Breast Cancer 101: Update on Treatment Julie R. Gralow, M.D. Director, Breast Medical Oncology Jill Bennett Endowed Professor of Breast Cancer University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle Cancer Care Alliance Breast Cancer Treatment: A Multidisciplinary Team Approach Fighting the Crab Kiev, Ukraine Radiology Pathology Surgery Radiation Oncology Medical Oncology Breast Cancer: Prognostic and Predictive Factors HER-2 + 25% of Breast Cancer Estrogen Receptor (ER) + 75% of Breast Cancer Stage: Tumor size Lymph node involvement Distant spread Grade Estrogen receptor status HER-2 expression Proliferation (Ki67) & DNA status Lymphovascular invasion Page 1
Genomic Profiling of Cancer: Breast Cancer is NOT One Disease! The Cancer Genome Atlas Network. Nature, epub Sept 23, 2012 4 main subtypes of breast cancer identified across multiple platforms Luminal A Luminal B HER2E Basal Subtypes vary with respect to: Likelihood of recurrence Sites of metastases Response to treatment Additional subtypes likely exist Breast Cancer Surgery Sometimes less surgery is better Mastectomy vs. lumpectomy Axillary lymph node dissection vs. sentinel lymph node biopsy Post-mastectomy Options Breast reconstruction Breast Cancer Radiation Therapy The future: is less radiation sometimes better? Brachytherapy, partial breast radiation Hypofractionation (higher individual doses, but shorter duration) Omitting radiation in low risk, elderly patients Page 2
Systemic Therapy for Breast Cancer Endocrine Therapy Chemotherapy Biologically-targeted Therapy New Strategies: Better Targeting Endocrine Therapy Luminal A and B Breast Cancer Subtypes: Estrogen Receptor as a Target for Therapy Aromatase inhibitors (letrozole, anastrozole, exemestane), ovarian suppression 75-80% of breast cancers express ER SERMS (tamoxifen), SERDS (fulvestrant) Estrogen Estrogen Receptor Cell Growth and Division Page 3
Selective Estrogen Receptor Modulators Early Breast Cancer Trialists Collaborative Group 2000 (Oxford Overview) Tamoxifen vs. Nil: Disease-free Survival ER Negative ER Positive tamoxifen nil Duration Of Tamoxifen Studies (5 Years Vs Longer) Early studies showed 5 years tamoxifen optimal ECOG, Scottish, NSABP B-14 ~1,600 patients total Recent studies: ATLAS ~ 11,500 total: Recently published attom ~7,100: to report at ASCO 2013 ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years) Davies C et al, Lancet 2012, epub ahead of print Breast cancer patients completing 5 years tamoxifen 54% node-negative Analysis only includes 6846 documented ER+ patients Randomized to continue tamoxifen to year 10, or stop at year 5 Reporting on 8 yrs median follow-up: compliance, recurrence, death ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years) Davies C et al, Lancet 2012, epub ahead of print Recurrence Overall mortality Breast cancer mortality 10 years 5 years P value 617 events 711 events 21.4% 25.1% P=0.002 639 events 722 events 12.2% 15% P=0.01 331 events 397 events P=0.01 Little effect years 5-9; benefit mainly after year 10 Compliance after 2 years 80% Only reported toxicity resulting in hospitalization/death Ischemic CVD HR 0.76 p=0.02 Endometrial cancer HR 1.74 p=0.0002 (3.1% vs 1.6%) PE HR 1.87 p=0.01 CVA HR 1.06 (ns) Page 4
