial and n =37 in the NCI-8070 trial) ( 117 ). Patients with low PTEN expression had significantly worse survival.…”