Assessment of erlotinib pharmacodynamics in tumors and skin of patients with head and neck cancer.
BACKGROUND
The purpose of the study was to evaluate the effects of erlotinib on epidermal growth factor receptor (EGFR)-related signaling elements in tumor and skin from patients with advanced squamous cell carcinoma of the head and neck (HNSCC) and seek relationships between relevant clinical, biological, and pharmacokinetic parameters.


METHODS
Immunostaining for EGFR, p-EGFR, p-ERK, p-Akt, and p27 were analyzed semiquantitatively in serial tumor and skin samples from participating patients. Steady-state trough concentrations of erlotinib and its metabolite OSI-420 were also determined.


RESULTS
Of 25 patients enrolled, 20 (80%) paired pre- and posttreatment skin biopsies and seven (28%) paired tumor biopsies were evaluable for at least one immunohistochemical parameter. The severity of skin toxicity related to time to progression (TTP) (P = 0.048) and overall survival (P < 0.001). C(ss,min) values for erlotinib and OSI-420 also related to TTP (P = 0.042 and 0.036, respectively). Erlotinib treatment was associated with decreased p-EGFR expression in 66% of evaluable tumor samples, which seemed related to increased TTP and survival, and p27 was up-regulated in 59% of evaluable skin biopsy samples following treatment.


CONCLUSIONS
The feasibility of obtaining serial evaluable biopsies of HNSCC was suboptimal. Nevertheless, erlotinib inhibited p-EGFR in HNSCC tumors, which appeared associated to clinical benefit, and induced p27 in biopsies of normal skin.
Calvo
E
E
Cancer Therapy and Research Center, The Institute for Drug Development, San Antonio, TX, USA.
Malik
S N
SN
Siu
L L
LL
Baillargeon
G M
GM
Irish
J
J
Chin
S F
SF
Santabarbara
P
P
Kreisberg
J I
JI
Rowinsky
E K
EK
Hidalgo
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D066246:ErbB Receptors / Q000032:analysis; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis; D005260:Female; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects*
D011799:Quinazolines; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases