期刊
CLINICAL CANCER RESEARCH
卷 21, 期 13, 页码 2932-2940出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-1428
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资金
- GlaxoSmithKline Oncology
- NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust
- Institute of Cancer Research
- Royal Marsden NHS Foundation Trust
- Cancer Research UK
- NIHR Clinical Research Network
- [CSMD CR007226]
- Cancer Research UK [15955] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10122] Funding Source: researchfish
Purpose: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors. Experimental Design: Women with primary breast cancer were randomized (3: 1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/post treatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2(+) was defined as 2+/3+ by IHC and FISH+. Results: One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2(+), 78% were HER2(-) nonamplified, 26% were EGFR(+). Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (-31%; P < 0.001), but not with placebo (-3%). Whereas Ki67 reduction with lapatinib was greatest in HER2(+) breast cancer (-46%; P = 0.003), there was a significant Ki67 decrease in HER2(-) breast cancer (-27%; P = 0.017) with 14% of HER2(-) breast cancer demonstrating >= 50% Ki67 reduction with lapatinib. Among HER2(+) patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho = -0.7; P = 0.002). Among HER2(-) tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P = 0.01). In HER2(-) breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression. Conclusions: Lapatinib has antiproliferative effects in a subgroup of HER2(-) nonamplified tumors characterized by high HER3 expression. The possible role of high HER2: HER3 heterodimers in predicting response to lapatinib merits investigation in HER2(-) tumors. (C) 2014 AACR.
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