1.  2013 Genentech USA, Inc. All rights reserved. Disclosure/Disclaimer The Molecular Basis of Breast Cancer slide presentation is not an independent educational program, and no CME credits will be provided. This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development. The contents of this slide presentation are owned solely by Genentech; any unauthorized uses are prohibited. This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. The following slides are selected samples from a complete presentation. They are for educational purposes only. BIO0002078200 1

2.  2013 Genentech USA, Inc. All rights reserved. Granulosa Sex hormone biology and its role in breast carcinoma Adrenal glands ESTRONE ESTRADIOL Corpus luteum Ovaries PREMENOPAUSAL POSTMENOPAUSAL Breast adipose tissue AROMATASEAROMATASE Breast Periphery AROMATASE (peripheral) ANDROSTENEDIONE Fabian CJ. Int J Clin Pract. 2007;61:2051-2063. 2

3.  2013 Genentech USA, Inc. MBoC Program HER2 protein expression measured by IHC IHC 0IHC 1+IHC 2+IHC 3+ HER2 expression and prognosis in breast cancer Shortened median survival in patients with HER2 overexpression (combined adjuvant and metastatic): HER2+ 2 to 3 years HER2 normal 6 to 7 years HER=human epidermal growth factor receptor; IHC=immunohistochemistry. Andrulis IL, et al. J Clin Oncol. 1998;16:1340-1349. Ellis CM, et al. J Clin Pathol. 2005;58:710-714. Banerjee R, et al. J Pharmacol Exp Ther. 2010;334:9-20. Images courtesy of Genentech. 3

4.  2013 Genentech USA, Inc. MBoC Program 4 BRCA1 and BRCA2 have important roles in DNA repair DNA damage Cancer Failed repair of checkpoint genes Accumulation of mutations Cell-cycle progression despite damage Mutations in BRCA1 or BRCA2 BRCA=breast cancer. Venkitaraman AR. J Cell Sci. 2001; 114:3591-3598. BRCA2 RAD51 BRCA1 Germline mutations in BRCA1 and BRCA2 genes predispose women to an increased risk of breast and ovarian cancers. References: Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci. 2001;114:3591-3598. Notes

5.  2013 Genentech USA, Inc. All rights reserved. 5 HER3 The HER2 signaling pathway and anti-HER2 monoclonal antibodies Cell-cycle control Proliferation ↑ Survival Ras Sos Grb2 Shc MEK Angiogenesis Raf Cyclin D1p27BAD GSK3  NFκB mTOR MAPK ↓ Apoptosis Akt PDK1 PI3K HER=human epidermal growth factor receptor; Ras=rat sarcoma; Sos=son of sevenless; Grb2=growth factor receptor-bound 2; PI3K=phosphatidylinositol 3-kinase; PDK=phosphoinositide-dependent kinase; PTEN=phosphatase and tensin homolog; Raf=rapidly accelerating fibrosarcoma; MEK=mitogen-activated protein kinase kinase; MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; BAD=Bcl-2–associated death promoter; NFκB=nuclear factor kappa–light-chain-enhancer of activated B-cells; GSK=glycogen synthase kinase. Adjei AA, Hidalgo M. J Clin Oncol. 2005;23:5386-5403. PTEN HER2 HER3 Domain IV A strategy to stem proliferative signaling in cancer cells is to target the extracellular region of growth receptors with monoclonal antibodies. Reference: Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol. 2005;23:5386-­5403. Notes