Overview. Presentation and prognosis Outcomes with standard therapy

Size: px

Start display at page:

Download "Overview. Presentation and prognosis Outcomes with standard therapy"

Shawn Ray
5 years ago
Views:

1 Emerging Therapies for Triple Negative Breast Cancer Joseph A. Sparano, MD Director, Breast Evaluation Center Montefiore-Einstein Cancer Center Professor of Medicine & Women s Health Albert Einstein i College of Medicine i Bronx, New York

2 Overview Presentation and prognosis Outcomes with standard therapy Biological agents Bevacizumab, cetuximab DNA damage Inducers of DNA damage (alkylators, platinums) Inhibitors of DNA repair (gemcitabine) PARP inhibitors Other agents 2

3 Triple-Negative Disease Compared with Other Phenotypes in the California i Cancer Registry Study Bauer et al. Cancer 2007: 109; 721 Population-based study 6370 with triple-negative disease compared with 44,704 other cases (12% of all cases) Findings more likely to be associated with Younger age (<40): OR 1.53 Non-Hispanic black (OR 1.77) or Hispanic (OR 1.23) Higher grade (72% grade 3) Poorer 5 year RFI irrespective of stage TNBC: 76% (similar to 76% for HER2-Pos) HR-Pos, HER2-Neg: 94%

4 Nomenclature: Basal-like and Triple-Negative Not all triplenegative are basal-like ~ 10-20% of triple-negative have a non- basal genomic profile IHC 15-40% of basal are not triple-negative Basal-like and triple-negative ~ ER+, PR+, or Array HER2+ on clinical assays -Terms are not synonymous -Terms are often used interchangeably % discordance across several studies Seal MD et al. Cancer J 2010; 16: 12-16

5 TNBC comprised of diverse molecular subtypes 0.3 Preliminary* Relativ ve frequency in panel basal claudinlow ERBB2 luminala luminalb normallike * Validation ongoing Affymetrix gene expression profiling of FFPE samples Intrinsic subtypes assigned using Sorlie et al, PNAS, 2003 data set and claudin-low classifier (Prat et al., BCR, 2010) [courtesy of J. Theilhaber and D. Bergstrom, Sanofi]

6 BLBC/TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast Cancers Characteristics ti Hereditary BRCA1 Basal-like/Triple- negative 1,2,3 ER/PR/HER2 status Negative Negative TP53 status Mutant Mutant BRCA1 status Gene-expression pattern Tumor histology Chemosensitivity to DNA-damaging agents Mutational inactivation* Basal-like Poorly differentiated (high grade) Highly sensitive Diminished expression* Basal-like Poorly differentiated (high grade) Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4 4 1 Perou et al. Nature. 2000; 406: Cleator et al.lancet Oncol 2007;8: Sorlie et al. Proc Natl Acad Sci U S A 2001;98: Miyoshi et al. Int J Clin Oncol 2008;13:

7 Timing of Recurrence in Triple Negative Disease vs. Other Phenotypes Dent et al. Clin Can Res 2007; 13: 4429

8 DFS and OS After Adjuvant AC-Taxane Therapy: Results by Breast Cancer Subtype in All Treatment Arms in Trial E1199 Sparano et al. NEJM year DFS 5 year OS HR-Pos, HER2-Neg 83% 91% Triple Negative 69% 77% HER2-Positive * 78% 86% * No adjuvant trastuzumab 8

9 J Clin Oncol 2009; 27:

10 Treatment No. TNBC Non- TNBC Single agent taxane % 2% FAC/FAC/AC % 5% T-FAC/T-FEC % 17% 10

11 DNA Damage/Repair 11

12 BRCA1-Deficient Cells are Hypersensitive to Cisplatin BRCA1 deficient cells have defect in DNA DS repair BRCA1 deficient cells were more sensitive to cisplatin compared to other cell lines BRCA1 loss increases sensitivity to DNA damaging agents like cisplatin HCC1937, BRCA-deficient cell line MCF-7, 7hormone-sensitive MDA-MB230, hormone-insensitive Tassone P et al. Br J Cancer 2003; 88:

13 pcr Rates after Single Agent Cytotoxic Neoadjuvant Therapy in Triple Negative Disease Reference Agent No. PCR Garber et al. Cisplatin 75 mg/m (22%) JCO 2009 q 3 wks x 4 Martin ASCO 2010 Doxorubicin 75 mg/m2 q 3wks x 4 Docetaxel 100 mg/m2 q 3 wks x (10%) 28 8 (27%) 13

14 pcr in BRCA1-Associated Breast Cancer Receiving i Neoadjuvant Chemotherapy J Clin Oncol. 2010; 28: Epub 2009 Dec 14. Registry of 6,903 patients 102 BRCA1 founder mutation and received neoadjuvant chemotherapy 24 (24%) has a pcr CMF: 1 of 14 (7%) AT (docetaxel): 2 of 25 (8%) AC of FAC: 11 of 51 (22%) Cisplatin: 10 of 12 (83%) 14

15 N Eng J Med 2009; 3060:

16 J Clin Oncol 1997; 15:

17 J Clin Oncol 1997; 15:

18 J Clin Oncol 1999; 17:

19 J Clin Oncol 1999; 17:

20 ASCO 2009, abstract

21 21

22 22

23 tango Treatment Schema E C T vs. E C G T Epirubicin i 90mg/m 2 Paclitaxel l 175mg/m 2 d1 Cyclophosphamide 600mg/m 2 Gemcitabine 1250mg/m 2 d1&8 Q 21/7 Q 21/7, P-then-G seq admin d1

24 Disease-Free Survival (DFS) No significant difference between treatments HR=1.0 (95% CI )

25 J Clin Oncol 2010; 328:

26 Other Adjuvant Strategies in TNBC BEATRICE (N=2581) Adjuvant chemotherapy +/- bevacizumab TITAN (N=1800) AC plus weekly paclitaxel x 12 vs. ixabepilone x 4 PACS08 (N=2500) FEC100 x 3 + docetaxel x 3 vs. ixabepilone x 3 26

27 Biological Agents +/- Taxanes or DNA Damaging Agents 27

28 E2100: Weekly paclitaxel alone or plus bevacizumab as first-line therapy for metastatic breast cancer outcomes by ER/PR expression PFS by Treatment ER Negative, PgR Negative ER/PR Negative PFS Probability PB P P+B P All 17% 34% P < Medians: 4.7, 8.6 Measurable 17% 41% (79%) PFS Probability ER and/or PR Positive Months P P+B PFS by Treatment ER Positive, PgR Positive PB P P < Medians: 7, 14.1 All 23% 37% Measurable (46%) 30% 51% Months 28

29 BALI-1 Trial Schema Eligibility (N = 173) Metatstatic triple- negative breast cancer (mtnbc) R 2:1 1 prior chemotherapy for metastatic disease allowed Cetuximab/cisplatin (n = 115) Cetuximab 400 mg/m 2 initial 250 mg/m 2 weekly Cisplatin 75 mg/m 2 d1 q3wk up to 6 cycles Cisplatin (n = 58)* Cisplatin 75 mg/m 2 d1 q3wk up to 6 cycles * Crossover allowed: 31 patients receiving cisplatin alone switched to cetuximab/ cisplatin after first disease progression. Baselga J et al. Proc SABCS 2010;Abstract PD01-01.

30 Response Rates Best Response Cetuximab + Cisplatin (n = 115) Cisplatin Alone (n = 58) Overall response (ORR)* 20.0% 10.3% Complete response (CR) Partial response (PR) 1.7% 18.3% 1.7% 8.6% Stable disease 41.7% 31.0% Progressive disease 29.6% 53.4% Odds ratio (95% CI) 2.13 ( ) 59) p-value 0.11 *ORR > 20% was a prespecified criterion to demonstrate superiority of cetuximab + cisplatin over cisplatin alone. Baselga J et al. Proc SABCS 2010;Abstract PD01-01.

31 Progression-Free Survival (PFS) ree survival Prob ability of pr rogression-f Cetuximab + cisplatin Cisplatin Cetuximab + cisplatin Cisplatin n = 115 n = 58 Number of Events Median PFS, months [95% CI] [ ] 43] [ ] 28] HR [95% CI] p-value 0.67 [ ] Months With permission from Baselga J et al. Proc SABCS 2010;Abstract PD01-01.

32 Overall Survival (OS) urvival of overall s Probability 1.0 Cetuximab cisplatin Cisplatin n = 115 n = Number of Events Median OS, months [95% CI] [ ] 6] [ ] HR [95% CI] p-value 0.82 [ ] Cetuximab + cisplatin Cisplatin Months With permission from Baselga J et al. Proc SABCS 2010;Abstract PD01-01.

33 PARP Inhibitors 33

34 History of Poly(ADP-ribose) Polymerase (PARP) as a Therapeutic Target Discovery of PARP 1963: Nuclear enzymatic activity that synthesizes an adenine containing RNA- like polymer (Chambon et al) : Confirmed by others, polymer identified as PARP (Nishizuka et al) Discovery of PARP Function 1979: PARP activated t by DNA strand breaks (Juarez-Salinas et al) 1980: PARP participates in DNA repair (Durkacz et al) 1986: PARP1 hyperactivation lead to NAD+ and ATP depletion after DNA damage, promoting metabolic cell death (parthanosis) (David et al) 2000: PARP knockouts confirm role in DNA repair (Shail et al) Discovery of PARP Inhibitors 1980: PARP inhibitors enhance alkylators (Durkacz et al) 2005: PARP inhibitors toxic to BRCA deficient cells (Bryant et al, Farmer et al) 2009: Clinical trials demonstrating PARPi activity in BRCA-deficient breast cancer and in combination with DNA damaging agents in sporadic TNBC (Tutt et al, O Shaugnessy et al) 34

35 Poly (ADP-ribose) Polymerase (PARP) DNA binding domain Automodification domain Catalytic Domain PARP homology domain PARP-1 Nuclear protein 3 functional domains Amino terminal: DNA binding Automodification: autoribosylation (protein-protein interactions) C-terminal: catalytic domain transfer ADP-ribose from NAD+ to protein acceptors, forming padpr (2x higher charge density than DNA) DNA damage PARPs recruited to altered DNA, catalytic activity up to 500-fold padpr localization to DNA and recruitment of proteins (eg, XRCC1) which assemble and activate DNA base excision repair NAD+ and ATP depletion contribute to cell death

36 DNA Damage Repair Pathways Single Singlestrand strand breaks breaks Double Doublestrand strand breaks breaks Type of damage: Bulky adducts O6- alkylguanine breaks breaks (SSBs) (SSBs) (DSBs) (DSBs) Insertions & deletions Base Base excision excision repair repair Recombination Recombination repair repair Repair pathway: Nucleotide- Mismatch repair Direct PARP PARP HR HR NHEJ NHEJ excision repair reversal PARP PARP ATM ATM BRCA BRCA DNA DNA-PK PK Repair enzymes: XP, polymerases MSH2, MLH1 AGT

37 37

38 PARP-1 Inhibition Increases DNA DS Damage DNA SSB pol β PNK 1 PARP XRCC1 Replication (S-phase) LigIII Inhibition of PARP-1 prevents recruitment of repair factors to repair SSB DNA DSB

39 PARP Inhibitors: Mechanisms of Action Synthetic ti lethality lit BRCA1/2 loss or other HR proteins (eg, RAD51) PTEN loss Inhibit repair of DNA damage DNA damaging agents (eg, alkylators/platinum) Topoisomerase I inhibitors Transcriptional regulation 39

40 Synthetic Lethality: Selective effect of PARP-1 inhibition on cancer cells with BRCA1 or BRCA2 mutation DNA Damage Base Excision Repair PARP Inhibitor Homologous Recombination BRCA Mutation Cell survival Cancer cell death

41 BRCA-Deficient Cells are Hypersensitive to PARP Inhibition 41 Bryant HE et al. Nature 2005;434:913-7

42 42

43 PARP Inhibitors H 2 N O R1 O NH N Olaparib R2 Benzamide Inhibitors 3-AB, PD N N Abbott ABT-888 (Veliparib) O H N NH 2 O H N O F N N H H H Pfizer AG BSI-201 (Iniparib) N Cephalon CEP-6800

44 Biomarkers of PARP Inhibitor Effects Poly ADP ribose PAR Indirect measure of PARP inhibition ELISA - PBMC Gamma H2AX Reflective of DNA DS breaks FLT-PET (3 -[F-18]Fluoro-3 deoxythmidine) Cellular l uptake of FLT regulated by cytosolic thymidine kinase I Key enzyme in pyrimidine salvage pathway of DNA replicaiton FLT update dependent on cell proliferation 44

45 45

46 Phase II Study of BSI Plus Chemotherapy in TNBC: Efficacy Data Efficacy Response BSI gem/carbo (n=42) Gem/carbo (n=44) p value ORR 20(48%) 6 (22%) 0.02 CBR 26 (62%) 9 (21%) Survival n=57 n=59 mpfs mos 6.9 months 3.3 months < months 5.7 months CBR: clinical benefit rate (CR+PR+SD) O Shaughnessy et al., NEJM,

47 Iniparib* (BSI-201) A novel, investigational, anti-cancer agent In triple negative breast cancer cell lines 1-4 : Induces cell cycle arrest in the G2/M phase Induces double strand DNA damage H2AX foci but does not inhibit PARP 1 and 2 at physiologic drug concentrations Potentiates cell-cycle arrest induced by DNA damaging agents, including platinum and gemcitabine Physiologic targets of iniparib and its metabolites are under investigation Clinical Data: In a randomized phase 2 study, addition of iniparib to gemcitabine/carboplatin improved CBR, ORR, PFS and OS in patients with mtnbc 5 No potentiation of chemotherapy-related toxicities when iniparib is combined with gemcitabine/carboplatin *Iniparib is the United States Adopted Name (USAN) for the investigational agent BSI Ossovskaya V, et al. SABCS 2010, San Antonio, TX. Poster P ; 2. Ossovskaya V, et al. AACR 2009, Denver, CO. Abstract 5552; 3. Ossovskaya V, et al. AACR 2011, Orlando, FL. Abstract LB-401; 4. Ji et al. AACR 2011, Orlando, FL. Abstract 4527; 5. O Shaughnessy J, et al. N Engl J Med 2011; 364:

48 Schema Study Design: Multi-center, randomized open-label Phase III Trial N = 519 Study Population: Stage IV TNBC ECOG PS 0 1 Stable CNS metastases allowed 0-2 prior chemotherapies for mtnbc R Gem/Carbo (GC) (N= 258) Gemcitabine 1000 mg/m 2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8 21-day cycles Crossover allowed to GCI following Disease Progression* (central review) Randomization stratified by prior chemo in the metastatic setting: 1 st -line (no prior therapy) 2 nd /3 rd -line (1-2 prior therapies) Gem/Carbo + Iniparib (GCI) (N= 261) Gemcitabine mg/m2 IV d 1, 8 Carboplatin - AUC2 IV d 1, 8 Iniparib mg/kg IV d 1,4,8,11 21-day cycles *Prospective central radiology review of progression required prior to crossover 96% (n=152) of progressing patients crossed over to GCI at time of primary analysis NCT

49 Efficacy Endpoints ITT population PFS Median PFS, mos (95% CI) GC (N=258) 4.1 (3.1, 4.6) GCI (N=261) 5.1 (4.2, 5.8) HR (95% CI) 0.79 (0.65, 0.98) p-value Pre-specified alpha = OS GC (N=258) GCI (N=261) Median OS, mos (95% CI) HR (95% CI) (9.2, 12.1) (10.6, 12.9) 088( (0.69, 112) 1.12) p-value 0.28 Pre-specified alpha = 0.04 urvival Probability of Pro ogression Free S ity of Survival Probabili Months Since Study Entry No. at risk GC GCI Months No. at risk GC GCI

