Adjuvant Systemic Therapy In Early Brest Cancer

Transcription

1 Ductal Carcinoma In-situ and Early Breast Cancer Symposium With International Contributions Adjuvant Systemic Therapy In Early Brest Cancer Vicente Valero, M.D., F.A.C.P. Professor of Medicine and Deputy Chairman Department of Breast Medical Oncology U. T. MD Anderson Cancer Center Houston, Texas

2 Factors Influencing Selection of Systemic Therapy for Primary Breast Cancer Risk of recurrence Or death Benefit from treatment Optimal Treatment selection Comorbidities Toxicities Tumor characteristics: ER, PR, HER-2, Ki-67

3 Assessment of Risk of Recurrence and Treatment Benefit

4 Historical Evolution of Biomarkers for Breast Cancer Histopathology Tumor size Lymph node involvement Grade Tumor type Lymphovascular invasion Single Molecular Markers Estrogen receptor Progesterone receptor (?) HER-2 Ki-67 Prognostic Indices Nottingham Prognostic Index Adjuvant! Composite expert opinion upa/pai-1 High throughput methods Gene Expression Microarrays: MammaPrint VDX2 array Oncotype DX 97-gene genomic grade index Intrinsic subtypes Predictive Indices: HOXB13:IL17RB 200-gene ER reporter index 97-gene genomic grade index Multigene predictors of docetaxel, paclitaxel, AC, EC, paclitaxel-fac

5 Benefits from Adjuvant Systemic Therapy It is estimated that Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70% Optimal chemotherapy would reduce annual odds of recurrence by about 50%-60% Trastuzumab would reduce annual odds of recurrence by 45%-55%

6 Do all patients with breast cancer benefit equally from current treatments?

7 Signature Molecular Signatures in Primary Breast Cancer Biological hypothesis Technique No. of genes Independent validation Prospective clinical validation Amsterdam (Mammaprint ) Clinical evolution Agilent (oligonucleotide) 70 Yes Yes (MINDACT) Recurrence Score (Oncotype Dx ) Clinical evolution RT-PCR 21 Yes Yes (TailoRX, RxPonder) Rotterdam (Affymetrix ) Clinical evolution Affymetrix (oligonucleotide) 76 Yes No Wound healing Wound healing and tumor progression cdna 512 Yes No Genomic grade (MapQuant Dx ) Histologic grade and tumor progression Affymetrix (oligonucleotide) 97 Yes No p53 p53 function Affymetrix (oligonucleotide) 32 Yes No Cancer death Self-regeneration og oncogenic pathways Affymetrix (oligonucleotide) 11 Yes No Invasion genes Cancer initiating cells Affymetrix (oligonucleotide) 186 Yes No

8 Management of ER+ and/or PR+/HER2-/Ki-67 low Breast Cancer

9 EBCTCG Tamoxifen Overview Metaanalysis of 21,457 patients from 20 trials of 5 years of tamoxifen vs. not 10,645 had ER+ tumors 13-year median followup for survivors Same effect in ER+/PR+ and ER+/PR- Follow-up in years Reduction in Risk of Recurrence EBCTCG, Lancet 2011

10 Tamoxifen Effects by Age Age in years HR for Recurrence Contralateral Breast Cancer Uterine Cancer < > EBCTCG, Lancet 2011

11 Endocrine Adjuvant Therapy Premenopausal women: Tamoxifen x 5 years Castration or LHRH Agonist x 2-5 years Combination of Tamoxifen + ovarian suppression/ablation Outstanding questions: Does combined endocrine therapy provide greater benefit than single agent therapy? If so, is this true for all patients with ER/PR+ breast cancer? Is it true in combination with chemotherapy? Is ovarian ablation/suppression + an AI better? Can we identify patients in this group who do not benefit from the addition of chemotherapy?

12 Endocrine Adjuvant Therapy Postmenopausal women: Aromatase inhibitor (AI) x 5 years Tamoxifen x 2-3 years followed by an AI x 2-3 years AI followed by tamoxifen is si,ilar to reverse sequence Neither sequence is better than AI x 5 years Outstanding questions: Is there a difference in safety between these approaches in subgroups of patients? Is longer (than 5 years) administration of an AI more effective? Will combinations of endocrine therapy and other targeted therapies overcome endocrine resistance? Can we identify patients in this group who do not benefit from the addition of chemotherapy?

