TY - JOUR
T1 - Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib
AU - Agulnik, Mark
AU - Santos, Gilda Da Cunha
AU - Hedley, David
AU - Nicklee, Trudey
AU - Dos Reis, Patricia Pintor
AU - Ho, James
AU - Pond, Gregory R.
AU - Chen, Heidi
AU - Chen, Shuo
AU - Shyr, Yu
AU - Winquist, Eric
AU - Soulieres, Denis
AU - Chen, Eric X.
AU - Squire, Jeremy A.
AU - Marrano, Paula
AU - Kamel-Reid, Suzanne
AU - Dancey, Janet
AU - Siu, Lillian L.
AU - Tsao, Ming S.
PY - 2007/6/1
Y1 - 2007/6/1
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.2006.07.6554
DO - 10.1200/JCO.2006.07.6554
M3 - Article
C2 - 17538163
AN - SCOPUS:34250195788
SN - 0732-183X
VL - 25
SP - 2184
EP - 2190
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 16
ER -