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Kevin R. Fox, M.D., Director, Rena Rowan Breast Center, Perelman Center for Advanced Medicine at Penn Medicine - Newest Approach to Breast Cancer ...

Kevin R. Fox, M.D., Director, Rena Rowan Breast Center, Perelman Center for Advanced Medicine at Penn Medicine - Newest Approach to Breast Cancer

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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    Newest Approach to Breast Cancer Newest Approach to Breast Cancer Presentation Transcript

    • Newest Approach to Breast Cancer Kevin R. Fox, MDMacDonald Professor of Medicine Abramson Cancer Center University of Pennsylvania
    • To follow:• Early stage breast cancer – Genomic testing to predict response – Controversies in HER2 positive disease• Advanced breast cancer – New chemotherapies – Agents targeting HER2 – MTOR inhibition – Whither bevacizumab? – PARP inhibitors
    • Genomic evaluation in early stage disease
    • 2000 Adjuvant Overview: Mortality Reduction Tam Chemo Combined<50 ER+ 25% 25% 45% ER- 0% 35% 35%>50 ER+ 25% 10% 35% ER- 0% 20% 20%
    • NSABP B-20 RNode negative AER positive N Tamoxifen Dbreast cancer O M I Z Chemo + Tam E
    • B-20 Chemotherapy Benefit By Recurrence Score Category Interm. Risk (RS 18–30) Low Risk (RS < 1.0 1.0 10 yr 0.9 0.8 18) 96% 0.9 0.8 95% 89% 0.7 0.7 0.6 0.6 N Events 90%DRFS DRFS 0.5 0.5 89 9 N Events p = 0.71 0.4 0.4 45 8 218 11 0.3 135 5 p = 0.76 0.3 0.2 0.2 Low Risk Patients (RS < 18) Int Risk (RS 18 - 30) 0.1 Tam + Chemo 0.1 Tam + Chemo Tam Tam 0.0 0.0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Years Years 1.0 0.9 0.8 88% 0.7High Risk 0.6 N Events 60% DRFS 0.5(RS ≥ 31) 0.4 117 47 13 18 p = 0.001 0.3 0.2 High Risk Patients (RS ≥ 31) Interaction p = 0.0368 0.1 Tam + Chemo Tam 0.0 0 2 4 6 8 10 12 Years Paik S, et al: SABCS 2004
    • Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+ RANDOMIZE n = 1477tamoxifen x 5 yrs CAF x 6, with CAF x 6, then (n = 361) concurrent tam tamoxifen (n = 550) (n = 566) Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years Albain, SABCS 2007, Abstract #10 Albain, et al. Breast Cancer Res Treat 2005
    • Disease-Free Survival by Treatment No benefit to 1.00 CAF over time Disease-free survival 0.75 Low risk (RS < 18) if low RS 0.50 Stratified log-rank p = 0.97 at 10 years 0.25 Strong benefit Tamoxifen (n=55, 15 events) CAF-T (n=91, 26 events) 0.00 if high RS 0 2 4 6 Years since registration 8 10 Disease-Free Survival by Treatment Disease-Free Survival by Treatment 1.00 1.00 Intermediate risk (RS 18-30) High risk (RS ≥31)Disease-free survival Disease-free survival 0.75 0.75 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=47, 26 events) Tamoxifen (n=46, 22 events) 0.00 CAF-T (n=71, 28 events) CAF-T (n=57, 20 events) 0.00 0 2 4 6 8 10 0 2 4 6 8 10 Years since registration Years since registration Albain, SABCS 2007, Abstract #10
    • CAF Benefit Greatest in Higher RS for Both Nodal Subsets, with No Benefit in Lower RS Five-Year Probability of Death or Disease Recurrence Linear model for Recurrence Score and interactions with treatment 1 Tam, 4+ nodes (n=54) Five Year Probability of an Event CAF-T, 4+ nodes (n=86) Tam, 1-3 nodes (n=94) .8 CAF-T, 1-3 nodes (n=133) .6 Chemo benefit 4+ nodes .4 Chemo benefit 1-3 nodes .2 0 0 20 40 60 80 100 Recurrence Score Albain, SABCS 2007, Abstract #10
    • Milan Trial Adjuvant Cyclophosphamide, Methotrexate and Fluorouracil in Node-Positive Breast Cancer 1.0 Probability of Relapse-Free Survival 12 X CMF, q28d 0.9 RFS n=207 0.8 Cyclophosphamide - 100 mg/m2 PO days 1-14 0.7 Methotrexate - 40 mg/m2 IV days 1 and 8 0.6 Fluorouracil - 600 mg/m2 IV days 1 and 8 0.5 0.4 CMF 0.3 P =0.004 (unadjusted) 0.2 P <0.001 (adjusted) Control 0.1 R 0.0 5 10 15 20 Observation Years After Mastectomy 1.0 n=179 OS Probability of Overall Survival 0.9 0.8 Median follow-up: 19.4 years 0.7 0.6 0.5 CMF Obs. 0.4 CMF 20 yr RFS: 36% 27% P =.004 0.3 0.2 P =0.04 (unadjusted) Control 20 yr OS: 34% 25% P =.04 0.1 P =0.03 (adjusted) 0.0 5 10 15 20Bonnadonna et al. NEJM (1995) 332:901-906 Years After Mastectomy
    • Appropriate for node-positive patients?Do any reasonable alternatives exist?
    • The use of trastuzumab in early stage breast cancer patients- what constitutes the “right” chemotherapy?
    • NCCTG N9831 Schema Arm A: AC q3w x 4 Paclitaxel qw x 12RANDO Arm B: AC q3w x 4 Paclitaxel qw x 12 H qw x 52MIZE Paclitaxel qw x 12 Arm C: AC q3w x 4 + H qw x 40 H qw x 12 Radiation and/or hormonal therapy as indicated Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg); doxorubicin dose 60mg/m2; cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2 q3w=every 3 weeks; qw=weekly
    • Disease-Free Survival: A vs C From the Joint Analysis 100 AC → T + H → H 90 Events=134 80 70 AC → T Events=261 60% 50 40 30 Hazard ratio=0.48 20 Stratified logrank 2P=3x10-12 10 0 0 1 2 3 4 Years Number of patients followed A 1162 689 374 193 59 C 1217 766 427 238 74
    • HERA TRIAL DESIGN Women with HER-2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT) ± radiotherapy StratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab Trastuzumab8 mg/kg  6 mg/kg 8 mg/kg  6 mg/kg Observation 3 weekly x 2 years 3 weekly x 1 year
    • DISEASE-FREE SURVIVAL 1 year trastuzumab % alive 100 and 90disease free 80 70 Observation 60 50 2-yr 40 Events DFS % HR [95% CI] p value 30 20 127 85.8 0.54 [0.43, 0.67] <0.0001 10 220 77.4 0 0 5 10 15 20 25 No. Months from randomization at risk 1694 1472 1067 629 303 102 1693 1428 994 580 280 87
    • BCIRG 006 4 x AC 4 x Docetaxel 60/600 mg/m2 100 mg/m2 ACT Her2+ 4 x Docetaxel (Central FISH) 4 x AC 60/600 mg/m2 100 mg/m2 N+ ACTH or high risk N- 1 Year Trastuzumab 6 x Docetaxel and Carboplatin N=3,222 75 mg/m2 AUC 6Stratified by Nodes TCHand HormonalReceptor Status 1 Year Trastuzumab Slamon D., SABCS 2005
    • 1.0 Disease Free Survival 93% 0.9 91% 86% 84% 86% 80% 80%% Disease Free 0.8 77% 73% 0.7 Patients Events 0.6 1073 147 AC->T 1074 77 AC->TH HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001 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 Year from randomization
    • Disease Free Survival - 2nd Interim Analysis Absolute DFS benefits (from years 2 to 4): 1.0 AC→TH vs AC→T: 6% 93% TCH vs AC→T: 5% 0.9 92% 87% 86% 83% 87% % Disease Free 0.8 82% 81% 77% 0.7 Patients Events 1073 192 AC->T 0.6 1074 128 AC->TH HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001 1075 142 TCH HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003 0.5 0 1 2 3 4 5 Year from randomization
    • Overall Survival – 2nd Interim Analysis 1.0 99% 98% 97% 97% 95% 92% 93% 0.9 91%% Survival 86% 0.8 0.7 Patients Events 0.6 1073 80 AC->T 1074 49 AC->TH HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] P=0.004 1075 56 TCH HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017 0.5 0 1 2 3 4 5 Year from randomization
    • Advanced Breast Cancer
    • New, and final (?)chemotherapies…
    • Survival for patients presenting with metastatic breast cancer Copyright © American Society of Clinical OncologyAndre, F. et al. J Clin Oncol; 22:3302-3308 2004
    • Survival curves for ER-positive and ER-negative metastatic breast cancers ER- negative ER- positive Median survival 4 years Median survival ≈ 1 year Andre F, et al. J Clin Oncol 22: 3302, 2004
    • Capecitabine +/- Ixabepilone in Triple-Negative MBC 046 / 048: Pooled Subset Analysis Ixa + Cape Cape (N = 213 for OS)a (N = 208 for ORR and PFS)a (N = 191 for ORR and PFS)b (N = 230 for OS)b Median PFS ORR Median OS 8 100 20 HR = 0.63 (95% CI, 0.52 to 0.77) 18 HR = 0.87 (95% CI, 0.71 to 1.07) 7 90 P < 0.0001 P < 0.1802Median PFS (months) Median OS (months) 80 16 Response Rate (%) 6 70 14 5 60 12 4 50 10 4.2 3 (95% CI: 40 8 10.3 3.6-4.4) (95% CI: 9.0 30 6 2 9.1-11.8) (95% CI: 31% 1.7 20 (24-38) 4 6.7-10.6) 1 (95% CI: 15% 10 2 1.5-2.4) (10-20) 0 a ORR 0 and PFS computed on all randomized pts in 046 and pts randomized to the measurable disease strata in 048 b All randomized Rugo H, et al. SABCS 2008 Poster Presentation. Available at: http://www.abstracts2view.com/sabcs/view.php?nu=SABCS08L_982.
    • Abstract 1004; Twelves
    • Therapies Targeting HER2
    • Targets in trastuzumab-resistant cancersT-DM1 TRAST PERT BEV IGFR EGFR HER2 VEGFR p110 p85LAP RAD 001PTEN PI3-Kinase 4E-BP1/PHAS-1 G1 + Translation (cyclin D1) Akt-Kinase mTOR S p70S6-kinase BAD BAD Emerging data supports co-targeting the HER2 pathway in trastuzumab-resistant cancers
    • Targets in trastuzumab-resistant cancersT-DM1 TRAST PERT BEV IGFR EGFR HER2 VEGFR p110 p85LAP RAD 001PTEN PI3-Kinase 4E-BP1/PHAS-1 G1 + Translation (cyclin D1) Akt-Kinase mTOR S p70S6-kinase BAD BAD Emerging data supports co-targeting the HER2 pathway in trastuzumab-resistant cancers
    • Targets in trastuzumab-resistant cancersT-DM1 TRAST PERT BEV IGFR EGFR HER2 VEGFR p110 p85LAP RAD 001PTEN PI3-Kinase 4E-BP1/PHAS-1 G1 + Translation (cyclin D1) Akt-Kinase mTOR S p70S6-kinase BAD BAD Emerging data supports co-targeting the HER2 pathway in trastuzumab-resistant cancers
    • Effects of mTOR inhibition on signaling pathways GF? Sensitize to upstream p110 Possible Downstream p85 markers of mTOR inhibition GF inhibitors MTOR inhibitor PI3-Kinase 4E-BP1/PHAS-1 G1 + Translation (cyclin D1) Akt-Kinase mTOR S Feedback loop p70S6-kinase BAD BAD
    • Phase 1 trial of RAD001 inTrastuzumab-resistant HER2+ MBC Open-label, multicenter, Phase I, dose- escalation study of everolimus in combination with trastuzumab and paclitaxel Paclitaxel: 80 mg/m2 (Days 1, 8, and 15, q28 days) Trastuzumab: 2 mg/kg/week (Day 1: 4mg/kg) ARM 1: Daily ARM 2: Weekly Everolimus 5 mg (starting dose) Everolimus 30 mg (starting dose) 10 mg/day 50 mg and 70 mg/week Treatment until progression or unacceptable toxicity Paclitaxel continuation after 6 cycles: optional
    • Phase 1 trial of RAD001 in Trastuzumab-resistant HER2+ MBC Best Overall Overall 5 mg Daily 10 mg 30 mg Weekly Response (N=27) (N=6) Daily (N=10) (PFS – wks) (N=11)Complete Response 1 (5%) 1 (42+) 0Partial Response 8 (36%) 4* (24, 29 1 (16+) 3 33, 39) (24+, 30, 36)Stable Disease 11 6 (8+, 9+, 10+, 5 (16, 24+, (50%) 24+, 24+, 32+) 41, 41, 48+)Disease Control 17 5 4 8(CR/PR/SD≥16 (77%) (24, 29 (16+, 24+, 24+, (16, 24+, 24+,30, 36, 33, 39, 42+) 32+) 41, 41, 48+)Weeks)Progressive Disease 2 0 1 1Not Evaluable 2 1 1Not yet available 3 3% based on evaluable patients (22 in total = 5 + 8 + 9)*Including two patients with unconfirmed CR Andre JCO 2010
    • Efficacy in Patients With Taxane- and Trastuzumab-resistant Tumors Best Overall Overall 5 mg Daily 10 mg 30 mg Weekly Response (N=11) (N=5) Daily (N=3) (PFS - weeks) (N=3) Complete Response 1 (11%) 1 (42+) 0 Partial Response 4 (44%) 3 0 1 (29, 33, 39) (30) Stable Disease 4 (44%) 2 (8+, 24+) 2 (16, 48+) Disease Control 8 4 1 3 (CR/PR/SD>16 (89%) (29, 33, 39, 42+) (24+) (16, 30, 48+) Weeks) Progressive Disease 0 0 0 0 Not Evaluable 1 1 Not yet available 1 1% based on evaluable patients (9 pts evaluables = 4 + 2 +3) Andre JCO 2010
    • BOLERO-3 : Trastuzumab-resistant Vinorelbine + Trastuzumab ± Everolimus R A Everolimus 10.0 mg PO daily Assessment N D Vinorelbine 25mg/m2 weekly q8wk O M Trastuzumab 2 mg/kga IV on days 1, 8, PFS I 15, 22 Z Response Placebo PO daily A Survival T Vinorelbine 25mg/m2 weekly I Trastuzumab 2 mg/kga IV on days 1, 8, Safety O N 15, 22 N = 572 • Patients with HER2-overexpressing, unresectable locally advanced, recurrent, or metastatic breast cancer; resistant to trastuzumabScreen < 14 days prior to day 1 aAfter a loading dose of 4 mg/kg on day 1, cycle 1 (1 cycle = 28 days)
    • More on M-TOR inhibition
    • Letrozole ± Lapatinib in HR-positive MBC ITT HER2+ HER2- let let + lap let let + lap let let + lap (n=644) (n=642) (n=108) (n=111) (n=474) (n=478)PFS 10.8 11.9 3.0 8.2 13.4 13.7(months) HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P =.188 28% 30% 15% 28% 32% 33%ORR P =.262 P =.021 P =.726 51% 56% 29% 48% 56% 58%CBR P =.096 P =.003 P =.761 NR NR 32.3 33.3 NR NROS (months) NR HR 0.74; P =.113 NR Johnston JCO 2009
    • Letrozole ± Lapatinib in HR-positive, HER2-negative MBC • Preplanned stepwise exploratory Cox proportional hazard analysis for PFS: – HER2- population: HR for treatment = 0.77; P = .010 ≥6 months since <6 months since discontinuation of discontinuation of tamoxifen or none tamoxifen let (n=370) let + lap let (n=104) let + lap (n=382) (n=96)Median PFS 15.0 14.7 3.1 8.3(months) HR 0.94; P = .522 HR 0.78; P = .117CBR 64% 62% 32% 44% Hormone-sensitive Hormone-refractorySuggests that HER2 may be a viable target in cancerswith acquired hormone-resistance (even if they wereHER2-negative at diagnosis) Johnston JCO 2009
    • BOLERO-2: Addition of everolimus to exemestane improves PFS in HR+ MBC HR = 0.36 (95% CI: 0.27–0.47) 100 Log rank P value = 3.3 x 10 -15 Probability of Event (%) EVE + EXE: 10.6 Months 80 PBO + EXE: 4.1 Months 60 40 20 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (weeks)Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
    • Whither bevacizumab?
