The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: a phase II study.
Estrogen receptor (ER)-positive acquired tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell lines exhibit epidermal growth factor receptor (EGFR) expression/signaling and are growth-inhibited by gefitinib (IRESSA). We examined the effect of gefitinib on ER-positive TAM-R and ER-negative hormone-insensitive breast cancer in a Phase II study. Fifty-four patients with breast cancer [ER-positive/acquired TAM-R (n = 28); ER-negative (n = 26)] received oral gefitinib 500 mg/day. Tumor biopsies were taken pre- (n = 28) and 8 weeks post-treatment (n = 14 matched samples). Gefitinib was well tolerated and the clinical benefit rate (objective response or stable disease >24 weeks) was 33.3% overall (n = 18/54), and 53.6 and 11.5% in ER-positive/TAM-R and ER-negative patients, respectively. Pretreatment ER and progesterone receptor-positivity were associated with response (p < 0.001 and 0.016, respectively) and longer progression-free survival (PFS; p= 0.001 and 0.013, respectively). All patients expressed EGFR, but high pretreatment levels predicted poorer outcome (p = 0.005) and shorter PFS (p = 0.012) with gefitinib. In patients with clinical benefit, reduced Ki67 staining during treatment (p = 0.024) was commonly observed, and those with >10% decline in EGFR phosphorylation demonstrated parallel decreases in ERK1/2 MAPK phosphorylation. Acquired tamoxifen resistance appears in part mediated through EGFR signaling and can be blocked with gefitinib.
Gutteridge
Eleanor
E
Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom.
Agrawal
Amit
A
Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom.
Nicholson
Robert
R
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom.
Cheung
Kwok Leung
KL
Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom.
Robertson
John
J
Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom.
Gee
Julia
J
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011799:Quinazolines / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D011799:Quinazolines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D066246:ErbB Receptors; D000077156:Gefitinib