Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and …
M Agulnik, G da Cunha Santos, D Hedley… - Journal of Clinical …, 2007 - ascopubs.org
Journal of Clinical Oncology, 2007•ascopubs.org
Purpose Pharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib
and cisplatin in patients with recurrent or metastatic head and neck squamous cell
carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream
signaling components, and markers of angiogenesis and apoptosis were evaluated to
determine the relationship between correlative end points and clinical outcomes. Patients
and Methods Pretreatment and during-treatment tumor and skin biopsies, and archival tumor …
and cisplatin in patients with recurrent or metastatic head and neck squamous cell
carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream
signaling components, and markers of angiogenesis and apoptosis were evaluated to
determine the relationship between correlative end points and clinical outcomes. Patients
and Methods Pretreatment and during-treatment tumor and skin biopsies, and archival tumor …
Purpose
Pharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream signaling components, and markers of angiogenesis and apoptosis were evaluated to determine the relationship between correlative end points and clinical outcomes.
Patients and Methods
Pretreatment and during-treatment tumor and skin biopsies, and archival tumor specimens were evaluated for EGFR, phosphorylated (p) -EGFR, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-Akt, Ki67, p27, p-nuclear factor kappa B (NFκB), p-signal transducer and activator of transcription 3 (STAT3), and EGFR gene copy number.
Results
On 37 archival samples, response to therapy was evident in two of four (50%) patients with high EGFR gene copy number tumors and in four of 27 (15%) patients with low gene copy number tumors. On nine paired tumor biopsies, elevated pretreatment levels of p27 and p-STAT3 predicted for prolonged time to progression (TTP) and overall survival (OS; P ≤ .03). With treatment, a decrease in p-EGFR, p-NFκB, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P ≤ .04). Multidimensional scaling (MDS) models revealed clustering profiles of tumor markers by immunofluorescence could predict response. On 32 paired skin biopsies, suppression of p-EGFR with therapy correlated with increased OS (P = .045).
Conclusion
High EGFR gene copy in tumor specimens may predict which patients have an increased likelihood of response to erlotinib, and decreased p-EGFR level in skin biopsies during therapy may represent a potential surrogate marker for improved clinical outcome. MDS represents a novel way to evaluate the relationships between molecular markers and clinical outcome. Additional biomarker studies with larger sample sizes are required to elucidate HNSCC patients who may benefit from this targeted therapy.