Anastrozole Letrozole Exemestane Aromatase Adrenal Hormones Cortisol Androstenedione Aldosterone Estrone Testosterone Aromatase inhibitors block post-menopausal estrogen production Estradiol Adjuvant Aromatase AIs have generally replaced tamoxifen as adjuvant therapy in postmenopausal, ER+ breast cancer Three Strategies AIs as Initial Therapy AIs After 2-3 Yrs of TAM AIs After 5 Years of TAM TAM X 5 Yrs TAM X 5 Yrs AI X 5 Yrs TAM X 2-3 AI X 2-3 AI X 5 Yrs TAM X 5 Yrs PLAC X 5 Yrs ATAC and BIG1-98 studies Reduction in recurrences IES, MA-17 Survival benefit for AI arm Fracture Rates in Adjuvant Aromatase Inhibitor vs Tamoxifen Trials % of patients with fracture Fractures and bone loss increased in patients on AIs ATAC Trialists Group, Lancet 365:60-62, 2005; Thurlimann et al, N Engl J Med 353:2747, 2005; Coombes et al, Lancet 369:559-570, 2008 Page 5
Under Study: Extended Adjuvant Aromatase Inhibitor Therapy NCIC MA.17R TAMOXIFEN ANY AI 0-5 yr 5 yr NSABP B-42 PLACEBO LETROZOLE 5 yr PLACEBO TAMOXIFEN ANY AI 0-5 yr 0-5 yr 5 yr total LETROZOLE 5 yr SOLE TAMOXIFEN ANY AI LETROZOLE 0-5 yr 0-5 yr LET LET LET LET 4-6 yrs total Overcoming Endocrine Resistance PI3 Kinase and mtor Pathways Integrins ER Cancer Cell Reduced Gene Transcription HER-2 PTEN PI3-K LKB1 AMPK ILK Akt/ PKB TSC1/TSC2 Energy 4E-BP1 elf-4e mtor RAD001 FKBP-12 P S6K1 S6 Reduced Cell Growth EGFR Reduced Proliferation Reduced VEGF Production PI3K and mtor pathways connected to HER-2, EGFR, VEGF and Estrogen Receptor (ER) Overcoming Endocrine Resistance BOLERO-2 Randomized Phase III Trial of Exemestane +/- Everolimus Baselga J et al, NEJM 366:520-529, 2012 N = 724 Postmenopausal ER+ Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole Randomized 2:1 Everolimus 10 mg daily + Exemestane 25 mg daily (n = 485) Placebo + Exemestane 25 mg daily (n = 239) Page 6
Overcoming Endocrine Resistance BOLERO-2 Randomized Phase III Trial of Exemestane +/- Everolimus Baselga J et al, NEJM 366:520-529, 2012 EXEM EXEM+RAD Response 1.3% 12% p<0.0001 Clinical Benefit 25.5% 55.5% p<0.001 PFS 4.1 mo 11.0 mo p<0.0001 Deaths (12 mo) 23% 17% Grade 3/4 toxicities >5%: Stomatitis Fatigue Dyspnea Anemia Everolimus FDA approved Fall 2012 in metastatic breast cancer SWOG S1207 Adjuvant everolimus trial about to open in early stage breast cancer Chemotherapy EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: Deaths (Overall 14.8% +/- 2.1 reduction) Entry Age Events/Women Ratio annual deaths Chemo Control Chemo: Control < 40 293/960 335/908 29%+/-7 (30.5%) (36.9%) 40-49 674/2480 783/2391 26%+/-5 (27.2%) (32.7%) 50-59 1658/4880 1918/5143 15%+/-3 (34.0%) (37.3%) 60-69 70+ 1851/4886 210/570 2000/4967 264/610 (37.9%%) (36.8%) (40.3%) (43.3%) 7%+/-4 11%+/-11 0.5 1.0 1.5 Page 7
Chemotherapy for Early Stage Breast Cancer THE PAST (2000 NCI Consensus Development Conference on Adjuvant Breast Cancer) Chemotherapy should be offered to the majority of women with early stage breast cancer regardless of size, lymph node, menopausal or hormone receptor status THE PRESENT AND FUTURE Individualizing estimates of recurrence risk and chemotherapy benefit using genomic/molecular profiling Many patients don t need chemotherapy Genomic Profiling in Clinical Prctice: 21-Gene Recurrence Score Assay Recurrence Score in LN-, ER+ if 5 Years Tamoxifen RS of 39 = 27% 10 yr distant relapse rate despite tamoxifen Lower RS Less likelihood of recurrence Greater tamoxifen benefit No to minimal chemotherapy benefit Higher RS Greater likelihood of recurrence Less tamoxifen benefit Clear chemotherapy benefit Ongoing SWOG S1007 validation study in 1-3+ LN Biologic Therapy Page 8
The Human Epidermal Growth Factor Family of Receptors Lapatinib HER1 EGFR HER2 HER3 HER4 Tumor Cell Erlotinib Gefitinib Cetuximab Trastuzumab Pertuzumab Ado-trastuzumab emtansine HER-2 Enriched Breast Cancer Subtype: Four FDA-Approved Drugs with HER-2 as a Target HER-2 cancer cell 20-25% of breast cancers Pertuzumab overexpress HER-2 Anti-HER-2 Antibody Trastuzumab Anti-HER-2 Antibody T-DM1 Antibody-Drug Conjugate nucleus cell division Lapatinib Dual HER-1/HER-2 Tyrosine Kinase Inhibitor Adjuvant (Early Stage) Trastuzumab: Combined Analysis of NSABP B-31 and N9831 Romond E et al, N Engl J Med 353, 2005 300 250 Number of patients 200 150 100 50 Chemo Alone Chemo + Trastuzumab 0 Recurrence Death Risk of breast cancer recurrence reduced by 52% at 3 yrs Risk of death decreased by 33% Increased risk of class III/IV CHF (absolute risk 3-4%) Page 9
Combined HER-2 Targeted Therapy ALTTO Trial: Adjuvant HER2+ Trial (Early Stage) Closed to Accrual PIs: M Piccart, E Perez Early stage HER-2+ Breast Cancer Patients R A N D O M I Z E (paclitaxel) trastuzumab (trast for 1 yr) (paclitaxel) lapatinib (lap for 1 yr) (paclitaxel) trastuzumab+ lapatinib (trast + lap for 1 yr) (paclitaxel) trastuzumab (12 weeks), 6-week wash out, lapatinib (34 weeks) N= 8,000 Lapatinib is a dual HER-1/HER-2 Tyrosine Kinase Inhibitor (TKI) Combined HER-2 Targeted Therapy Neo ALTTO: Preoperative HER-2+ Therapy Baselga J et al, Lancet 379:633-640, 2012 Invasive, operable HER-2+ breast cancer N=450 R A N D O M I Z E Lapatinib 1500 mg/d paclitaxel Trastuzumab weekly paclitaxel Lapatinib 1000 to 750 Trastuzumab paclitaxel S U R G E R Y F E C X 3 lapatinib trastuzumab lapatinib trastuzumab Will increased pcr rates translate to improved PFS and OS? Pathologic Complete Response Rates (at the time of surgery) FDA investigating pcr as an accelerated approval pathway Combined HER-2 Targeted Therapy CLEOPATRA Phase III Trial: Trastuzumab/ Docetaxel +/- Pertuzumab 1 st Line HER2+ Metastatic Breast Cancer Baselga J et al, NEJM 366:109-19, 2012 HER2-positive Metastatic Breast Cancer (N = 808) 1:1 n=406 n=402 Placebo + Trastuzumab Docetaxel Pertuzumab + Trastuzumab Docetaxel Pertuzumab is a monoclonal antibody to HER-2 with a different binding site from trastuzumab Page 10
