Phase II, randomized trial of preoperative epirubicin-paclitaxel +/- gefitinib with biomarker evaluation in operable breast cancer.
OBJECTIVE
To evaluate the in vivo effect of adding gefitinib to preoperative chemotherapy on the EGFR-dependent p42/44 MAPK in operable breast cancer (BC) patients. Secondary aims: to evaluate EGFR, (p)-EGFR, Ki67, apoptotic index (TUNEL test) and VEGFR2 expression from baseline to surgery, percentage of pathologic complete response (pCR), and toxicity.


METHODS
90 patients with stage II-IIIA BC have been randomized to receive epirubicin 90 mg/sqm and paclitaxel 175 mg/sqm on day 1 plus: gefitinib 250 mg daily from day 5 to 16 (Arm A, intermittent), gefitinib 250 mg daily from day 1 to 21 (Arm B, continuous), or placebo (Arm C). Treatment plan: 4 courses every 3 weeks, followed by surgery.


RESULTS
After preoperative therapy, 86/90 patients underwent surgery; 46 patients (51%) received breast conservative surgery. A pCR was observed in 4 patients. No significant differences in the expression of p42/44 MAPK, EGFR, (p)-EGFR, VEGFR2, proliferation index and apoptosis were observed comparing the combined Arms A + B vs C, and comparing Arm A vs B. Hematologic toxicities were not significantly different comparing Arms A + B vs Arm C, and comparing Arm A vs B. Significantly higher skin and mucosal toxicities were observed when comparing the two gefitinib Arms (A + B) vs Arm C (32% vs 9.6%, P = 0.018; 57% vs 29%, P = 0.009 respectively), while no significant differences were observed comparing Arm A vs B.


CONCLUSIONS
Adding gefitinib to chemotherapy did not result in different effects on the EGFR-dependent pathway, proliferation, apoptosis and VEGFR2 expression as compared to placebo, while enhancing skin and mucosal toxicity. The two schedules of gefitinib (intermittent vs continuous) did not result in different biologic effects.
Guarneri
Valentina
V
Department of Oncology and Hematology, Modena University Hospital, via del Pozzo 71, 41100 Modena, Italy. guarneri.valentina@unimore.it
Frassoldati
Antonio
A
Ficarra
Guido
G
Puglisi
Fabio
F
Andreetta
Claudia
C
Michelotti
Andrea
A
Cresti
Nicola
N
Boni
Corrado
C
Bisagni
Giancarlo
G
Berardi
Rossana
R
Battelli
Nicola
N
Santoro
Armando
A
Banna
Giuseppe
G
Bottini
Alberto
A
Di Blasio
Beatrice
B
Maiorana
Antonino
A
Piacentini
Federico
F
Giovannelli
Simona
S
Jovic
Gordana
G
Conte
PierFranco
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015251:Epirubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D010349:Patient Compliance; D011799:Quinazolines / Q000008:administration & dosage; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D011799:Quinazolines; D015251:Epirubicin; D066246:ErbB Receptors; D040281:Vascular Endothelial Growth Factor Receptor-1; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel; D000077156:Gefitinib