13 Tamoxifen Exemestane Adjuvant Multinational (TEAM) Phase III Trial Postmenopausal women with early, HR+ breast cancer. N=9,779 Exemestane x 5 years vs. Tamoxifen exemestane x 5 years Five-year DFS rates: 86% vs. 85% Van de Velde et al, Lancet, 2011

14 Strategies to Overcome Resistance in HR+ Breast Cancer IGFR-1 HER2-1 Plasma membrane P P P P Estrogen PI3-K P P SOS RAS RAF ER mtor Akt P P MAPK MEK P P Cytoplasm P P P ER P ER p160 CBP Basal transcription machinery Nucleus ERE ER target gene transcription DiCosimo & Baselga. Nature Clin Prac Oncol

15 Chemotherapy for ER+ and/or PR+, HER2- Breast Cancer Sequential administration of chemotherapy followed by endocrine therapy provides optimal benefit for the overall group of patients with ER+ and/or PR+ breast cancer Retrospective analyses suggest that not all patients with ER+ tumors benefit from chemotherapy Patients with strongly ER+/PR+, HER2- and Ki-67-low tumors seem to have marginal or no benefit from chemotherapy Patients with low and intermediate Recurrence Score (defined by the OncotypeDX assay) seem to have marginal or no benefit from chemotherapy

16 Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0 100) Low risk RS < 18 Int risk RS 18 and < 31 High risk RS 31 Paik S, NEJM 351(27):2817, 2004

17 B-20: Tam alone vs. Tam + Chemotherapy in Node Negative ER+ DRFS Years Paik S, et al. JCO. Low risk (RS<18) Intermediate risk (RS = 18-30) P = 0.76 Low risk patients (RS < 18) Tam + Chemo Tam DRFS N Events DRFS High risk (RS 31) P = High Int Risk Patients Risk (RS(RS 31) N Tam + Chemo Tam Years P = 0.71 Int Risk (RS 18-30) Tam + Chemo Tam Years Events N Events

18 Oncotype DX: Prediction of Response to Therapy Based on multiple retrospective analyses: Patients with low and intermediate Recurrence Score (RS) benefit from tamoxifen; those with high RS do not. Patients with high RS benefit from CMF, MF and CAF chemotherapy; those with low RS do not. These retrospective observations appear to apply to lymph node-negative and positive tumors, but are restricted to ER+ tumors

19 TAILORx SCHEMA Pre-REGISTER ONCOTYPE DX ASSAY REGISTER Specimen Banking Secondary Study Group 1 RS < 11 ~29% of Population Primary Study Group RS ~44% of Population Secondary Study Group 2 RS > 25 ~27% of Population ARM A Hormonal Therapy Alone RANDOMIZE Stratification Factors: Tumor Size, Menopausal Status, Planned Chemo, Planned Radiation ARM D Chemotherapy Plus Hormonal Therapy ARM B Hormonal Therapy Alone ARM C Chemotherapy Plus Hormonal Therapy

20 RxPONDER: Schema and Patient Flow Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 8,800) Patients consent to study-sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data (N= 600) RS already Available Physician and patients discuss randomization knowing the RS STEP 1 REGISTRATION Tumor tissue submission for RS STEP 2 RANDOMIZATION (N= 3,800) Discuss alternative trials for high risk patients RECURRENCE SCORE RS > 25 RS < 25 N= 5,600 Physician and patients discuss randomization knowing the RS Refuse Accept STEP 2 REGISTRATION/ RANDOMIZATION N= 4,000 Randomization stratified by 1. RS 0-13 vs Menopausal status 3. Axillary node dissection vs. Sentinel node biopsy N= 2,000 Chemotherapy; appropriate endocrine therapy N= 2,000 No Chemotherapy; appropriate endocrine therapy N= 1,600 Record chosen therapy and followed for vital status through cancer registry

21 Management of ER-, PRand HER2+ Breast Cancer

22 HER2 Targeting Monoclonal Antibodies Trastuzumab* Pertuzumab Small Molecule TKIs Lapatinib* HKI-272 CI-1033 EKB-569 ARRY-380 Immunotoxin: Trastuzumab-DM1 Other Targets IGF-IR PI3K mtor HSP90 HDAC *FDA-approved for breast cancer Adapted from Esteva FJ, Hortobagyi GN. Sci Am 2008

23 Adjuvant Trastuzumab Reduces Risk of Recurrence and Death in HER-2 Positive Early Breast Cancer Pooled results of 5 randomized trials show trastuzumab significantly reduces recurrence and mortality, compared to no trastuzumab. Recurrence OR: 0.53 (0.46, 0.60) p< Death OR: 0.52 (044, 0.62) p< Results also show increased cardiac toxicity (4.5% vs. 1.8%) Adapted from the Viani GA, et al. BMC Cancer. 2007;7:

24 Adjuvant Trastuzumab in HER2-Positive Breast Cancer Women with HER2-positive node-positive of high-risk node-negative breast cancer. N=3,222 Clinical Event AC T AC T plus Trastuzumab TCH Total events Distant breast cancer recurrence year DFS 75% 84% 81% 5-year OS 87% 92% 91% Grade 3 /4 CHF 0.7% (7) 2% (21) 0.4% (4) Cardiac deaths Acute leukemia Slamon D, et al. NEJM 365(14): , 2011