CLEOPATRA Results Doc/Trast/Placebo Doc/Trast/Pertuzumab PFS 12.4 mo 18.5 mo Response 69.3% 80.2% CR 4.2% 5.5% PR 65.2% 74.6% Deaths (19 mos) 96 69 Pertuzumab increased diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin»no increase in cardiac adverse events Pertuzumab FDA approved June 2012 High response rates with trastuzumab alone which HER-2+ tumors really need both drugs 1 st line? Ado-Trastuzumab Emtansine (T-DM1) The Magic Bullet Approach Trastuzumab Mertansine: anti-tubulin Comparison Between HER2 Targeted Agents EMILIA: T-DM1 vs. Capecitabine + Lapatinib in Refractory HER-2+ Metastatic Breast Cancer Verma S et al, NEJM 367:1783-1791, 2012 HER-2+ metastatic breast cancer previously rec d taxane and trastuzumabbased Rx (n>600) T-DM1 (ado-trastuzumab emtansine) (3.6 mg/kg) IV q3w Lapatinib (1250mg/day) Days 1-21 + Capecitabine(1000mg/m 2 ) Days 1-14 q2w Page 11
Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0.0 Progression-Free Survival 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mos) EMELIA: Results Proportion surviving 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (mos) PFS PFS events OS OS events Cap + Lap 6.4 mos 304 23.3 mos 129 T-DM1 9.6 mos 265 NR 94 HR=0.650 (95% CI, 0.55, 0.77) HR=0.621 (95% CI, 0.48, 0.81) P=0.0005 P<0.0001 Efficacy stopping boundary P=0.0003 or HR=0.617 T-DM1 superior to capecitabine/lapatinib in tumors progressing on trastuzumab 1.0 0.8 0.6 0.4 0.2 0.0 Overall Survival 84.7% T-DM1 (adotrastuzumab emtansine) FDA approved March, 2013 77.0% 65.4% 47.5% Basal/Triple Negative Breast Cancer Subtype: A Highly Diverse Group of Cancers Lehmann BD, et al. J Clin Invest 121:2750-67, 2011 15-20% of breast cancer does not express ER, PR, or HER-2 6 subtypes of TNBC identified by gene expression array Is Triple Negative Breast Cancer Positive for Anything? EGFR expression and p53 mutations commonly increased Other receptors and pathways can be altered (c-kit, c-met, RAS-MAPK) Differential sensitivity to chemotherapy: Platinum agents Associated with DNA repair defects PARP1 commonly increased Page 12
Poly ADP-Ribose Polymerase (PARP) as a Target for Therapy PARP1 Enzyme with role in DNA repair Upregulated in triple negative (ER-, PR-, HER2-) breast cancer Needed for survival of BRCA-deficient cells Environmental factors (UV, radiation, chemicals) Normal physiology (DNA replication) Chemotherapy, Radiotherapy DNA DAMAGE Cell Death Single Strand Breaks Base excision repair PARP1 Replication Lesions DNA REPAIR PATHWAYS Base excision repair PARP1 Double Strand Breaks DNA Adducts/Base Damage Homologous recombination Base excision repair BRCA1/BRCA2 PARP1 Ongoing UW/SCCA Phase I Trial of Cisplatin/Vinorelbine with PARP Inhibitor ABT-888 (Veliparib) in Triple Negative Breast Cancer PI: E Rodler Maximum Tumor Response (%) from Baseline 36 patients enrolled to date Metastatic, TNBC Currently at dose level 7 of veliparib Targeting the Cancer Environment In Addition to Targeting the Cancer Cell, We Can Also Target the Cancer Environment to Make it Less Friendly Cancer cell Fibroblast Immune cell Blood vessels Page 13
Targeting the Immune System Ongoing UW HER-2 Vaccine Therapy Trials N. Disis and L. Salazar Whole HER-2/neu Protein 1255 Amino Acids WILL NOT STIMULATE AN IMMUNE RESPONSE Selected Peptide fragments of 9-15 Amino Acids in length PREDICTED TO STIMULATE AN IMMUNE RESPONSE Ongoing UW HER-2 Vaccine Therapy Trials N Disis and L Salazar HER-2 Peptides Immune Adjuvant Vaccine for Injection Targeting the Cancer Environment: Bone Inhibition cancer cells PTHrP, prostaglandins, interleukins, RANK-L osteoclasts osteoblasts, macrophages IGF, PDGF, TGF-B Page 14
