Emerging Advances in Metastatic Breast Cancer

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1 Emerging Advances in Metastatic Breast Cancer Bryan P. Schneider, MD Assistant Professor of Medicine & Medical Molecular Genetics IU Simon Cancer Center

2 AT LEAST THREE types of breast cancer TNBC HER2+ ER+ Schneider, et al CCR, 2008

4 Therapeutic advancements in the specific subtypes of breast cancer

5 Manipulation of hormonal milieu is critical for ER+ tumors SERMS Progestins Aromatase Inhibitors Estrogen Receptor SERDS Testosterone

6 Estrogen for ER+ tumors: what was once old is new again Sir Alexander Haddow

7 James Ingle 1981 Tamoxifen versus Diethylstilbestrol Event DES N=74 TAM N=69 Emesis 18 (25%) 8 (12%) Edema 39 (53%) 8 (12%) Phlebitis 2 (3%) 0 Vag Bleed 11 (15%) 1 (1%) CCF 2 (4%) 0 Hotflashes 2 (3%) 20 (29%) Ingle et al NEJM 304:

8 Low dose estrogen for ER+ breast cancer ER+ MBC (n=66) Estradiol: 6mg Estradiol: 30mg JAMA, August 19, 2009 Vol 302, No. 7

9 6 mg (n=34) 30 mg (n=32) CR 0% 0% PR 9% 3% SD 20% 25% 7 patients re-treated with AI after progression: 2 PR, 1SD Estradiol 6mg daily is a reasonable and cost effective option for patients with ER+ advanced breast cancer and acquired AI resistance JAMA, August 19, 2009 Vol 302, No. 7

10 Therapeutic individualization is a function of the disease, host, and drug Walgren et al. JCO 2005;23: Copyright American Society of Clinical Oncology

Nucleotide Polymorphism Genotype: the combination of two inherited bases

11 Evaluation of the most common form of Most of the population genetic variability G to C At least 1 percent of the population SNP= Single Nucleotide Polymorphism Genotype: the combination of two inherited bases Wild Type (wt) SNP Common sequence Variant sequence SNP site National Cancer Institute

12 SNPs and Drug Interactions Drug Cytochrome P450 =CYP Absorption in the breast Drug in breast tissue Metabolism in the liver Transportation in the blood Drug in bloodstream Transporter Drug becomes inactive or toxic Excretion in the kidney

13 Cytochrome P450 2D6 (CYP2D6) Catalyzes metabolism of common drugs: codeine, -blockers, TCA, tamoxifen Inhibited by: fluoxetine, paroxetine, quinidine Highly polymorphic Absent in 5-10% of Caucasians

14 Tamoxifen is Metabolized by 2D6 Tamoxifen 4-OH-Tamoxifen CYP 3A N-Desmethyl- Tamoxifen Endoxifen CYP 2D6 Desta, et al. J Pharmacol Exp Ther. 2004; 310:

15 Plasma Endoxifen (nm) CYP2D6 Genotype Predicts Endoxifen Concentration Wt/Wt Wt/*4 *4/*4 CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state) Jin Y et al: J Natl Cancer Inst 97:30, 2005 P<0.001, r 2 =0.24 CP

16 Plasma Endoxifen (nm) Inhibition of CYP2D6 Affects Endoxifen Concentrations Wt/Wt, no inhibitor Venlafaxine Sertraline Paroxetine *4/*4, no inhibitor Jin Y et al: J Natl Cancer Inst 97:30, 2005 CP

17 Relapse Free Survival Disease Free Survival Overall Survival Moderate or severe hot flashes *4/*4 0% Wt/Wt or Wt/*4 20% Goetz, M. P. et al. J Clin Oncol; 23:

18 E3108 Schema Tamoxifen 20 mg PO daily Eligible: Metastatic breast cancer starting tamoxifen Measureable/ Evaluable disease G E N O T Y P E CYP2D6 1-2 CYP2D6 0 R E S P O N S E Continue tamoxifen until progression Stratify: Menopausal status Prior AI use N = months: tamoxifen/ metabolite concentration

19 The EGFR/HER Family Ligand binding domain Transmembrane Tyrosine kinase domain erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 Slamon, NEJM

20 Probability of survival Hitting the target is essential FISH+ FISH 1.0 Trast. + CT (n = 176) CT (n = 169) 1.0 Trast. + CT (n = 50) CT (n = 56) 0.8 RR = 0.71 p = RR = 1.11 p = NS mo 26.2 mo mo 24.0 mo Months Months Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.

21 Abraham, CCR 2007, 13 (11)

22 Alternative blockade at the extracellular portion of the HER2 receptor

Activity in patients who have received multiple prior HER-2 based therapies Pertuzumab +trastuzumab ASCO 2007 Baselga: n=66 (JCO; 2010) CR=8% PR=17% CBR=50% PFS=5.

23 Activity in patients who have received multiple prior HER-2 based therapies Pertuzumab +trastuzumab ASCO 2007 Baselga: n=66 (JCO; 2010) CR=8% PR=17% CBR=50% PFS=5.5 mo Portera: n=11 CR=0% PR=18% Side effect: rash and diarrhea TDM-1 ASCO 2009 n=112 Median time since dx of met dz: 32 mo 3 prior tx (median) CR-2.7% PR: 35.7 % PFS=4.9 mo Common G 3/4 tox: thrombocytopenia

$nd line +) *Cardiac ejection fraction >55% Primary Objectives: *Safety/tolerability *PK *Efficacy: ORR Abstract #1012; Miller et al Data presented: n= 44$ for toxicity; n=28 for efficacy Total prior systemic agents, median (range) : 8 (2-16) Median time since metastatic diagnosis, mo (range): 34.

for toxicity; n=28 for efficacy Total prior systemic agents, median (range) : 8 (2-16) Median time since metastatic diagnosis, mo (range): 34.

