Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.
OBJECTIVE
To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics.


METHODS
Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained.


RESULTS
The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor.


CONCLUSIONS
Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.
Cancer Therapeutics Branch, Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Warren G Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20889, USA.
Antoinette R
AR
Tan
Xiaowei
X
Yang
Stephen M
SM
Hewitt
Arlene
A
Berman
Erin R
ER
Lepper
Alex
A
Sparreboom
Allyson L
AL
Parr
William D
WD
Figg
Catherine
C
Chow
Seth M
SM
Steinberg
Stephen L
SL
Bacharach
Millie
M
Whatley
Jorge A
JA
Carrasquillo
Jaime S
JS
Brahim
Seth A
SA
Ettenberg
Stan
S
Lipkowitz
Sandra M
SM
Swain
D000284:Administration, Oral; D015415:Biomarkers / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D023381:Endpoint Determination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D009061:Mouth Mucosa / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D010865:Pilot Projects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000378:metabolism; D014055:Tomography, Emission-Computed
D015415:Biomarkers; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases