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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

Mark Agulnik, Gilda da Cunha Santos, David Hedley, Trudey Nicklee, Patricia Pintor dos Reis, James Ho, Gregory R. Pond, Heidi Chen, Shuo Chen, Yu Shyr, Eric Winquist, Denis Soulieres, Eric X. Chen, Jeremy A. Squire, Paula Marrano, Suzanne Kamel-Reid, Janet Dancey, Lillian L. Siu, Ming S. Tsao

From the Princess Margaret Hospital Phase II Consortium; Ontario Cancer Institute, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; Vanderbilt University Medical Center, Nashville, TN; and the National Cancer Institute, Bethesda, MD

Address reprint requests to Lillian L. Siu, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Suite 5-718, Toronto, Ontario, M5G 2M9, Canada; e-mail: lillian.siu{at}uhn.on.ca

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 (NFB), 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-NFB, 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.

Supported in part by National Cancer Institute Contract No. N01-CO-124001, Subcontract No. 22XS035A-P5380.

Presented in part at the Annual American Association for Cancer Research- National Cancer Institute-European Organization for Research Treatment of Cancer-Molecular Targets and Cancer Therapeutics Conference, November 14-18, 2005, Philadelphia, PA.

M.A. and G.d.C.S. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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