Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial.
BACKGROUND
Some oestrogen-receptor (ER) positive breast cancers express epidermal growth factor receptor (EGFR), but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known.


METHODS
In a double-blind, placebo-controlled randomised trial of 56 postmenopausal patients with ER-positive and EGFR-positive primary breast cancer, 27 women were randomly assigned to the tyrosine-kinase inhibitor of EGFR gefitinib (250 mg given orally once a day) and the aromatase inhibitor anastrozole (1 mg given orally once a day), and 29 women to gefitinib (250 mg given orally once a day) and placebo of identical appearance to anastrozole given orally once a day, all given for 4-6 weeks before surgery. Primary outcome was inhibition of tumour-cell proliferation, as measured by Ki67 antigen labelling index. Secondary outcomes were reduction in EGFR phosphorylation at Tyr 845, reduction in ER phosphorylation at Ser 118, tumour size, and toxic effects. Analyses were by intention to treat.


RESULTS
Patients assigned gefitinib and anastrozole had a greater reduction from pretreatment values in proliferation-related Ki67 labelling index than did those assigned gefitinib alone (mean % reduction 98.0 [95% CI 96.1-98.9] vs 92.4 [85.1-96.1]; difference between groups 5.6% [5.1-6.0], p=0.0054). Tumour size was reduced by 30-99% (partial response) in 14 of 28 patients assigned gefitinib and [corrected]in 12 of 22 assigned gefitinib, as assessed by ultrasonography. Reduction in phosphorylation of ER at Ser 118 was similar for both groups. Treatment was well tolerated and much the same for both groups.


CONCLUSIONS
Single-agent gefitinib and gefitinib combined with anastrozole are well-tolerated and effective treatments for reducing the size of breast tumours and levels of ER phosphorylation when given as neoadjuvant therapy.
Polychronis
Andreas
A
Cancer Research UK Laboratories, Department of Cancer Medicine, Imperial College, London, UK.
Sinnett
H Dudley
HD
Hadjiminas
Dimitri
D
Singhal
Hemant
H
Mansi
Janine L
JL
Shivapatham
Dharsha
D
Shousha
Sami
S
Jiang
Jie
J
Peston
David
D
Barrett
Nigel
N
Vigushin
David
D
Morrison
Ken
K
Beresford
Emma
E
Ali
Simak
S
Slade
Martin J
MJ
Coombes
R Charles
RC
D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D004739:England; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019394:Ki-67 Antigen; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009376:Neoplasms, Hormone-Dependent / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage*; D017698:Postmenopause; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*; D014463:Ultrasonography
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D019394:Ki-67 Antigen; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole; D066246:ErbB Receptors; D000077156:Gefitinib