25 Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer (A)DFS and (B) OS for the comparison of arm A and arm B and (B)(C) DFS and (D) OS for the comparison of arm B and arm C Perez E A et al. JCO 2011;29: by American Society of Clinical Oncology

26 Adjuvant HER2-directed Therapy Benefits of Trastuzumab are restricted to HER2+ tumors (definition of HER2+?) Can we predict response to individual HER2-directed agents? Trastuzumab weekly or three-weekly for one year, concurrent with or in sequence with chemotherapy is the standard of care Anthracycline/taxane regimens Docetaxel/carboplatin regimen Shorter regimens provocative, but not validated Patients with HER2+/ER+ tumors should also receive adjuvant endocrine therapy, following usual endocrine guidelines Whether small tumors (T1a,bN0) benefit (and how much) from trastuzumab + endocrine therapy without chemotherapy remains to be determined

27 Potential Molecular Mechanisms of Trastuzumab Resistance Disrupted antibodyreceptor interaction HER-2 Increased receptor signaling: HER members, IGF-IR MAPK PI3K p27-cdk2 cyclin D1 Alterations in downstream molecules: PTEN downregulation, increased Akt signaling, reduced p27 kip1

28 Strategies to Overcome/Reverse Resistance to HER2-directed Therapy Targeting the same pathway at different levels with different agents: Trastuzumab + lapatinib (neratinib) Trastuzumab + pertuzumab Trastuzumab + PI3K/AKT/mTOR inhibitor Targeting cross talk of complementary pathways: Trastuzumab + antiestrogen (AI) Trastuzumab + IGF1R inhibitor Trastuzumab + angiogenesis inhibitor Trastuzumab + src inhibitor

29 NeoSphere: study design Gianni L, et al, 2010 SABCS Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) TH (n=107) docetaxel + trastuzumab THP (n=107) docetaxel + trastuzumab + pertuzumab HP (n=107) trastuzumab + pertuzumab TP (n=96) docetaxel + pertuzumab Study dosing: q3w x 4 S U R G E R Y FEC q3w x 3 trastuzumab q3w cycles 5 17 FEC q3w x 3 trastuzumab q3w cycles 5 17 docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5 17 FEC q3w x 3 trastuzumab q3w cycles 5 21 BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=t2 3, N2 3, M0 or T4a c, any N, M0; operable=t2 3, N0 1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel 3

30 NeoSphere pcr rates: ITT population summary p = p = p = pcr, % ± 95% CI TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel 6

31 NEO-ALTTO Study Design Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF 50% N=450 Stratification: T 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR N 0-1 vs. N 2 Conservative surgery or not R A N D O M I Z E lapatinib paclitaxel trastuzumab paclitaxel lapatinib trastuzumab paclitaxel lapatinib trastuzumab lapatinib trastuzumab 6 wks + 12 wks 34 weeks 52 weeks of anti-her2 therapy S U R G E R Y F E C X 3

32 NEO-ALTTO: Efficacy pcr and tpcr L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pcr pathologic complete response

33 Closure of Lapatinib Arm on ALTTO Complete all (neo-) adjuvant anthracycline-based chemotherapy prior to administering targeted therapy Closed to screening: March 15, 2009 Approximately 4566 patients were enrolled.

34 BETH Trial: CIRG 011/NSABP B-44 Node-Positive or High Risk Node-Negative Breast Cancer HER2 Positive by Central Testing STRATIFICATION Number of positive Nodes (0, 1-3, 4+) Hormone Receptor Status (+ vs -) Chemotherapy* q3wks x 6 + Trastuzumab x 1 yr Chemotherapy* q3wks x 6 + Trastuzumab x 1 yr + Bevacizumab x 1 yr It includes T1 a, b, N0 patients. Must be grade 2-3 or ER/PR negative or <35 years old Accrual Goal = 3,500

35 Management of ER-, PR-, and HER2- (Triple-negative) Breast Cancer

36 Basal-like subtype HER2 CRYAB ID4 EGFR/HER1 c-kit Keratin 5 Keratin 17 P-Cadherin Luminal Proliferation % of all tumors 2. ~50-75% of TNBC 3. distinct cell type of origin or developmental stage of arrest 4. >50% TP53 mutated 5. highly proliferative (RB-loss) 6. BRCA1-associated/defective homologous recombination mediated DNA repair 7. Baseline prognosis is poor 8. Chemotherapy benefit is high Therapeutic Questions Benefit from platinum salts? PARP inhibitor benefit? Angiogenesis inhibitors? EGFR inhibitors?

37 Management of Triple-negative Breast Cancer Agents/regimens of proven benefit: Chemotherapy: TAC x6, Dose-dense ACx4+Tx4, wtx12+fac/fec or FECx3 + Tx3 Platinum/taxane or gemcitabine/taxane combos (?) VEGF-directed therapy: Bevacizumab + taxane chemotherapy in front line MBC It is estimated that optimal chemotherapy would reduce annual odds of recurrence by about 50%-60% Reductions in odds of mortality are somewhat more modest because of competing causes of death and delays between recurrence and death

38 EBCTCG Metaanalysis of Adjuvant Chemotherapy for Breast Cancer Metaanalysis of 100,000 women in 123 randomized trials Taxane vs. not Anthracyclines vs. CMF Polychemotherapy vs. Nil EBCTCG, Lancet, 6776(11):61625, 2011

39 EBCTCG Metaanalysis of Adjuvant Chemotherapy for Breast Cancer EBCTCG, Lancet, 6776(11):61625, 2011

40 NSABP B-38 Schema Stratification: # nodes, Hormone receptor, Surgery and RT TAC q 3 wk All arms pegfilgrastim or filgrastim AC q 2 wk P q 2 wk EPO: rec for Hgb 11 gm/dl N+ AC q 2 wk PG q2 wk ER positive: hormonal therapy for 5 yrs after chemo

41 NSABP B-38 Disease-Free Survival Disease-Free Survival Treat N Events P-value* (vs AC PG) TAC AC P AC PG # at risk Years since Randomization * Stratified log-rank test adjusting for randomization factors

42 Triple-Negative Breast Cancers: Some Potential Therapeutic Targets Cetuximab EGFR Tyrosine Kinase MET tyrosine kinase MET mab MAPK inhibitors; NOTCH inhibitors MAP Kinase Pathway Transcriptional Control Akt Pathway PARP inhibitors Anti- Angiogenesis Bevacizumab Cell Cycle DNA Repair pathways Cell Death After Cleator S et al. Lancet Oncol. 2006:8:

43 PARP-inhibitors: Summary of Clinical Trials Olaparib is highly effective in BRCA-mutated breast and ovarian cancers Iniparib appears to be a weak PARP-inhibitor; while a randomized phase II study of iniparib in combination with chemotherapy appeared sugnificantly better than chemotherapy alone, these results could not be reproduced in a Phase III trial of identical design. Other PARP-inhibitors are currently in early clinical trials

44 40% of breast cancers harbor several, different, rare but readily targetable mutations % 2% 2.5% 4% 3% AKT ALK BRAF CDK4 CTNNB1 2.5% 16% EGFR FBWX7 FGFR2 FGFR3 IDH2 KIT KRAS PDGFRA 45% of breast cancers harbor some activating mutations in the PI3K-AKT-mTOR pathway PIK3CA PHLLP2# PIK3R1 PRKAG2 13% had two mutations and 6% had > 3 mutations

45 The Pie chart trial Informed consent for biopsy and targeted therapy Mutation profiling ALK EGFR ERα FGFR1 FGFR2 FGFR3 KIT IGF1R MET RET PDGFRα Consent for specific mutation-directed therapy AKT (2%) MK 2206 ALK (2%) PF CDK4 (4%) AT 7519 EGFR (2.5%) CI 1033 FGFR3 (14%) AZD 0530 CTNNB1 (3%) AVN 316 PIK3CA (17%) GSK Each arm is a separate Phase II study

46 We Are Awaiting With Great Interest the Results of: SOFT, and TEXT TAILORx and MINDACT ALTTO and BETH E5103, BETH and BEATRICE

47 Conclusions Hormonal therapy is the most effective adjuvant therapy fro patients with ER+ HER-2 neu normal EBC Anthracyclines and taxanes current backbone of adjuvant chemotherapy for patients with most patients with early breast cancer Trastuzumab-base adjuvant therapy is standard of care for patients with HER-2 amplified EBC Recent studies suggest that different breast cancer subtypes respond differentially to cytotoxic treatment More research needed on alternative methods to select patients for chemotherapy More research needed on alternative non-chemotherapy therapies for patients with ER+, HER-2 normal EBC

48 Treatment Selection Driven by Clinical, Pathological and Genomic Factors Conclusions Breast cancer is a conglomerate of multiple, molecularly defined syndromes with different natural histories and sensitivities to therapeutics ER, PR, HER2 and Ki67 represent critical molecular markers that identify the largest molecular subsets High throughput diagnostic techniques identify novel molecular markers that might serve to identify new subsets, new targets We have taken the first steps towards understanding the importance of genetic polymorphisms in prediction and selection of treatment. Molecular diagnostics is an indispensable companion to molecular therapeutics

49 If it were not for the great variability among individuals, medicine might as well be a science, not an art. Sir William Osler, Physician 1892

50