Pathways Underlying Aggressive Breast Cancers

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Origin of Breast Cancer Subtypes Pathways Underlying Aggressive Breast Cancers

Triple Negative -- a mixture of subtypes Joyce O Shaughnessy, MD Baylor

15:842, 29 Triple Negative Breast Cancer is Biologically Heterogeneous Prat

1 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 Cancer Center Texas Oncology US Oncology Pratt and Perou, Nature Med 15:842, 29 Triple Negative Breast Cancer is Biologically Heterogeneous Prat and Perou, Mol Oncol211 Prognostic Impact of Residual Disease Differs by Subtype Liedtke, C, et al J Clin Oncol 26:1275, 28 1

Meta-analysis of First-line Bevacizumab Plus Chemotherapy in Triple-negative Breast Cancer: Efficacy Bevacizumab + chemo (n = 363) Chemo alone (n = 258) HR (95% CI) This meta-analysis represents the

improved PFS? P value Median PFS (mo) 8.1 5.4.649 (.538-.783) <.1 ORR (%) 42 23 NR <.1 Median (mo) 18.9 17.5.959 (.79-1.164).6732 1-yr rate 71 65 NR.114 O Shaughnessy et al.

2 Meta-analysis of First-line Bevacizumab Plus Chemotherapy in Triple-negative Breast Cancer: Efficacy Bevacizumab + chemo (n = 363) Chemo alone (n = 258) HR (95% CI) This meta-analysis represents the largest reported population of patients randomized to treatment for metastatic TNBC The addition of bevacizumab significantly improved PFS, but not Do tumor-related symptoms improve with ORR and improved PFS? P value Median PFS (mo) ( ) <.1 ORR (%) NR <.1 Median (mo) ( ) yr rate NR.114 O Shaughnessy et al. SABCS 21; abstract P Capecitabine ± Ixabepilone in Triple Negative MBC Rugo et al. SABCS 28, Abstract 357 Pooled triple negative subgroup (n = 443) Efficacy Ixa + Cape (n = 191) Cape (n = 28) ORR 31% 15% CR 3% 1% PR 28% 14% Median PFS 4.2 mos 1.7 mos HR.63 P value <.1 Median 1.3 mos (n = 213) HR.87 P value mos (n = 23) EMBRACE: Overall survival subsets Overall results (N=762) Hazard ratio (95% CI) Phase II Polymer-Conjugated Irinotecan in A/T-pretreated MBC Receptor status No. of organs involved Sites of disease ER/PR + (n=528) ER/PR - (n=187) HER2 + (n=123) HER2 - (n=565) ER/PR/HER2 - (n=144) 2 (n=537) >2 (n=217) Visceral (n=624) Non-visceral (n=13) Favors ERIBULIN Favors TPC ITT population; Twelves, CJ, SABCS, 21, abst P Based upon a stratified Cox analysis including geographic region, HER-2/neu status, and prior capecitabine therapy as strata Awada, A, et al Proc SABCS, 21, P Normal Breast Luminal A Claudin-low Luminal B Basal-like HER2-enriched Mechanisms of DNA Double Strand Break Repair TNBC Molecular Targets? 2% TNBC BRCA1/2 mutations Gonzales-Angulo, A. ASCO Breast, 21, abst 16 Cells with BRCA mutations are deficient in homologous recombination and lack the ability to efficiently repair DSBs. Sehl, ME, et al. Clin Cancer Res 15:2192, 29 2

3 Iniparib* (BSI-21) 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 γ 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 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 21, San Antonio, TX. Poster P5-6-9; 2. Ossovskaya V, et al. AACR 29, Denver, CO. Abstract 5552; 3. Ossovskaya V, et al. AACR 211, Orlando, FL. Abstract LB-41; 4. Ji et al. AACR 211, Orlando, FL. Abstract 4527; 5. O Shaughnessy J, et al. N Engl J Med 211; 364: Schema Study Design: Multi-center, randomized open-label Phase III Trial Study Population: Stage IV TNBC ECOG PS 1 Stable CNS metastases allowed -2 prior chemotherapies for mtnbc Randomization stratified by prior chemo in the metastatic setting: 1 st -line (no prior therapy) 2 nd /3 rd -line (1-2 prior therapies) N = 519 R Gem/Carbo (GC) (N= 258) Gemcitabine 1 mg/m 2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8 21-day cycles Gem/Carbo + Iniparib (GCI) (N= 261) Gemcitabine - 1 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 Crossover allowed to GCI following Disease Progression* (central review) 96% (n=152) of progressing patients crossed over to GCI at time of primary analysis NCT Probability of Progression Free Survival Efficacy Endpoints ITT population GC PFS (N=258) Median PFS, mos 4.1 (95% CI) (3.1, 4.6) GCI (N=261) 5.1 (4.2, 5.8) 1. HR (95% CI) p-value.79 (.65,.98).27.9 Pre-specified alpha = Since Study Entry GC GCI Probability of Survival Median, mos (95% CI) GC GCI (N=258) (N=261) (9.2, 12.1) (1.6, 12.9) HR (95% CI).88 (.69, 1.12) p-value 8 Pre-specified alpha = GC GCI O Shaughnessy et al. ASCO 211 abstr. 17 Probability of Progression Free Survival Exploratory Analysis 1 st -line ITT Population 1 st -line = 57% of patients (297/519) PFS 1. GCI 5.6 mos (4.2, 6.9).9 GC 4.6 mos (3.9, 5.7) HR=.88 (.66, 1.13); 197 events GC GCI Probability of Survival 1. GCI 12.4 mos (1.6, NE).9 GC 12.6 mos (11.9, NE) HR=1.1 (.78, 1.56); 129 events O Shaughnessy et al. ASCO 211 abstr Probability of Progression Free Survival Exploratory Analysis 2 nd /3 rd -line ITT Population 2 nd / 3 rd -line = 43% patients (222/519) PFS 1. GCI 4.2 mos (3.8, 5.7).9 GC 2.9 mos (1.9, 4.1 ) HR=.67 (.5,.92); 169 events GC GCI O Shaughnessy et al. ASCO 211 abstr. 17 Probability of Survival 1. GCI 1.8 mos (9.7,13.1).9 GC 8.1 mos (6.6, 1) HR=.65 (.46,.91); 132 events TNBC comprised of diverse molecular subtypes Relative 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, 23 data set and claudin-low classifier (Prat et al., BCR, 21) [courtesy of J. Theilhaber and D. Bergstrom, Sanofi] Preliminary* 3

Subtypes of TNBC Pathway Activation in TNBC Subtypes Lehmann, BD, et al Lehmann, BD, et al.

SABCS, 29; 11 Rodriguez A, et al. SABCS, 29; 11 Mendes-Pereira.

SABCS, 2:13, 21 29 DNA SS and DS Repair Pathways ATM Kinase Cell Cycle Checkpoint Control and DNA Damage

protein expression evaluated in 113 BRCA1/2 WT breast cancers 2% TNBC ATM deficient Chk-2/ATM deficiency

4 Subtypes of TNBC Pathway Activation in TNBC Subtypes Lehmann, BD, et al Lehmann, BD, et al.sabcs, 21 Pathways in TNBC Subtypes Rodriguez A and Chang J, et al. SABCS, 29 Rodriguez A, et al. SABCS, 29; 11 Rodriguez A, et al. SABCS, 29; 11 Mendes-Pereira. EMBO Mol Med 1:315, 29 Rodriguez Sourisseau A and T. Chang EMBO J, Mol et Med al. SABCS, 2:13, DNA SS and DS Repair Pathways ATM Kinase Cell Cycle Checkpoint Control and DNA Damage ATM heterozygous breast cancers increased sensitivity to radiation and increased late fibrosis ATM kinase protein expression evaluated in 113 BRCA1/2 WT breast cancers 2% TNBC ATM deficient Chk-2/ATM deficiency enhances sensitivity camptothecins in CRC 73% of 47 primary TNBCs pchk-2 deficient on TMA Plummer R. Clin Ca Res 16: 4527, 21 Tommiska J. Oncogene 27:251, 28 Sakasai R. J Biol Chem 285:1521, 21 4

Survival in Early Breast Cancer MMR-deficiency and breast cancer MMR-deficient Breast Cancer High grade/ki-67, more LN-, confluent necrosis; peritumor lymphocytes, less LVI, 6% TN, all HER2-

CRC: TGFbR2, Walsh, MD. Clin Cancer Res 16:2214, 21 Vilar E. Clin Cancer Res 15:2829, 29 IGF2R, PTEN, RAD5, ATR, p53 15% CRC MMR-deficient and are Martin, SA. 1158/178-432.

J Clin Oncol 18:87-93, 2 Alexander, BM, et al Clin Cancer Res 16:5796, 21 DNA Damage Response in TNBC Subtypes Loss of HR capacity (BRCA/ATM pathways) with dependence on DNA-PK & Base Excision Repair

5 Survival in Early Breast Cancer MMR-deficiency and breast cancer MMR-deficient Breast Cancer High grade/ki-67, more LN-, confluent necrosis; peritumor lymphocytes, less LVI, 6% TN, all HER2- CRC:Resistant to 5-FU, cis/carboplatin CRC:Sensitive to oxaliplatin, camptothecins, etoposide Jiang H, Genes & Development 23:1895, 29 MSH2 mutation synthetic lethal with methotrexate Other mutations CRC: TGFbR2, Walsh, MD. Clin Cancer Res 16:2214, 21 Vilar E. Clin Cancer Res 15:2829, 29 IGF2R, PTEN, RAD5, ATR, p53 15% CRC MMR-deficient and are Martin, SA. 1158/ CCR sensitive to PI3K pathway inhibitors MLH1 expression predicts prognosis following preop chemotherapy in LABC DNA Repair Proteins Associated with Time to Recurrence in TNBC Mackay H, et al. J Clin Oncol 18:87-93, 2 Alexander, BM, et al Clin Cancer Res 16:5796, 21 DNA Damage Response in TNBC Subtypes Loss of HR capacity (BRCA/ATM pathways) with dependence on DNA-PK & Base Excision Repair highly unstable genomes; very highly proliferative high sensitivity to DNA-damaging cytotoxic agents and PARP inhibitors? iniparib? higher pcr rates Mesenchymal TNBC - strong survival pathways Resistant to DNA-damaging agents Luminal B, claudin low? Targets? Randomized Phase II Irinotecan/Carboplatin + Cetuximab (anti-egfr MAb) Stage IV breast cancer, unselected population: Arm 1 Irinotecan+carbo. PD cetuximab Randomized Phase II Arm 2 Irinotecan+Carboplatin +cetuximab IC IC+E All subjects 21/69 (31%) 26/69 (38%) Triple Negative 1/33 (3%) 19/39 (49%) ER+ 1/35 (29%) 7/28 (25%) IC IC+E O Shaughnessy J et al, SABCS 7 5

$SABCS 29 Metastatic TNBC Durable Response with Cetuximab 34 yo woman third trimester pregnancy with left breast mass, infraclavicular adenopathy and lung metastases, grade 3 TNBC No response to preop$ AC Post-partum CR breast, nodes, lung with ICb + E lumpectomy and radiation + continued E 2 years later resection of solitary recurrent lung metastasis -- very low expression PTEN 6 cycles ICb + E

AC Post-partum CR breast, nodes, lung with ICb + E lumpectomy and radiation + continued E 2 years later resection of solitary recurrent lung metastasis -- very low expression PTEN 6 cycles ICb + E

5+ yrs DAT clinical activity: MpBC Metaplastic MBC generally chemotherapyresistant >5% PI3K mutations or PTEN loss DAT: Pegylated liposomal doxorubicin, bevacizumab, temsirolimus Response in 1

6 MAPK and PI3K Pathways In Basal Breast Cancer EGFR Pathway Cetuximab Benefit in TNBC: PTEN+ and CRYAB-low PTEN-positive + CRYAB-Low Profile Chemotherapy PTEN IHC & CRYAB qpcr : ICb Chemotherapy + Cetuximab PTEN IHC & CRYAB qpcr: ICb+C n HR 95% CI p PTEN-pos & CRYAB-low other 1 1 ref n HR 95% CI p PTEN-pos & CRYAB-low other 17 1 ref MEK/ERK Growth, migration, apoptosis, differentiation, adhesion Only 8% mtnbc are both PTEN+ and CRYAB-low Carey, L and O Shaughnessy, J, et al. SABCS 29 Metastatic TNBC Durable Response with Cetuximab 34 yo woman third trimester pregnancy with left breast mass, infraclavicular adenopathy and lung metastases, grade 3 TNBC No response to preop AC Post-partum CR breast, nodes, lung with ICb + E lumpectomy and radiation + continued E 2 years later resection of solitary recurrent lung metastasis -- very low expression PTEN 6 cycles ICb + E and continues E for 2.5+ yrs DAT clinical activity: MpBC Metaplastic MBC generally chemotherapyresistant >5% PI3K mutations or PTEN loss DAT: Pegylated liposomal doxorubicin, bevacizumab, temsirolimus Response in 1 evaluable patients: 3% Complete Response (CR)=1 Partial Response (PR)=2 Sarcomatoid MpBC predominant responders SD> 6 months (1), CR (1), PR (2): 4% Moulder, S. AACR, 211 and J Clin Oncol 29:e572-5, 211 Complete Response in MpBC Partial Response in MpBC Baseline 2 nd cycle Baseline PI3K/PTEN Mutation status: None detected 8 cycles + Temsirolimus x 1year Moulder, S. AACR, 211 and J Clin Oncol 29:e572-5, of 9 pts had PI3K mutation or PTEN deletion PI3K/PTEN Mutation status: Not done Moulder, S. J Clin Oncol 29:e572-5, 211 6

USON # 9133 TGEN Drug Development Services Life Technologies Triple Negative Breast Cancer Sequencing Study Next Generation Whole Genome Sequencing Identifying and Targeting Driving Mutations in

7 USON # 9133 TGEN Drug Development Services Life Technologies Triple Negative Breast Cancer Sequencing Study Next Generation Whole Genome Sequencing Identifying and Targeting Driving Mutations in mtnbc Primary Objective: Treat patients with targeted agents identified on DNA and RNA sequencing tumor and normal tissue Conclusions Both lineage and specific mutation drivers of the TNBC subtypes Basal, mesenchymal (claudin low or luminal B?), apocrine MMR-deficient breast cancers --?role of irinotecan, methotrexate, oxaliplatin BRCA or ATM/ATR-deficient breast cancers may benefit from PARP inhibitors and DSB-inducing cytotoxic agents MAPK pathway and PI3K pathway amplicons/deletions worthy of dual targeting trials FOXM1 and AURKA highly active in TNBC targets? 7

ENFERMEDAD AVANZADA Qué hacemos con el triple negativo? Nuevas aproximaciones

ENFERMEDAD AVANZADA Qué hacemos con el triple negativo? Nuevas aproximaciones Javier Cortes, Hospital Universitario Ramon y Cajal, Madrid Vall d Hebron Institute of Oncology (VHIO), Barcelona Triple Negative