TY - JOUR
T1 - Antiproliferative effect of lapatinib in HER2-Positive and HER2-Negative/HER3-High breast cancer
T2 - Results of the presurgical randomized MAPLE Trial (CRUK E/06/039)
AU - Leary, Alexandra
AU - Evans, Abigail
AU - Johnston, Stephen R.D.
AU - A'Hern, Roger
AU - Bliss, Judith M.
AU - Sahoo, Rashmita
AU - Detre, Simone
AU - Haynes, Benjamin P.
AU - Hills, Margaret
AU - Harper-Wynne, Catherine
AU - Bundred, Nigel
AU - Coombes, Gill
AU - Smith, Ian
AU - Dowsett, Mitch
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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: Womenwith 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-/posttreatment 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. Clin Cancer Res; 21(13); 2932-40-2014 AACR.
AB - 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: Womenwith 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-/posttreatment 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. Clin Cancer Res; 21(13); 2932-40-2014 AACR.
UR - http://www.scopus.com/inward/record.url?scp=84941966977&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-1428
DO - 10.1158/1078-0432.CCR-14-1428
M3 - Article
C2 - 25398453
AN - SCOPUS:84941966977
SN - 1078-0432
VL - 21
SP - 2932
EP - 2940
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -