Abstract LB-222: Lapatinib has antiproliferative effects in both HER2 positive (+) and HER2 negative (-) breast cancer (BC): results from the MAPLE short-term pre-surgical trial (CRUK E/06/039)
Authors: Evans Abigail , Leary Alexandra F. , Johnston Stephen , A'Hern Roger , Bliss Judith M. , Hills Margaret Joy , Harper-Wynne Catherine , Bundred Nigel , Coombes Gill , Sahoo Rashmita , Detre Simone , Smith Ian E. , Dowsett Mitch 
Published: August 2012

Abstract
Not all patients (pts) with HER2 positive (+) breast cancer (BC) benefit from treatment (tx) with EGFR/HER2 tyrosine kinase inhibitor lapatinib (L) & it is not known whether HER2 over-expression or amplification are obligate requirements for L response. Assessment of in vivo biomarkers of drug activity, e.g. change in Ki67, after short-term pre-surgical tx may elucidate the differential molecular profile of sensitive vs. resistant tumors. Aims: i) Determine whether L induces anti-proliferative effects in HER2+ & HER2 negative (-) BC & ii) identify biomarkers of sensitivity/resistance to anti-proliferative effects of L. Methods: Women with newly diagnosed BC were randomized (3:1) to receive 10-14 days of pre-operative L (1500mg/day) or placebo (P) in a multicentre phase II trial (ISRCTN68509377). Paired core biopsies before & after tx were analyzed for Ki67, TUNEL, HER2, EGFR, ER, PgR, pAkt, pErk, & stathmin (candidate marker of PI3K/Akt activation) by IHC +/− FISH. HER2, HER3 & ligands EREG, AREG & NRG1 mRNA was measured by RT-PCR. The primary endpoint was change in Ki67. HER2+ was defined as 3+ or 2+ by IHC and FISH+. Differences in geometric means were assessed by Mann-Whitney & correlations by Spearman rank. Results: 121 pts (L=94, P=27) were randomized between 12/2007-04/2011, 70% were ER+/PgR+, 13% ER+/PgR- & 17% ER-; 22% were HER2+ (including one 2+/FISH+) & 26% were EGFR+. L pts reported significantly more frequent G1-2 (64%) or G3 (6%) rash, & G1 diarrhea (56%); the only other G3 toxicity was infection in 1 pt. There were no delays in surgery. Paired samples containing tumor were obtained for 98% (118/121) of randomized pts. Ki67 fell significantly in the L group (relative reduction in post- vs. pre-tx samples = -31%, 95%CI: -44 to -16; p&lt;0.001), but not in the P group (-3%, 95%CI: -16 to 13). There was no increase in apoptosis (-21%, 95%CI: -39 to 2.2). While Ki67 reduction in the L group was greatest in HER2+ BC (- 46%, 95%CI: -63 to -23; p&lt;0.01), there was also a significant Ki67 fall in HER2- BC (-27%, 95%CI: -42 to -8; p&lt;0.05) with 13% (9/72) of HER2- BC demonstrating ≥50% Ki67 reduction with L. Both pERK & stathmin were also significantly downregulated by L. Among HER2+ pts, there was a trend for high nuclear pAkt to predict for Ki67 response (R=−0.4; p=0.1). Among HER2- pts, neither moderate HER2 nor EGFR expression nor any other biomarker correlated with Ki67 fall. The only biomarker change associated with Ki67 fall among HER2- L-treated pts was stathmin (R=0.4; p=0.001); stathmin did not correlate with pAkt at baseline or with tx. RT-PCR analyses of HER2, HER3 & ligands are ongoing. Conclusion A short-term pre-surgical study for an agent such as L where the main endpoint is molecular rather than clinical, is feasible & safe. Whilst L is currently used exclusively in HER2+ disease, MAPLE has shown it also has antiproliferative effects in a subset of HER2- BC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-222. doi:1538-7445.AM2012-LB-222