24 A Phase Ib/II Trial of T-DM1+Pertuzumab for HER2+ Advanced BC with prior trastuzumab Eligibility Criteria: *Metastatic HER2+ *Prior HER2-directed therapy (2 nd line +) *Cardiac ejection fraction >55% Primary Objectives: *Safety/tolerability *PK *Efficacy: ORR Abstract #1012; Miller et al Data presented: n= 44 for toxicity; n=28 for efficacy Total prior systemic agents, median (range) : 8 (2-16) Median time since metastatic diagnosis, mo (range): 34.7 (5 150) Cohort 1 (n=3) Cohort 2 (n=25) Total (n=28) CR PR 2 (66.7) 8 (32.0) 10 (35.7) SD 1 (33.3) 12 (48.0) 13 (46.4) PD 0 4 (16.0) 4 (14.3) Missing 0 1 (4.0) 1 (3.6)

25 mtor inhibition in trastuzumab-refractory disease Receptor dimerization HER-2 Cancer cell Trastuzumab P P Ras/Raf MAPK PTEN PI3K AKT/PKB Everolimus mtor ps6 kinase Proliferation and angiogenesis 1 Huang S et al. Curr Opin Investig Drugs. 2002;3: ; 2 Abraham RT et al. Clin Cancer Res. 2007;13: ; 3 Berns K et al. Cancer Cell. 2007;12: ; 4 Nagata Y et al. Cancer Cell. 2004;6:

Survival Everolimus Paclitaxel (P) Trastuzumab: 2

resistant *Prior lapatinib permitted >>60% lapatinib

chemo: 3 (0-8) PR=19% SD=62% TTP= 6 mo Everolimus: 10

*Progression on trastuzumab >>Prior lapatinib= 19%

4 mo Survival Plot 1.000 0.750 0.500 0.250 0.000 0.0 66.

26 Survival Everolimus Paclitaxel (P) Trastuzumab: 2 mg/kg/week *HER2+ MBC (n=55) *(T) resistant *(P) resistant *Prior lapatinib permitted >>60% lapatinib resistant *No limit to # of prior tx >>Median prior chemo: 3 (0-8) PR=19% SD=62% TTP= 6 mo Everolimus: 10 mg/day Trastuzumab: 2 mg/kg/week *HER2+ MBC (n=47) *Progression on trastuzumab >>Prior lapatinib= 19% *Visceral disease= 83% PR=15% SD=19% TTP= 3.4 mo Survival Plot C1 ASCO 2010:Abstr#1013; Dalenc et al ASCO 2010 Abstr #1014: Morrow et al

27 TNBC targeted therapies Treatment Target Rationale/evidence Studies Platinating agents PARP-1 inhibitors DNA: inter-strand breaks PARP-1 *defective DNA repair *in vitro chemo-sensitivity in BRCA-1 *over-expression *in vitro sensitivity *neoadjuvant DFCI *CALGB *positive randomized phase II trial *accrued phase III Anti-VEGF VEGF over-expression of VEGF *positive phase III trial (unplanned subgroup) EGFR inhibition EGFR over-expression Negative phase II trials c-kit inhibition c-kit over-expression Negative phase II trials

28 PARP inhibitors Olaparib for BRCA 1/2 carriers with breast cancer (median 3 prior tx) 100 mg BID n=27: ORR=22%; PFS=3.8 mo Synthetic Lethality 400 mg BID n=27: ORR=41%; PFS=5.7 mo Iglehart; NEJM 2009 Minimal Toxicity Tutt et al; ASCO 2009

29 Rationale for PARP inhibition in non-brca PARP differentially up-regulated in primary breast tumors, including TNBC subtypes TNBC: BRCAness Synergy of DNA damaging agents + PARPi

30 Randomized phase II trial of PARPi BSI-201 Metastatic TNBC (n=120) Gemcitabine Carboplatin 21 day cycle Gemcitabine Carboplatin BSI-201 Gem/carbo (n=44) Gem/carbo/BSI (n=42) P-value ORR 7 (16%) 20 (48%) CBR 9 (21%) 26 (62%) CBR= CR +PR +SD 6mo ASCO-Plenary; 2009

31 ASCO-Plenary; 2009 PARP inhibitor: Overall Survival BSI Gem/Carbo (n = 57) Median OS = 9.2 months Gem/Carbo (n = 59) Median OS = 5.7 months P = HR = (95% CI, ) O Shaughnessy et al

32 Moving forward: identification of novel targets using transcriptomics (RNA-seq) RNA seq: TNBC vs. normal breast Cutting edge technology: ALL genes (including those without names) Gene Fusions SNPs & mutations Uncover novel targets for drug discovery

33 Substantial genetic variability between tumor and normal 7,286 differentially expressed genes Radovich et al, AACR 2010

34 Honorable mention/other cool stuff Chemotherapy Eribulin HER-2 Fusion antibodies, neratinib Angiogenesis VEGF trap, bavituximab, metronomic Receptor inhibition IGFR-1 Signal transduction inhibitors PI3K inhibitors Epigenetic Modulators HDAC inhibitors Novel pathway inhibition/stimulation Death receptors (apoptosis), telomerase inhibition Immune modulation Vaccines (HER2, MUC1) Bone Health Denosumab

36 Thanks!!!!

Resistance to anti-her2 therapies. Service d Oncologie Médicale

Resistance to anti-her2 therapies Pr David Khayat Service d Oncologie Médicale Groupe Hospitalier Pitié Salpêtrière -Paris Disclosure statment Trastuzumab in HER2+ MBC A major impact but resistance will