50 Overall Response Rate* ITT Population GC GCI Response, n (%) N = 258 N = 261 Complete response 4 (1.6) 5 (1.9) Partial response 74(29) 83 (32) Stable disease 89 (35) 99 (38) Progressive disease 62 (24) 62 (24) Inevaluable 29 (11) 12 (4.6) SD > 6 months 14 (5.4) 19 (7.3) ORR, n (%) 78 (30) 88 (34) (95% CI) (25 36%) (28 40%) Clinical Benefit Rate, n (%) [CR +PR +SD(> 6 mos)] 92 (36) 107 (41) * Independent central review, RECIST confirmation of response 50

51 Exploratory Analysis 1 st -line ITT Population 1 st -line = 57% of patients (297/519) PFS OS Pr robability of Pro ogression Free Su urvival GCI 5.6 mos (4.2, 6.9) GC 4.6 mos (3.9, 5.7) HR=0.88 (0.66, 1.13); 197 events al Probabi ility of Surviv GCI 12.4 mos (10.6, NE) GC 12.6 mos (11.9, NE) HR=1.1 (0.78, 1.56); 129 events No. at risk Months GC GCI Months

52 Exploratory Analysis 2 nd /3 rd -line ITT Population 2 nd / 3 rd -line = 43% patients (222/519) PFS OS Pro obability of Prog gression Free Sur rvival GCI 4.2 mos (3.8, 5.7) GC 2.9 mos (1.9, 4.1 ) HR=0.67 (0.5, 0.92); 169 events ity of Survival Probabili GCI 10.8 mos (9.7,13.1) GC 8.1 mos (6.6, 10) HR=0.65 (0.46, 0.91); 132 events No. at risk Months GC GCI Months

53 Multivariate Analysis - OS Evaluate impact of imbalances in specific baseline characteristics on OS per multivariate analyses as specified in the statistical analysis plan (SAP) Analyses based on : 1. Pre-specified baseline factors: age, disease burden, ECOG PS, line of therapy, race, time since diagnosis of mtnbc, visceral disease, and elevated alkaline phosphatase 2. Pre-specified baseline factors above - but replace time since diagnosis of mtnbc with Disease Free Interval from primary BC surgery to onset of metastatic disease Treatment Estimates for OS determined using Multivariate Cox Model ITT Population 1 st -line 2 nd /3 rd -line HR p HR p HR p Unadjusted Using pre-specified baseline factors Using pre-specified baseline factors with DFI replacement * * * * * * * p-value is Wald Chi-Square test

54 Other Strategies 54

55 VM Richon et al. Can Lett 2009

56 Palmieri et al. Clin Cancer Res 2009;15(19): ) 56

57 Effect of HDAC Inhibitor Vorinostat in Human Breast Cancer in Vivo Ramaswamy et al. Submitted 57

58 P7703: Vorinostat Induces Hyperacetylation In Vivo 58

59 Relationship Between GRB7 Expression and Recurrence in TNBC Sparano et al. Clin Cancer Res patients t with TNBC (central IHC) and 0-3 pos axillary nodes in E2197 Treated with adjuvant doxorubicin/cyclophosphamide or dox/docetaxel GRB7 5 year Recurrence Rate 95% C.I. rd Ratio 2 1 Low 10.5% 7.8%, 14.1% Log Haza -1 0 High 20.4% 16.5%, 25.0% GRB7-2 59

60 Results: Estimated Hazard Ratios and 95% C.I. from Joint Models for Recurrence Rates in TNBC Model I Model II Age 45 vs. > (0.17,1.42) 0.49 (0.17,1.46) Age vs. > (0.25,1.84) 0.63 (0.22,1.78) Nodes 1 vs (1.17,3.57) 2.27 (1.32,3.92) Nodes 2-3 vs (0.65,3.83) 1.96(0.86,4.47) 47) Grade Poor vs. Mod/Well 1.62 (0.53,4.95) 1.43 (0.51,3.98) Tumor size >2 vs. 2 cm 1.97 (1.10,3.55) 1.95 (1.09,3.47) GRB7 x+2 vs. x 3.41 (1.78,6.53) p= GRB7 High vs. Low 2.31 (130411) (1.30,4.11) p=

61 Grb7 Adapter Protein Member of a family of adapter proteins no enzymatic activity calmodulin-binding protein with an SH2 (Src homology 2) domain that binds to phosphorylated RTKs and other protein targets role in signaling (EGFR, HER2), motility (ephrins), migration (focal adhesion kinase), and cell-matrix/cell-cell interactions (integrins) Share region with sequence homology to the Mig-10 C. elegans gene required for migration of neuronal cells in embryonic development suggests role for Grb7 in cell migration Grb7 present in focal adhesions bound and phosphorylated by focal adhesion kinase (FAK) critical for cell migration Grb7 also found in the cytoplasm interacts with other upstream binding partners, including ErbB2 role in regulation of cell proliferation Oncogene 2001; 20: 6315 BMC Structural Biol 2007; 7: 58 61

62 GRB7 Peptide Inhibitor Inhibits cell migration and proliferation of cell lines with varying Her2 expression (SK-BR-3, MDA-MB-361, MDA-MB-231, ZR75-30) Enhances effects of doxorubicin and trastuzumab in the HER2- pos cell line (SK-BR-3) Effective in pancreatic xenograft model Porter et al. BMC Structural Biology 2007; 7: 58; Tanaka et al. JNCI 2006; 98: 491; Pero et al. Br J Cancer 2007; 96:

63 Effect of GRB7 Inhibitor (G7-18NATE) on Basal Cell Lines Kenny et al. BCRT 2011 MDA- MB-468 MDA- MB-468 Invasion Transwell Matrigel Assay Motility Monoloyer Wound Healing Assay Kenny et al. AACR

64 Effect of GRB7 Inhibitor (G7-18NATE) on Basal Cell Lines Proliferation 3D Culture MDA- MB-468 Kenny et al. CCR 2011

65 Significantly Higher RNA Expression in TNBC vs. HR+, HER2- Disease (Top 10%) Sparano et al. Clin Can Res 2011 Cell cycle/proliferation/mitosis Markers: (eg, BUB1, MKI67) Targets (eg, AURKB, PLK1, KIFC1) DNA repair (CHEK1, RAD45L, TOP2A) Transcriptional regulation (FOXM1, MYBL2, PTTG1) Invasion (CTSL2, MMP12) Motility y( (KIFC2) Hypoxia (CA9) Signaling (DEPDC1) Ubiquitin-mediated protein catabolism (CDC20) Cox proportional hazards model score tests; methods of Korn used to control false discovery rates (J Stat Planning Inference, 124: , 2004) 65

66 E2197 Results: Differentially Expressed Genes That are Potential Therapeutic Targets Gene Function Drugs AURKB Binds microtubule K fibers AZD1152, VX , near kinetichores AT9283 PLK1 Regulates G2/M transition BI6727, ON01910 KIFC1 Microtubule motor activity ARRY-250, ispinesib, SB CHK1 Regulates G2/M checkpoint AZD7762, PF FOXM1 G1 S and G2 M cell cycle Siomycin A phase progression; mitotic spindle integrity it 66

67 Conclusions: Management of TNBC and Emerging Therapies Anthracyclines, alkylators, taxanes play important role Aklylators l dose escalation not effective Gemcitabine no role as adjuvant therapy Capecitabine no role for adjuvant monotherapy Biological agents bevacizumab, EGFR inhibitors PARP inhibitors role remains to be defined Predictive markers? What level and/or duration of PARP inhibition is sufficient? PARPi plus other non-cytotoxic and/or cytotoxic agents? Other potential therapeutic targets HDAC inhibitors Others 67

Pathways Underlying Aggressive Breast Cancers

Origin of Breast Cancer Subtypes Pathways Underlying Aggressive Breast Cancers HER2 and ER can be expressed in any subtype. Triple Negative -- a mixture of subtypes Joyce O Shaughnessy, MD Baylor Sammons