title: 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.
abstract: 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 (NFkappaB), 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 < or = .03). With treatment, a decrease in p-EGFR, p-NFkappaB, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P < or = .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.
authors.affiliation: Princess Margaret Hospital Phase II Consortium, Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Agulnik
authors.forename: Gilda
authors.initials: G
authors.lastname: da Cunha Santos
authors.forename: David
authors.initials: D
authors.lastname: Hedley
authors.forename: Trudey
authors.initials: T
authors.lastname: Nicklee
authors.forename: Patricia Pintor
authors.initials: PP
authors.lastname: Dos Reis
authors.forename: James
authors.initials: J
authors.lastname: Ho
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Pond
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
authors.forename: Denis
authors.initials: D
authors.lastname: Soulieres
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Paula
authors.initials: P
authors.lastname: Marrano
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Ming S
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D014408:Biomarkers, Tumor; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D018628:Gene Dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009364:Neoplasm Recurrence, Local; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D012867:Skin / Q000737:chemistry* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors