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The effects of gefitinib in tamoxifen‐resistant and hormone‐insensitive breast cancer: A phase II study
Author(s) -
Gutteridge Eleanor,
Agrawal Amit,
Nicholson Robert,
Cheung Kwok Leung,
Robertson John,
Gee Julia
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24884
Subject(s) - gefitinib , tamoxifen , breast cancer , medicine , epidermal growth factor receptor , estrogen receptor , oncology , egfr inhibitors , cancer , cancer research , endocrinology
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.