Updates in the Treatment of Breast cancer Mohammad Jahanzeb, MD, FACP Professor of Clinical Medicine, Hematology-Oncology Director, UM Sylvester Deerfield Campus Associate Center Director for Community Outreach Sylvester Comprehensive Cancer Center University of Miami, Miller School of Medicine Clinical Breast Cancer Subsets defined by IHC ER+ 65-75% All Breast Cancers HER2+ 15-20% Triple negative 15% H Burstein and A Goldhirsch St Gallen 2007 HER2 Positive Disease Milestones of HER2/anti-HER2 therapies in BC 1978 1982 1983 1984 1985 1987 1998 2006 2010 2007 2013 2012 EGFR discovery Cohen FDA approves trastuzumab alone for 2nd line and in with paclitaxel for 1st line MBC neu oncogene discovery Weinberg Her2 cloned Ullrich and Coussens EGFR MoAb inhibited growth Mendelsohn Her2/neu amplification correlates with shorter survival Slamon Her2 amplification in breast cancer Aaronson MBC : metastatic breast cancer; MoAb : monoclonal antibody FDA approves lapatinib + letrozole for MBC FDA approves trastuzumab emtansine for MBC FDA approves lapatinib + capecitabine for MBC FDA approves trastuzumab in adjuvant setting FDA approves pertuzumab + trastuzumab + docetaxel for MBC Accelerated approval of pertuuzmab/ trastzumab as neoadjuvant therapy Expanding Options in HER2 Targeting Block heterodimerization – Add pertuzumab Antibody-toxin conjugate – TDM1 Downstream pathway inhibition – Block MTOR/PI3K? Oral panHER TKI – Lapatinib, neratinib Alternate antibody-drug conjugate – MM302 Optimal HER-2 Directed Therapy Sequencing for HER-2+ Advanced Breast Cancer Verma S et al. The Oncologist 2013;18:1153-1166 ©2013 by AlphaMed Press First results from the phase III ALTTO trial (BIG 02-06; NCCTG 063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L) or their combination (L + T) in the adjuvant treatment of HER2-positive <br />early breast cancer (EBC) Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting Adjuvant Lapatinib (ALTTO) Schema n=8381 total/6281 analyzed Chemotherapy + Trastuzumab X 1 year + Lapatinib X 1 year HER2+ ESBC + Trastuzumab+ Lapatinib X 1 year + Trastuzumab X 3 months → Lapatinib X 9 months Different treatment approaches • Sequential anti-HER2 therapy after all chemo (N= 4,613) • Concurrent anti-HER2 therapy after anthracycline-based chemo (N=3,337) • Concurrent anti-HER2 therapy with non-anthracycline chemo (N=431) Piccart et al, ASCO 2014 DISEASE-FREE SURVIVAL (DFS) ANALYSIS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting OVERALL SURVIVAL (OS) ANALYSIS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting Take Home Message from ALTTO While there was doubling of pCR in the NEOALTTO study, it did not translate into improved survival outcomes in ALTTO at 4.5 years follow up There was increased toxicity noted with lapatinib: diarrhea, rash or erythema APHINITY ADJUVANT TRIAL N=4805 TCa x 6 Completed recruitment on 31-Aug-2013 TCa x 6 TCa = 6 cycles of docetaxel and carboplatin 11 I-SPY 2 Trial Neratinib Arm HER2(+) Subset (n = 66 v 22 control) Signature Estimated pCR rate Neratinib Concurrent Controls Probability Neratinib is Superior to Control Predicted Probability of Success in Phase 3 HER2+/HR- 56% 33% 95% 79% HER2+/HR+ 30% 17% 91% 65% Neratinib is an oral dual HER2 and EGFR tyrosine kinase inhibitor Park et al AACR 2014 Neratinib Phase III Trials – Extending adjuvant therapy – Nala trial Neratinib/capecitabine vs lapatinib/capecitabine > 2 lines of HER2 targeted regimens for MBC – ISPY3 Neoadjuvant trial to follow ISPY2 Afatinib – Lux trial Vinorelbine/afatinib vs vinorelbine/trastuzumab Can HER2 PET Predict Response to Anti-HER2 therapy? THE ZEPHIR TRIAL Presented By Geraldine Gebhart at 2014 ASCO Annual Meeting Slide 9 Presented By Geraldine Gebhart at 2014 ASCO Annual Meeting Conclusions Absence of HER2 target per HER2 PET predicts treatment failure Imaging early treatment response with FDG PET predicts treatment success Combining both imaging modalities improves predictive accuracy – HER PET+/FDG decline – 100% PPV – HER2 PET-/No FDG decline- 100% NPV Hormone Receptor Positive Disease Current Standard Options for Adjuvant Endocrine Therapy Menopausal Status at Diagnosis Pre / perimenopausal Postmenopausal Initial Therapy Extended Therapy Tamoxifen5 Tamoxifen5 Tamoxifen5 AI5 (*if post-menopausal) AI5 Tamoxifen2-3 AI2-3 Tamoxifen5 AI5 Tamoxifen5 Tamoxifen5 There are insufficient data currently to recommend AI for > 5 years What about ovarian suppression? What about AI + OFS in premenopausal women? Adapted from ASCO Guidelines 2014. Available at: www.asco.org SOFT/TEXT SOFT: SUPPRESSION OF OVARIAN FUNCTION TRIAL TEXT: TAMOXIFEN AND EXEMESTANE TRIAL (at NYU) Both Phase III Trials; Exemestane Plus gonadotrophin-releasing hormone (GnRH) Analogue as adjuvant therapy for premenopausal women with hormone receptor positive breast cancer Question: is temporary ovarian function suppression with GnRH analogues (ovarian ablation permanent with surgery or radiation) useful when combined with AI or TAM. Goserelin (zoladex 3.6 sc monthly), leuprorelin (lupron 3.75 im monthly), buserelin, triptorelin (3.75 im monthly) DFS event rate much lower than anticipated combined analysis (4690 patients) TEXT & SOFT Tamoxifen + OFS vs. Exemestane + OFS Stratified by trial, use of chemotherapy, nodal status TEXT Premenopausal, HR+ BC Tamoxifen 20 mg/day + OFS* (n = 1338) Joint Analysis Tamoxifen + OFS* ≤ 12 wks after surgery N = 2672 • SOFT Premenopausal HR+ BC ≤ 12 wks after surgery (if no chemo) or • ≤ 8 mos after chemo if Exemestane 25 mg/day + OFS* (n = 1334) Tamoxifen 20 mg/day + OFS* (n = 1024) Exemestane 25 mg/day + OFS* (n = 1021) N = 2344 Median follow up: 68 months 42% N+ Neo/Adjuvant chemotherapy: 58% Exemestane+ OFS* premen status confirmed • N = 3066 Tamoxifen 20 mg/day *OFS TEXT: triptorelin 3.75 mg IM every 28 days for 6-8 weeks prior to initiation of HT or concurrently with chemotherapy. SOFT: triptorelin, bilateral oophorectomy or Ovarian irradiation N = 2346 Pagani O, et al. NEJM July 2014. SOFT/TEXT: Exemestane + OFS better DFS Median f/u 5.7 years SOFT/TEXT: selected AEs QOL not different Early cessation of treatment 16 vs 11% SOFT/TEXT: take home message Low event rates Exemestane with ovarian function suppression is a new evidence based treatment option for premenopausal women with HR+ early breast cancer Important question from SOFT (tamoxifen+OFS vs tamoxifen) will be answered end of 2014 Some premenopausal women diagnosed with HR+ breast cancer have an excellent prognosis with highlyeffective endocrine therapy alone (>97% BC free at 5 yrs) Need longer f/u, esp OS ABCSG-12: Study Design Key endpoints – Primary: DFS at 5 yrs – Secondary: relapse-free survival, OS, BMD, safety Treatment 3 yrs (median follow-up: 62 mos) 1803 premenopausal pts with stage I/II BC • 80% > 40 yrs • N+ 30% • OFS: Goserelin Q 28 days • OFS started concurrently with endocrine therapy • Only 5% received Chemotherapy TAM 20 mg/day ANA 1 mg/day R TAM + ZA 4 mg q6m ANA + ZA 4 mg q6m Long-term monitoring for 5 yrs for recurrence and survival (DFS, OS) 3-yr BMD Gnant M, et al. N Engl J Med. 2009, Lancet 2011 5-yr BMD ABCSG-12 (84 Months) ET + Zometa Vs ET DFS 80 80 60 60 88% vs 92 % p=0.009 40 40 20 20 0 0 0 12 24 36 48 60 72 84 96 108 Mos Since Randomization Patients at Risk, n No ZA 903 858 833 807 ZA 900 862 841 822 758 653 788 674 Gnant M, et al. Lancet 2011. OS 100 OS (%) DFS (%) 100 521 405 544 419 95% vs 97% p=0.09 0 12 24 36 48 60 72 84 96 108 Mos Since Randomization 191 208 Patients at Risk, n No ZA 903 864 856 839 ZA 900 868 858 849 811 706 818 708 576 456 587 454 215 232 ABCSG-12 (84 Months): DFS Tamoxifen vs AI Conclusions Highly effective endocrine therapy alone offers excellent prognosis for some premenopausal women with HR+ BC – 95% 5 year OS in all three studies. Role of OFS: Await data on Tam vs Tam + OFS Side effects of OFS should not be underestimated. I am not ready to use AI + OFS in premenopausal women yet. Targeted Therapies for ER+ MBC CDK 4/6 regulates cell cycle progression • Palbociclib is an oral, potent inhibitor of CDK4/6 • PALOMA-1: – Palbo + Letrozole is superior to Letrozole in 1st line ER+ MBC (median PFS 20.2 vs. 10.2 mo, HR 0.49, p=0.0004) CDK4/6 inhibitor summary Palbociclib improves PFS with letrozole – Confirmatory phase III trials ongoing – Watch for maturing data in combination with fulvestrant or paclitaxel Several other CDK4/6 inhibitors in development, such as abemaciclib and LEE011 Many remaining questions: – Is there an optimal endocrine, chemotherapy or targeted therapy partner? – How do we sequence these relative to everolimus? – What are mechanisms of resistance? Presented by: Tiffany A. Traina, MD Next? Palbociclib: accelerated FDA submission expected PALOMA 2 (Letrozole +/-) PALOMA 3 (Faslodex +/-) Novartis: Monaleesa (Let +/-) Lilly: RTC Others? Triple Negative Disease TNBC patients have a worse prognosis NTN stage I TN stage I Non TN stage II TN stage II Non TN stage III TN stage III Bauer et al Cancer May 2007 Triple-negative phenotype and molecular sybtypes. Carey L A The Oncologist 2010;15:49-56 TNBC Shares Clinical and Pathologic Features With BRCA1-Related Breast Cancers Characteristics ER/PR/HER2 status TP53 status BRCA1 status Gene-expression pattern Tumor histology Chemosensitivity to DNAdamaging agents Hereditary BRCA1 Triple Negative/Basal-like[1-3] Negative Negative Mutant Mutant Mutational inactivation* Diminished expression* Basal-like Basal-like Poorly differentiated (high grade) Poorly differentiated (high grade) Highly sensitive Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4 1. Perou CM, et al. Nature. 2000; 406:747-752. 2. Cleator S, et al. Lancet Oncol. 2007;8:235-44. 3. Sorlie T, et al. Proc Natl Acad Sci U S A. 2001;98:10869-10874. 4. Miyoshi Y, et al. Int J Clin Oncol. 