    • PARP Inhibition
    • Targeting BRCAness for tumor selective killing BRCA1 or BRCA2 Carrier BRCA1 or BRCA2 Normal tissues Carrier Tumor tissue DNA DAMAGE DNA DAMAGE HR NHEJ SSA BER NER etc HR NHEJ SSA BER NER etc x x x Tumour specific lethalityTutt A et al. Cold Spring Harb Symp Quant Biol. 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115.
    • PARP inhibitors in BRCA1/2 mutationcarriers • Olaparib • Phase I trial – Dose escalation – Established favorable toxicity profile – Proof of principal with responses seen only in BRCA1 and BRCA2 mutation carriers • Fong et al, NEJM 2009 • Phase II studies – Ovarian cancer: Audeh et al, Lancet 2010 – Breast cancer: Tutt et al, Lancet 2010
    • Study Design and Eligibility • To assess the efficacy and tolerability of oral olaparib in BRCA1/ BRCA2 mutation carriers with breast cancer • Proof-of-concept phase II study, single-arm, international multicenter Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy Cohort 1 (enrolled first) Cohort 2 * Olaparib 400 mg po bid Olaparib 100 mg po bid 28-day cycles; 27 patients 28-day cycles; 27 patients *Withdrawal rate in cohort 2 monitored and compared with cohort 1. If significantly greater withdrawal rate in cohort 2 dose escalation was triggered
    • Objective tumor response rate (RECIST) Olaparib Olaparib ITT cohort 400 mg bid 100 mg bid (n=27) (n=27)Overall Response Rate, n (%) 11 (41)* 6 (22)* Complete Response, n (%) 1 (4) 0 Partial Response, n (%) 10 (37) 6 (22)Stable disease, n (%) 12 (44) 12 (44)Progressive disease, n (%) 4 (15) 9 (33) Favorable toxicity profile: mild nausea, fatigue
    • Resistance? • Secondary mutations with functional restoration of BRCA proteins • Identified in BRCA1 and BRCA2 mutation carriers with cisplatin resistant recurrent ovarian cancer – Sakai et al Nature, 2008, Swisher et al Cancer Res, 2008; Sakai et al Cancer Res, 2009 • Identified in BRCA2 mutation carrier with progression through PARP inhibition – Edwards et al, Nature 2008
    • More than BRCA1/2? • The concept of “BRCA-ness” – Basal phenotype of breast cancer – Ovarian cancer • Phase II trial in triple negative breast cancer – 120 patients randomized to carboplatin/gemcitabine and BSI PARP inhibitor – iniparib – 201 compared to carboplatin/gemcitabine alone – Significant improvement in progression free and overall survival with PARP inhibitor – No increased toxicity – Phase III trial has completed accrual and results are……. O’Shaughnessy, NEJM 2011
    • NegativeTrial did not meet its primary endpoint
    • Why did the iniparib study fail? • The concept of “BRCA-ness” – Is this wrong? – Increasingly recognized that there are multiple molecular subtypes of triple negative breast cancer – Did it work in BRCA1 mutation carriers? Will we ever know? • Iniparib used as a chemosensitizer • Second and third line apparently did meet primary endpoint • Lessons: - ? Make sure you have your group well defined - Or at least get DNA on everyone
    • Future of PARP inhibitors? • Olaparib – Development suspended in BRCA1/2 related cancers – Studies planned in sporadic ovarian cance • Iniparib - has never been developed in mutation carriers • Veliparib – Abbott compound – Combination with temazolamide - activity in BRCA1/2 mutation carriers • Merck and Pfizer – early phase studies - ?development • All PARP inhibitors are not alike
    • Concluding comments• Oncotype testing in node-positive patients?• Optimum chemotherapy for HER2 positive patients with early-stage breast cancer?• Trastuzumab DM-1• MTOR inhibition• Whither bevacizumab?• PARP inhibitors?