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TAILORED THERAPIES: PROGNOSTIC & PREDICTIVE FACTORS

BELGIAN BREAST MEETING 2008 October 4-5, 2008. TAILORED THERAPIES: PROGNOSTIC & PREDICTIVE FACTORS. F. Cardoso, MD Jules Bordet Institute, Brussels, Belgium. THE GOALS OF TREATMENT TAILORING. INDIVIDUALIZE TREATMENT. AVOID UNDER- AND OVER-TREATMENT. New/better PREDICTIVE FACTORS.

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TAILORED THERAPIES: PROGNOSTIC & PREDICTIVE FACTORS

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  1. BELGIAN BREAST MEETING 2008 October 4-5, 2008 TAILORED THERAPIES: PROGNOSTIC & PREDICTIVE FACTORS F. Cardoso, MD Jules Bordet Institute, Brussels, Belgium

  2. THE GOALS OF TREATMENT TAILORING INDIVIDUALIZE TREATMENT AVOID UNDER- AND OVER-TREATMENT New/better PREDICTIVE FACTORS New/better PROGNOSTIC FACTORS

  3. NEW PROGNOSTIC BIOMARKERS MULTI-GENE TOOLS Genomic signatures Oncotype DX (predictive & Px) MammaPrint™ (70-gene signature) 76-gene signature UNI-GENE TOOLS Genomic grading uPA, PAI-1

  4. “Top-down” approach Clinical outcome Signature Microarray “Bottom-up” approach Biological Hypothesis Signature Clinical Outcome Microarray Signature Development Approaches Tumor specimen “Candidate gene” approach Clinical outcome Candidate Genes = Breast Cancer Biology Signature Q-RT-PCR C Sotiriou – used with permission

  5. 4 assays commercially available… Several signatures shown to outperform current clinico-pathological parameters for treatment decision making C Sotiriou – adapted with permission

  6. 500+ genes 21 genes 70 genes 200+ genes CONCORDANCE OF PREDICTION RESULTS OF 5 DIFFERENT PREDICTORS APPLIED TO THE SAME 295 CASES DESPITE < 5% OVERLAP IN GENES, THERE WAS CLOSE TO 80% CONCORDANCE IN PROGNOSTIC PREDICTION C Fan et al., N Engl J Med 355:560, 2006

  7. DISSECTING GENE EXPRESSION SIGNATURES Amsterdam No (%) 70 genes (Van de Vijver et al. NEJM, 2002) 35 (50) 6 (9) 34 (49) 10 (14) 4 (6) 7 (10) 9 (9) Rotterdam No (%) 76 genes (Wang et al. The Lancet, 2005) 17 (18) 2 (3) 30 (39) 1 (1) 6 (8) 4 (5) 30 (39) Microarray Indices ESR1 = luminal/basal ERBB2 = Her2-neu STK6 = proliferation/GGI PLAU = stroma/invasion STAT1 = immune response VEGF = angiogenesis NA = undetermined C. Sotiriou – used with permission

  8. WITH ALL GENE SIGNATURES HR VARIES WITH TIME Time to distant metastasis HR all endpoints strongest in the first 5 years after diagnosis

  9. EORTC 10041 BIG 3-04 trial MINDACT TRIAL DESIGN 6,000 Node - & 1-3 N+ women Evaluate Clinical-Pathological risk and 70-gene signature risk 55% 32% 13% N=780 N=3300 Discordant cases Clinical-pathological and 70-gene both LOW risk Clinical-pathological and 70-gene both HIGH risk Clin-Path HIGH 70-gene LOW Clin-Path LOW 70-gene HIGH R-T N=1920 Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not Chemotherapy Endocrine therapy Potential CT sparing in 10-15% pts

  10. MINDACT ACCRUAL STATUS • First patient screened February 2007 & First patient enrolled March 2007 • As of 1/10/08: 1530 screened pts & 625 enrolled (first 800 – pilot phase – estimated in December) • 49 centers are open in 8 countries • Overall: • 44% of screened patients are enrolled • 79% of screened patients have a sample shipped • 38%: N+ • 32%: less than 50% tumor cells • 30%: late enrollment • AMENDEMENT: extended timelines, N+ eligible, and decrease of needed % of tumor cells  will increase the ratio enrolled/screened

  11. Key Eligibility: • Node-negative • HR-positive • Her2-negative • Age < 75 years • Candidate for chemo TAILORx Study Design Accrual: 2834 / 4,400 pts with RS 11-25 Non-inferiority design for RS 11-25 Courtesy J. Sparano

  12. COMPARISON OF TAILORX AND MINDACT TRIALS Courtesy & adapted from M. Piccart

  13. BEYOND FIRST PROJECTS…Node positive disease

  14. GOOD PROFILE: SUFFICIENTLY LOW RISK 34% ADJUVANT! HIGH RISK PATIENTS ARE LOW RISK BY THE 70-GENE PROFILE Courtesy of S. Mook; SABC 2007

  15. Predictive value of 21-Gene RS Disease-Free Survival by Treatment 1.00 Low risk (RS < 18) 0.75 0.50 Disease-free survival Stratified log-rank p = 0.97 at 10 years 0.25 Tamoxifen (n=55, 15 events) CAF-T (n=91, 26 events) 0.00 0 2 4 6 8 10 Years since registration Disease-Free Survival by Treatment Disease-Free Survival by Treatment 1.00 1.00 Intermediate risk (RS 18-30) High risk (RS ≥31) 0.75 0.75 Disease-free survival Disease-free survival 0.50 0.50 Stratified log-rank p = 0.48 at 10 years Stratified log-rank p = 0.033 at 10 years 0.25 0.25 Tamoxifen (n=46, 22 events) Tamoxifen (n=47, 26 events) CAF-T (n=57, 20 events) CAF-T (n=71, 28 events) 0.00 0.00 0 2 4 6 8 10 0 2 4 6 8 10 Years since registration Years since registration No benefit to CAF over time if low RS Strong benefit if high RS Courtesy K. Albain SABCS 2007, #10

  16. SWOG 8814/TBCI 0100 Ten-Year DFS Point Estimates (95% CI) *40% event rate over 10 years and resistance to CAF Courtesy K. Albain SABCS 2007, #10

  17. BEYOND FIRST PROJECTS…Predictive of response to CT

  18. Low risk but still … might opt for chemotherapy L Pusztai & al; ASCO 2008 Predicted not to be sensitive either to T/FAC or Tamoxifen Suggest Clinical Trial May do well with current best chemo and endocrine therapies Four different genomic outcome predictors applied to the 198 cases from the TRANSBIG data: (i) 70-gene MammaPrintTM prognostic signature, the Genomic Grade Index prognostic index (GGI) (iii) a 200-gene endocrine sensitivity index (SET) and (iv) a second generation phenotype-specific Paclitaxel-FAC chemotherapy response predictor

  19. CONCLUSIONS • Patients predicted to be at low risk for recurrence are predicted to be mainly sensitive to HT. However, 6% of these low risk by MammaPrint pts were also predicted to achieve excellent pathologic response to CT, and thus might consider adjuvant CT as a reasonable option. • 40-50% of high risk patients are predicted to be refractory to existing therapies & need clinical trials of new agents. • Simultaneous prediction of risk of recurrence and sensitivity to endocrine- and chemo-therapies is currently possible and could allow more personalized treatment decisions in the future. L Pusztai & al; ASCO 2008

  20. Higher RS predictive of chemotherapy (ie, CMF/MF) benefit(Paik et al. JCO 2006) 1.31 (0.46-3.78) Low RS<18 Inter RS 18-30 0.61 (0.24-1.59) Interaction p = 0.0368 0.26 (0.13-0.53) High RS≥31 0.5 1.0 1.5 B20: Relative Risk of Chemotherapy by RS Group (Cox model)

  21. PATIENT RISK PROFILES Prognostic BIOMARKERS MULTI-GENES TOOLS Genomic signatures Oncotype DX (predictive & Px) MammaPrint™ (70-gene signature) 76-gene signature UNI-GENES TOOLS Genomic grading uPA, PAI-1

  22. CLINICAL RELEVANCE OF uPA & PAI-1 IN PRIMARY BREAST CANCER • uPA and PAI-1:first novel tumor biological factors in breast cancer with clinical relevance validated at highest level of evidence (LOE I) • Standardized quality assured ELISA tests: Sweep et al, Br J Cancer 78: 1434-41, 1998 • Prospective multi-center therapy trial („Chemo N0“): Jänicke et al, JNCI 93: 913-20,2001 • EORTC RBG meta analysis (n=8,377): Look et al, JNCI 94:116-28, 2002 • Recommended for clinical risk assessment: AGO Therapy Guidelines „breast cancer“ (since 2002):www.ago-online.de • Recommended for clinical use by ASCO Guidelines in 2007 Harris et al, JCO 25 (33), 2007 Adapted from N. Harbeck with permission

  23. Prognosis: Patient survival Benefit from chemotherapy 1.0 .5 p = 0.019; RR = 0.42 (0.20 – 0.87) uPA and PAI-1 low .9 .4 n = 91, 12 relapses n = 90, 20 relapses observation uPA / PAI-1 high .8 .3 58 % .7 .2 Probability OS CMF .6 .1 p = 0.003 n = 245, 7 deceased n = 164, 17 deceased .5 0.0 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84 Time (months) Time (months) Chemo N0: uPA / PAI-1 high (per protocol) Chemo N0 : Prospective multicenter therapy trial in node-negative breast cancer Chemo N0: no adjuvant systemic therapy Jänicke et al, JNCI 2001; Harbeck et al, Breast Cancer Res Treat 2001 N. Harbeck – used with permission

  24. CLINICAL VALIDATION TECHNICAL VALIDATION The test identifies subsets with significantly different * risks of relapse * chances of response The test is * sensitive * specific * reproducible UPA-PAI-1 YES YES (level 1) Ready for use routine use in the clinic? YES

  25. WX/60-006 – study scheme Staging intervals at baseline and every 6 weeks until progression or toxicity Monotherapy armCapecitabine: 2000 mg/m2 Days 1-14 q3ws Placebo once daily per os Patients with HER2-negative MBC appropriate for first-line mono chemotherapy with Capecitabine N = 100 Overall survival Combination arm Capecitabine: 2000 mg/m2 Days 1-14 q3ws WX-671 once daily po • Efficacy endpoints: • PFS • ORR at week 12 and 24 weeks • Overall survival WX-671 is the oral pro-drug to the active metabolite WX-UK1 WX-UK1 is an uPA inhibitor with broad activity against a number of serine proteases

  26. PREDICTIVE FACTORS PgR Ki67 UNI-GENE TOOLS HER-2 AIB1 Topo-II- PHARMACOGENOMICS Oncotype DX (predictive & Px) MULTI-GENE TOOLS Genomic signatures

  27. NIH Consensus Panel 2000 St Gallen Consensus Panel 2005 ASCO Guidelines 2001 Oxford Overview 2000 Accepted Predictive Markers In Breast Cancer HER-2 neu ER/PgR 95% Negative predictive value 30-70% Positive predictive value 30%-70% chances of responding to HT (ER) & 40%-50% of responding to TRASTUZUMAB (HER-2) <5% chances of responding to TRASTUZUMAB (HER-2) or to HT (ER)

  28. ADVANCES IN ADJUVANT CHEMOTHERAPY • CAN WE DO SAFELY AVOID ANTHRACYCLINES? • In HER-2+ pts • In all pts or THE TOPO-II SAD STORY!!!!!!!!!!!

  29. BCIRG 006 at SABCS 05 (D. Slamon) Disease Free Survival 1.0 93% 0.9 AC->TH 91% 86% 84% 86% 80% 80% TCH 0.8 77% 73% % Disease Free AC->T 0.7 Patients Events 1073 147 AC->T 0.6 HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001 1074 77 AC->TH 1075 98 TCH HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002 0.5 0 1 2 3 4 5 Slamon D., SABCS 2005 Year from randomization

  30. AC → TH >>AC → T or TCH Anthracyclines & trastuzumab are imp AC → TH & TCH >>AC → T Only trastuzumab is imp

  31. UPDATE ON BCIRG 006 at SABCS 06 (D. Slamon) • AC → TH ≈ TCH • even when TOPO II is co-amplified !!! UPDATE ON BCIRG 006 at SABCS 07 (D. Slamon) AC-T = AC-TH = TCH when TOPO II is co-amplified ONLY POSSIBLE CLINICAL RECOMMENDATION: TCH is a very good option and should be chosen when cardiac risk factors or c.i. for anthracyclines are present

  32. HER-2 AND TOPOISOMERASE-II AS POTENTIAL PREDICTIVE MARKERS OF ANTHRACYCLINE EFFICACY: A META-ANALYSIS DANISH TRIAL FEC vs CMF UK TRIAL ECMF vs CMF FIRST RESULTS AT SABCS 2008 BELGIAN TRIAL EC vs CMF NCIC-CTG TRIAL CEF vs CMF Tampere University Laboratory Central evaluation of HER-2/TOPO II gene amplificationby FISH Correlation with outcome of CMF or anthracycline-based therapy with  4,500 tumor samples

  33. TRASTUZUMAB IN THE METASTATIC SETTING Highly selected population Using a targeted agent HOWEVER Responses in only ± 50% patients Median duration of response: 9 to 12 months RESISTANCE TO TRASTUZUMAB (DE NOVO AND ACQUIRED)

  34. POTENTIAL MECHANISMS OF RESISTANCE TO TRASTUZUMAB • IS THE TARGET PRESENT? • HER-2 status: Technical limitations (IHC; FISH; central evaluation) • IS THE TARGET ACTIVE? • Role of truncated HER-2 receptor(p95-HER-2) • Role of activated form of HER-2 (p-HER-2) • Mechanical blockade of the receptor (Mucin 1 or 4 Interference) • IS THE TARGET BEHAVING DIFFERENTLY?(HER-2 as transcription factor) • ROLE OF POTENTIAL ADDITIONAL TARGETS • Other HER family members: Upregulation of HER1 or HER3 • ROLE OF REDUNDANT PATHWAYS • PI3K / AKT, IGF-IR pathways, MAP-kinase, ER pathway • Role of immune function, ↑ expression of growth factors (ligands), etc

  35. POTENTIAL WAYS OF OVERCOMING RESISTANCE TO TRASTUZUMAB • OPTIMAL SELECTION OF PATIENTS • Quality of HER-2 testing is essential (high level of discordance between central & local labs for both IHC & FISH) • Primary vs. Metastatic sites • Use of other predictive markers: c-myc; p95HER2; PTEN; pHER-2; ECD-HER2; survivin; patterns of HER-receptors co-expression and/or of functional HER-2 heterodimers; • USE OF OTHER ANTI-HER-2 AGENTS(Lapatinib, HKI-272, Pertuzumab, Trastuzumab-DM1, HSP-90 inhibitors) • “MULTI-TARGETED THERAPY” • Simultaneous blockage of same pathway in several sites(pan-HER inhibitors) • Simultaneous blockage of redundant pathways: combinations with other biological agents(IGF-I inhibitors, PI3K inhibitors, AKT or mTOR inhibitors, MAPK inhibitors)

  36. ECD/ p95: POTENTIAL DISCRIMINATIVE MARKER BETWEEN T vs L • P95 is a truncated HER-2 receptor which lacks the external domain (do not bind trastuzumab) • Approximately 25% of breast cancers express p95, 9% of breast cancers high levels of p95 - it predicts worse outcome • Truncated receptor demonstrates increased kinase activity and transforming potential serum 185kd p95 Trastuzumab binds to extracellular domain and can not inhibit “free” p95 Saez et al, Clin Can Res 12:424, 2006

  37. 100 90 80 70 60 50 0 1 2 3 4 5 cMYC and Outcome in NSABP B31 Trial Time to First Recurrence MYC+,AC->TH MYC-,AC->TH MYC-,AC->T MYC+,AC->T P-value for Interaction = 0.007 (N=1549) Paik et al, SABCS 2005

  38. Activated PI3K pathway: Low PTEN or mutant PIK3CA Non-activated PI3K pathway: High PTEN and wild type PIK3CA Low PTEN: 25% of breast cancers Mutant PI3K: 25% of breast cancers (mutually exclusive) René Bernards, SABCS 2007

  39. ALTTO:Pre-defined subgroup analyses Molecular marker Distribution Hypotheses c-Myc co-amplified30% “Exquisitely sensitive to trastuzumab” c-Myc Group where L benefits more likely(80% power for any pair-wise comparison to detect DFS 0.754) c-Myc not co-amplified70% “Resistant to trastuzumab” Loss / reduced expression in 40% PTEN Group where L benefits more likely(80% power for any pair-wise comparison to detect DFS 0.72) “Resistant to trastuzumab” p95HER2 Seen in 10% Group where L benefits more likely(80% power for any pair-wise comparison to detect DFS 0.638)

  40. COMBINATION OF TRASTUZUMAB WITH OTHER BIOLOGICAL AGENTS Adapted with permission from E Azambuja

  41. NEW ANTI-HER-2 AGENTS Adapted with permission from E Azambuja

  42. ASCO 2006 : CYP2D6 AND THERAPEUTIC INDEX OF TAMOXIFEN

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