Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer.
OBJECTIVE
Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients.


METHODS
Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays.


RESULTS
EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014).


CONCLUSIONS
EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials.
Noordhuis
Maartje G
MG
Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Eijsink
Jasper J H
JJ
Ten Hoor
Klaske A
KA
Roossink
Frank
F
Hollema
Harry
H
Arts
Henriëtte J G
HJ
Pras
Elisabeth
E
Maduro
John H
JH
Reyners
Anna K L
AK
de Bock
Geertruida H
GH
Wisman
G Bea A
GB
Schuuring
Ed
E
van der Zee
Ate G J
AG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D001918:Brachytherapy / Q000379:methods; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D010766:Phosphorylation; D011446:Prospective Studies; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy*
D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt