A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer.
OBJECTIVE
Increased epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial.


METHODS
Postmenopausal women with stage I to IIIB hormone receptor-positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2:5:5 to receive, in addition, gefitinib 250 mg/d orally for 16 weeks: placebo 1 tablet/d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response (OR).


RESULTS
Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were -77.4% and -83.6%, respectively, between baseline and 16 weeks (geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P = .26), -80.1% and -71.3% between baseline and 2 weeks (geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P = .22) and -19.3% and -43% (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% (estimated difference = -13.1%; 95% CI, -27.3% to 1.2%), respectively, with a nonsignificant trend against the combination (P = .08) and 48% versus 72% (estimated difference = -24.1%; 95% CI, -45.3% to -2.9%) in the progesterone-receptor-positive subgroup, which was significant (P = .03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction.


CONCLUSIONS
Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis.
Smith
Ian E
IE
Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom. ian.smith@rmh.nhs.uk
Walsh
Geraldine
G
Skene
Anthony
A
Llombart
Antonio
A
Mayordomo
José Ignacio
JI
Detre
Simone
S
Salter
Janine
J
Clark
Emma
E
Magill
Patrick
P
Dowsett
Mitch
M
D000368:Aged; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D066246:ErbB Receptors / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008408:Mastectomy; D009570:Nitriles / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage*
D000077384:Anastrozole; D066246:ErbB Receptors; D004958:Estradiol; D000077156:Gefitinib; D019394:Ki-67 Antigen; D009570:Nitriles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D014230:Triazoles; C512478:EGFR protein, human; C508053:ERBB2 protein, human