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.

BIO00020782001

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

AROMATASE Breast

PeripheryAROMATASE

(peripheral)

ANDROSTENEDIONE

Fabian CJ. Int J Clin Pract. 2007;61:2051-2063. 2

2013 Genentech USA, Inc. MBoC Program

HER2 protein expression measured by IHC

IHC 0 IHC 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 yearsHER=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

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

2013 Genentech USA, Inc. All rights reserved.5

HER3

The HER2 signaling pathway and anti-HER2monoclonal antibodies

Cell-cyclecontrol

Proliferation

↑Survival

Ras Sos Grb2 Shc

MEK

Angiogenesis

Raf

Cyclin D1

p27

BAD

GSK3b

NFκBmTOR

MAPK

↓Apoptosis

AktPDK1

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