Bone is the Most Common Site of Breast Cancer Metastasis Complications of Breast Cancer Bone Metastases Hypercalcemia Radiation therapy Pain Spinal cord compression Orthopedic surgery Fractures Treatment of Bone Metastases Osteoclast-Targeted Agents Reduce Skeletal Related Events in Breast Cancer % pts with SRE Placebo 65% 24 months 1 Pamidronate 46% Pamidronate 49% 24 months 2 Zoledronic Acid 46% (not sig) Placebo 50% 12 months 3 Zoledronic Acid 30% Zoledronic Acid 36.5% 17 months 4 Denosumab (RANK Ligand Inhib) 30.7% 1 Lipton A et al, Cancer, 2000; 2 Rosen LS et al, Cancer, 2003; 3 Kohno N et al, J Clin Oncol 23, 2005, 4 Stopeck A et al, JCO 2010 Page 15
Osteonecrosis of the Jaw (ONJ): Increased with Long-term Use of High Dose Bisphosphonates and RANK Ligand Non-healing, exposed bone in the jaw Can Adjuvant Bisphosphonates Reduce Recurrence? ABCSG-012: Premenopausal Breast Cancer Pts Receiving Adjuvant Hormonal Rx Gnant M et al, N Engl J Med 360:679-691, 2009 Gnant M et al, SABCS 2011, Abstract S1-2 1800 premenopausal women with hormone-responsive early breast cancer Goserelin 3 years Randomised 1:1:1:1 Anastrozole Tamoxifen No ZOL + ZOL Recurrences 132/903 98/900 (14.6%) (10.9%) (p=0.014 HR 0.72) Distant 65 56 Locoregional 36 19 Zoledronic acid 4mg q6 mo Control Zoledronic acid 4mg q6 mo Control Deaths 49/903 33/900 (5.4%) (3.7%) (p=0.049 HR 0.63) Identifying Additional Targets in the Treatment of Breast Cancer Metastasis Anti- Angiogenesis HIF Raf Death Receptors EGFR Proteosome HER-2 mtor HSP90 MEK Tubulininteracting Agents IGF-R Src Cell Cycle HDAC MUC-1 Antibodies Farnesyl Transferase Pro-apoptotic Drugs Mdm2 Kinesins Aurora Kinase Courtesy of D. Budman Page 16
UW Center for Cancer Innovation PI: T Blau Tailor made Treatment Patient Panel of Top Medical Scientific Expertise Across Institutions - High Quality Tissue Procurement/storage IT Technology Disease Pathways Processing DNA Copy # Variation Omics Epigenomics Methylomics Mutation Amplification Deletion Methylation Next Gen Seq Deep Seq Whole M Del Genome Seq Exomics Genomics Regulation activator, repressor, CoA, Co R or translocation (not shown) RNA M Transcriptomics (mostly quantitative expression; some qualitative) Splice Variant; isoforms or or Protein M Proteomics Post Trans Modification or or Metabolites Metabolomics Courtesy of D. Hayes Maximizing Overall Health and Quality of Life after a Breast Cancer Diagnosis and Treatment Managing menopausal effects Physical activity Nutrition Body weight Sexuality Fertility Cognitive function Page 17
Managing Menopause: Gabapentin and Venlafaxine for Alleviation of Hot Flashes in Breast Cancer Survivors Loprinzi C et al, J Clin Oncol 2009 Patients: Breast cancer patients with bothersome hot flashes (70% on tamoxifen) Results: Mean hot flash score reduced (daily frequency x average severity) Therapy weeks Drug Pt # Baseline 1 2 3 4 Gabapentin 20 100% 59% 43% 32% 27% Venlafaxine 47 100% 62% 51% 49% 47% Team Survivor Northwest An Exercise and Fitness Program for Women Cancer Survivors Page 18