Mothaffar F. Rimawi, Ingrid A. Mayer, Andres Forero, Rita Nanda, Matthew P. Goetz, Angel A. Rodriguez, Anne C. Pavlick, Tao Wang, Susan G. Hilsenbeck, Carolina Gutierrez, Rachel Schiff, c. Kent Osborne JOURNAL OF CLINICAL ONCOLOGY VOLUME 31. NUMBER 14. MAY Multicenter Phase II Study of Neoadjuvant Lapatinib and Trastuzumab With Hormonal Therapy and Without Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer: TBCRC 006

INTRODUCTION 0 human epidermal growth factor receptor 2 (HER2) 0 HER2 is amplified or overexpressed in 20% to 25% of breast cancers. 0 estrogen receptor (ER) 0 cytotoxic agents + trastuzumab

INTRODUCTION 0 cytotoxic agents + trastuzumab 0 Trastuzumab : * effectively inhibit signaling from HER2 homodimers * induce antibody-dependent cellular cytotoxicity acquired resistance ? 1) downstream activation of the pathway by PTEN loss, activating mutations in PI3K, or amplification of cyclin E 2) p95 : a short form of HER2 missing the extracellular domain 3) upregulation of receptor ligands or the receptors themselves 4) escape pathways such as ER or insulin-like growth factor receptor signaling

INTRODUCTION 0 Geftinib, erlotinib : potent kinase inhibitors of HER1 0 Pertuzumab : * binds to heterodimerization domain of HER2  blocks interaction w/ HER1 and HER3 * does not block HER1 homodimers or HER1:HER3 heterodimers 0 Lapatinib : a dual-kinase inhibitor (HER1 and HER2) 0 Arpino G, Gutierrez C, Weiss H, et al: Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. Natl Cancer Inst 99: , 2007 geftinib + pertuzumab + trastuzumab 0 Rimawi MF, Wiechmann LS, Wang YC, et al: Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu- overexpressing breast tumor xenografts. Clin Cancer Res 17: , 2011 lapatinib + trastuzumab + endocrine therapy (in ER+ tumors)

PATIENTS AND METHODS 0 Women age ≥ 18 years 0 Histologically confirmed invasive HER2-positive breast cancer overexpression by immunohistochemistry (3+) amplification by fluorescent in situ hybridization 0 > 3 cm by clinical measurement > 2cm with a palpable ipsilateral axillary LN confrimed by 2 physicians 1,000mg po qd 4mg/kg loading + 2mg/kg qw 2.5mg po qd ±trastuzumab-based CTx ±adjuvant therapy after sx surgery

PATIENTS AND METHODS Study goals ypT 0-is 0 pathologic complete response (pCR) = disappearance of all invasive tumor in the breast; ypT 0-is pCRypT 1a-b 0 pathologic response rate = pCR + residual invasive disease of ≤ 1cm (ypT 1a-b ) at the time of surgery 0 ER status (+/-)

RESULTS 0 June 11, 2008 ~ November 2, women 0 Baylor College of Medicine, Vanderbilt University, University of Alabama in Birmingham, University of Chicago, Mayo Clinic

RESULTS

DISCUSSION 0 oncogene-addiction hypothesis 0 study with transgenic mice : * HER2 activation  causes breast cancer * down-regulation of HER2  shut down of pathway  complete tumor eradication 0 potent cocktail of drugs that more completely blocks the HER network causes pCR in the breast in a substantial percentage of patients “targeted therapy only and without using CTx” 0 Residual invasive disease of of ≤ 1cm (ypT 1a-b ) in the ER-positive : 33%  treatment beyond 12 weeks? 0 There may be a subset of patients with HER2+ breast cancer who do not need CTx

DISCUSSION 0 Arpino G, Gutierrez C, Weiss H, et al: Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. Natl Cancer Inst 99: , Rimawi MF, Wiechmann LS, Wang YC, et al: Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu- overexpressing breast tumor xenografts. Clin Cancer Res 17: , trastuzumab + lapatinib > either of the single agents 0 mechanism of action of trastuzumab & lapatinib ㅡ likely to involve different signaling pathways 0 trastuzumab + pertuzumab > either agent alone 0 + geftinib (to inhibit HER1) > trastuzumab + pertuzumab 0 ER + HER2 blockation  eradication ㅡ may function as an escape pathway in some tumors

DISCUSSION 1. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer ( NeoSphere ): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, pCR rate of biologic Tx only (trastuzumab + pertuzumab – CTx) : ER+/HER2+ = 6%,ER-/HER2+ = 26% 2. Baselga J, Bradbury I, idtmann H, et al: Lapatinib with trastuzumab for HER2-positive early breast cancer ( NeoALTTO ): A randomised, open-label, multicentre, phase 3 trial. Lancet 379: , pCR rate : lapatinib + trastuzumab + paclitaxel > lapatinab or trastuzumab alone 0 Targeting HER2+ tumors with multiple agent  more effective blockade & better results 0 Sizable subset of patients with HER2+ tumors may not require CTx  Need of biomarkers