2008;13:395-400. Platinum Agents in TNBC Good preclinical rationale, particularly in BRCA-associated Clinical data: Trial Population Results Control arm BALI-1 (CDDP) Sporadic TNBC 10% RR Control arm phase III iniparib (gem/carbo) Sporadic TNBC 30% RR TBCRC 001 (cetuximab/carbo) Sporadic TNBC 17% RR BRCA1+ 86% pCR Sporadic TNBC 15% pCR 14-pt trials neoadj CDDP (Byrski + Silver) 24-pt trial neoadjuvant CDDP (Silver) Clinical role of platinums less clear: promising in BRCA+ CALGB 40603 and other trials designed to clarify Baselga J, et al. Ann Oncol. 2010;21(Suppl 8). Abstract 274O. O’Shaughnessy J, et al. J Clin Oncol. 2011;29(Suppl). Abstract 1007. Carey L, et al. 2008;26(Suppl). Abstract 1009. Byrski T, et al. J Clin Oncol. 2010;28:375-379. Silver DP, et al. J Clin Oncol. 2010;28:1145-1153. Neoadjuvant Carboplatin for TNBC Summary of recent randomized trials Study Design N pCR Control Platinum GeparSixto nplDox/Pac/Bev +/- wCb (AUC1.5) X 18 wks 315 42.7% 53.2% ALLIANCE 40603 2x2 design wPac +/- Cb (AUC 6) +/- bev AC X 4 433 41% 54% GEICAM/2006-03 ECX4D +/-Cb AUC6 X 4 94 30% 30% ISPY2 wPac+/-Cb/veliparib ACx4 71 26%(est) 52%(est) Both GeparSixto and CALGB 40603 included Bev along with Cb and I spy included PARPi von Minckwitz, Lancet Oncol 2014; 15: 747–56; Sikov, SABCS 2013; Rugo SABCS 2013; Alba, BCRT, 2012 (136) Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide / epirubicin / 5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA breast cancer. Kenji Tamura, Jun Hashimoto, Hitoshi Tsuda, Masayuki Yoshida, Hideko Yamauchi, Kenjiro Aogi, Satoru Shimizu, Hiroji Iwata, Norikazu Masuda, Naohito Yamamoto, Kenichi Inoue, Shinji Ohno, Katsumasa Kuroi, Tamie Sukigara, Yasuhiro Fujiwara, Masashi Andoh Abstract 1017 Aims • Compare pCR in HER2 Negative tumors with paclitaxel +/- carbo followed by CEF (note: ER+ and TNBC combined) • Evaluate pretreatment biomarkers Ki-67, EGFR, Cytokeratin (CK) 5/6, BRCA1, vimentin, ERCC1 and ZEB1 by IHC Study Schema Paclitaxel 80 mg/m2 qwk x 12 CP-CEF Carboplatin AUC5 q3wks x 4 R Enrolled 181 pts N= 75 for TNBC 56% Node positive P-CEF Paclitaxel 80 mg/m2 qwk x 12 CEF 500/100/500 mg/m2 q3wks x 4 S U R G E R Y HER2 (-) BC Stage II/IIIA 18-70 years PS 0/1 Good Organ function Written IC CEF 500/100/500 mg/m2 q3wks x 4 Results 100 80 pCR rate (%) pCR rate (%) 80 pCR rates 100 Primary Endpoint P =0.04 60 32% 40 17% 20 0 CP-CEF P-CEF All patients 62% 60 40 26% 20 0 CP-CEF P-CEF TNBC patients p= N.S. p=0.040 pCR rates by EGFR expression pCR rate (%) 80 p=0.010 63.6 60 45.0 40 20 11.5 22.2 18.2 6.7 0 All CP EGFR- P All CP EGFR+ P Mechanisms of Synthetic Lethality-PARP-1 41 Image from: Iglehart JD, Silver DP. Synthetic Lethality-A new direction in cancer-drug development. NEJM 2009; 361 (2) ; 189-191. 2009 Massachusetts Medical Society. All rights reserved. Permission requested. I-SPY 2 TRIAL: Learn, Drop, Graduate, and Replace Agents Over Time Paclitaxel+ Trastuzumab Randomize HER 2 (+) Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + Trastuzumab* + New Agent B AC Learn and adapt from each patient as we go along Paclitaxel Paclitaxel ++ Trastuzumab* Trastuzumab* ++ New New Agent Agent F C Patient is on Study Key Paclitaxel Randomize MRI Residual Disease Surgery HER 2 (–) Paclitaxel + F New Agent C Paclitaxel + New NewAgent AgentGH D AC Surgery (Pathology) Paclitaxel + New Agent E 42 The I-SPY 2 Bayesian model estimates the probability distribution of pCR rates in each signature Actual pCR rates are biased by the adaptive randomization and are not calculated Rugo et. al. SABCS 2013 Veliparib/Carboplatin GRADUATES in the Triple Negative Signature Estimated pCR Rate (95% probability interval) SIGNATURE All HER2HR+/HER2- HR-/HER2- Veliparib/ Concurrent Carbo Control 33% 22% (22-43%) (10-35%) 14% 19% (4-27%) (6-35%) 52% 26% (35-69%) (11-40%) Probability Veliparib + Carbo is Superior to Control Predictive Probability of Success in Phase 3 92% 55% 28% 9% 99% 90% Rugo et. al. SABCS 2013 PARP Inhibitors in Development • • • • • • • • • Olaparib (Astra Zeneca) PO Veliparib (ABT888 - Abbvie) PO BMN-673 (Biomarin) PO Niraparib (MK-4827) PO CEP 9722 (Cephalon) PO GPI 21016 (MGI Pharma) PO Iniparib (BSI 201 – Sanofi-Aventis) IV Rucaparib aka AGO 14699 (Pfizer) IV INO 1001 (Inotek – Genentech/Roche) IV • Others? TNBC: potential therapeutic targets Mayer I A et al. Clin Cancer Res 2014;20:782-790 ©2014 by American Association for Cancer Research Novel Agents in Development for TNBC Met inhibitor: ARQ197, onartuzumab (Metmab), foretinib PI3K and/or inhibitor: BKM 120, temsirolimus (+ neratinib) HDAC inhibitors: entinostat, vorinosat Demethylating agents: azacitidine (+ entinostat) PARP inhibitors: ABT-888, E7449, Biomarin-BMN673, AZD2281, rucaparib Olaparib+ BKM120; Angiogenesis inhibitor: cediranib (+ olaparib), ramicurumab, IMC18F1, foretenib, sorafenib Hsp90 inhibitors: ganetespib Aurora kinase inhibitors: ENMD 2076 Androgen Receptor Blockers: EGF inhibitors: erlotinib (+ metformin), apatanib Lucitanib (FGFR+VEGF inhibitor) Masitinib (C-Kit inhibitor) MEK inhibitors: GSK1120212 Wnt inhibitor: LGK974 CDK inhibitor: dinaciclib, P276-00 FMS-Kit inhibitor: PLX3397 Apoptosis inducer: LCL161 (deactivating inhibitor of apoptosis proteins) Immunotherapy: MUC1 vaccine, adoptive cellular therapy (DC-CIK) Cytotoxics: SN38 -NK012, AEZS108 (LHRH-dox); Checkpoint inhibitors (anti PD-1, anti PDL-1) Biologics in Breast Cancer: Bevacizumab Antibody designed to normalizing the tumor blood vessels (antiangiogenic) and aid delivery of chemotherapy: Avastin (Bevacizumab) E5103: addition of Bev to standard AC-T in women with high risk breast cancer LN+ LN – (TN>1cm, HR+ >5 cm or <5 cm with oncotype >11) Bev at 15mg/kg given concurrently with chemo and +/maintenance In 2010 FDA rescinded Bev approval for metast BC E5103: Bevacizumab 2986 patients No benefit from addition of Bev Bevacizumab: take home message No role for bevacizumab in breast cancer (FDA approval rescinded for metastatic disease and no benefit shown in earlier stages, including E5103) Biospecimen bank with be utilized for predictors of toxicity and late relapse SWOG Proposed Study TNBC Post NAC PT1C or N+ N=400 Placebo x 1 year Primary endpoint: DFS R MK3475 x 1 year Anti-PD1 antibody A randomized, phase III trial to evaluate the efficacy and safety of MK3475 as adjuvant therapy for triple receptor-negative breast cancer with >1 cm residual invasive cancer or any positive lymph nodes (>pN1mic) after neoadjuvant chemotherapy Slide 28 Presented By Melinda Telli at 2014 ASCO Annual Meeting EA 1131A Placebo TNBC Post NAC PT1C or N+ Primary endpoint: DFS R Carboplatin X 4 cycles EA 1131A : A randomized, phase III trial to evaluate the efficacy of adjuvant carboplatin for triple receptor-negative breast cancer with residual invasive cancer SAFIR 01 Molecular-Driven Study Flow 427 Enrolled 407 MBC Bx (13%) 55 Genomic-driven Rx 299 Genomics 195 Druggable Lesions Most Activating Mutations are Rare Andre F, et al. Lancet Oncol 2014 17 Targeted Regimens SAFIR 01 Study Outcomes Targets addressed: • PI3KCA mutation • EGFR amplification • AKT mutation • FGFR amplification • IGF-1R amplification Overall Benefit Rate:12/407 (3%)Response Rate: 4/407 (1%) Andre F, et al. Lancet Oncol 2014 PREVENTION, SUPPORTIVE CARE & SURVIVORSHIP Prevention of Early Menopause Study<br />(POEMS)-S0230<br /> Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in early stage, hormone receptornegative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance) Presented By Halle Moore at 2014 ASCO Annual Meeting Background Presented By Halle Moore at 2014 ASCO Annual Meeting POEMS/S0230 Schema Presented By Halle Moore at 2014 ASCO Annual Meeting Results Ovarian failure at 2 years – Standard chemotherapy: 15/69- 22% – Standard chemotherapy + Goserelin: 5/66- 8% More women attempted and achieved successful pregnancies in the goserelin arm compared to the chemotherapy alone arm – 12/113 (12%) vs 22/105: (21%) Total number of babies: 12 vs 18 Increased menopausal symptoms during treatment No negative impact on cancer outcomes Take Home Message Fertility preservation is an important issue for young patients Current Options: - Ovarian Stimulation and embryo cryopreservation - Oocyte cryopreservation - Ovarian tissue cryopreservation (Experimental) - GnRH agonist during chemotherapy? Vitamin d and breast cancer<br />Background Presented By Ana Elisa Lohmann at 2014 ASCO Annual Meeting PROGNOSTIC ASSOCIATIONS OF 25OH VITAMIN D <br /> IN NCIC CTG MA.21 <br />A PHASE III ADJUVANT RANDOMIZED CLINICAL TRIAL <br />OF THREE CHEMOTHERAPY REGIMENS<br /> (CEF, EC/T, AC/T) IN HIGH RISK BREAST CANCER <br /> <br /><br /> Presented By Ana Elisa Lohmann at 2014 ASCO Annual Meeting Results Sample size – MA.21: N = 2104 patients – Vit D sub-study: N = 934 patients Low VIT D level was not associated with recurrence free survival, breast cancer free survival or overall survival However, – Most patients had adequate VIT D levels at study entry (mean VIT D level 27.9ng/ml), only 20% were deficient – One time point – Lack of data on VIT D supplementation – Analysis of a subset of patients not fully representative of the entire population – Restrictive study population (white, young and with high risk BC) Take Home Message Link between VIT D and breast cancer outcomes remains inconclusive Randomized trial desirable but not feasible – Common use of VIT D and better VIT D levels – Patients with low level might not want to get randomized to placebo Effect of obesity in premenopausal ER+ early breast cancer: EΒCΤCG data on 80,000 patients in 70 trials Independent prognostic factor (regardless of surgery type, tumor size, grade, LN status, chemo, hormonal therapy) Dose response: increasing BMI increasing BC mortality Pan et. al.PASCO201 4 abst # 503 Obesity confers worse outcomes in premenopausal ER+ BC Pan et. al. PASCO2014 abst # 503 THANK YOU!