Midwest Metastatic Breast Cancer Conference Douglas Yee, M.D. Director Masonic Cancer Center University of Minnesota Presented By: Title Sponsor:
Historical Overview & Evolution of Metastatic Breast Cancer Douglas Yee, MD Director, Masonic Cancer Center Professor of Medicine and Pharmacology Midwest Metastatic Breast Cancer Conference November 4, 2017
And you may ask yourself Well How did I get here? -Talking Heads (Eno, Frantz, Byrne, Harrison, Weymouth
How Did We Learn About Breast Cancer? Estrogen Receptor lucky guess HER2 nagging clinical question Triple-negative breast cancer new technology What s next?
Targeted Breast Cancer Therapy - 1896 Beatson GT Lancet 2:104-107 1896
Estrogen and Estrogen Receptor Ovary Ovary Estrogen Receptor Growth Genes - Off Estrogen Estrogen Receptor Growth Genes On!
Blocking Estrogen Production Pre-menopausal women make ovarian estrogen Ovary Ovary Stop ovarian function Goserelin/Leuprolide Surgical removal Estrogen Receptor Estrogen Receptor Growth Genes - Off Growth Genes - Off
Blocking Estrogen Receptor Function Ovary Block estrogen receptor filling Tamoxifen Fulvestrant Estrogen Receptor Estrogen Receptor Growth Genes - Off Growth Genes - Off
Turning Off Estrogen Post-menopausal women still make estrogen Adrenal Adrenal Stop estrogen production Anastrozole Letrozole Exemestane Estrogen Receptor Estrogen Receptor Growth Genes On! Growth Genes - Off
Angela M.H. Brodie 1934-2017
Inhibition of ERa Function LHRH LH, FSH LHRH Agonists/Antagonists Leuprolide Goserelin Adrenal Peripheral Ovary E1 Oopherectomy E2 Aromatase Inhibitor Anastrazole Letrozole Exemestane SERM Tamoxifen Torimefene Raloxifene Fulvestrant ERa ERE Co-Repressor NCo-R SMRT
Other Pathways Activate Estrogen Receptor Cell Signaling Pathways Cell Signaling Pathways Trastuzumab Everolimus Many experimental drugs Estrogen Receptor Estrogen Receptor Growth Genes On! Growth Genes - Off
Cross-talk between signal transduction pathways and ER signaling in endocrine-resistant breast cancer, with opportunities for targeted intervention. Johnston S R Clin Cancer Res 2010;16:1979-1987 2010 by American Association for Cancer Research
mtor Inhibition (Everolimus/Afinitor ) Enhances ER Targeting Strategies Exemestane Tamoxifen 1 o Resistance 2 o Resistance BOLERO 2 Phase 3 randomized to exemestane with or without everolimus (1:2) Previous treatment for MBC with nonsteroidal AI required TAMRAD Phase 3 randomized to tamoxifen with or without everolimus (1:1) Previous AI treatment required Baselga, et al. N Engl J Med 366:520 2012 PMID: 22149876 Bachelot, et al. J Clin Oncol 30:2718 2012 PMID: 22565002
Making the Lever Harder To Push Make ER lever stiffer Palbociclib Ribociclib Abemaciclib Estrogen Receptor Growth Genes On! Estrogen Receptor Growth Genes - Off
The role of CDK 4/6 in cell-cycle progression. Aki Morikawa, and N. Lynn Henry Clin Cancer Res 2015;21:3591-3596 2015 by American Association for Cancer Research
Palbociclib/Ibrance Improves Response To Fulvestrant/Faslodex Turner, et al. N Engl J Med 373:209 2015 PMID: 26030518
2 nd Drug Approved Ribociclib/Kisqali with Letrozole/Femara Hortobagyi, et al. N Engl J Med 375:1738 2016 PMID: 2771730
3 rd Drug Approved Abemaciclib/Verzenio Sledge, et al. J Clin Oncol 35:2875 2017 PMID: 285808
What s Next For Estrogen Receptor? More anti-estrogens oral fulvestrants Inhibitors of other pathways mtorc1 and mtorc2 Upstream and downstream of mtorc New pathways
1980s Why Do Identical Tumors Have Different Rates Of Recurrence? Clark, et al. New England Journal of Medicine 320:627
HER2/neu Oncogene Rat neuroblastoma used in 3T3 assay and neu identified in 1986. Neu related to Epidermal Growth Factor Receptor superfamily - HER2. Viral oncogene (avian erythroblastosis virus -erbb) related to EGFR family EGFR family members bind to multiple ligands and are transmembrane tyrosine kinases.
HER2 Amplification in Node-positive Breast Cancer Any Amplification > 5 copies Disease-free Survival Overall Survival Slamon et al. Science 235:177 1987
HER2 Amplification in Breast Cancer Green = Centromere Orange= HER2 Pauletti et al. J Clin Oncol 18:3651 2000
Trastuzumab (Herceptin ) Humanized Anti-HER2 Antibody Effective only in HER2 overexpressing or amplified breast cancer Synergy with chemotherapy in metastatic disease Unexpected cardiac toxicity (CHF) observed in clinical trials Slamon, et al. N Engl J Med 344:783 2001 PMID: 1124815
How Do Anti-HER2 Therapies Work? Singh, et al. Br J Cancer 2014 PMID: 25025958
Is Trastuzumab An Immune Therapy? Pohlmann, et al. Clin Cancer Res 15:7479 2009 PMID:
HER Family Targeting Prevent dimerization of HER2 with other partners HER2 pertuzumab/perjeta HER3 MM121, LJM716 HER2/3 MCLA128 Inhibit HER family member tyrosine kinase biochemical activity Lapatinib/Tykerb Neratinib/Nerlynx Poziotinib Tucatinib (ONT-380) Antibody drug conjugates Ado-trastuzumab emtansine (Kadcyla, TDM-1) Trastuzumab Deruxtecan (DS-8201a) Antibodies with better immune activation Margetuximab MCLA-128 Combine HER2 targeting with immune enhancers
Perou, et al. Proc Natl Acad Sci U S A 96:9212 1999 PMID: 2000s - Molecular Portraits of Breast Cancers Normal Luminal B Claudin-low Basal-like Luminal A HER2-enriched Adapted from Perou
Molecular Subtypes Predict Response To Neoadjuvant HER2-based Therapy Carey, et al. J Clin Oncol 34:542 2016 PMID:
What Is Triple Negative Breast Cancer? TNBC 587 TNBC tumors 767 TNBC tumors Before 2011 2011 2016 Lehmann, Chen, Shyr, Pietenpol; JCI, 2011 Lehmann, Chen, Shyr, Pietenpol; PLoS One, June, 2016 4 TNBC Subtypes, plus immune phenotyping Courtesy of J. Pietenpol
What Is The Immune TNBC Subset? Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, et al. (2016) Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLOS ONE 11(6): e0157368. https://doi.org/10.1371/journal.pone.0157368 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157368
These Are Not The Cells You re Looking For
PDL1/PD1 Interactions = Jedi Mind Trick Antibodies Disrupt The Trick PD-1 Pembrolizumab/Keytruda Nivolumab/Opdivo PD-L1 Atezolizumab/Tecentriq Avelumab/Bavencio Durvalumab/Imfinzi Pardoll Nat Rev Cancer 12:252 2012 PMID: 224378
Checkpoint Inhibitors Have Some Activity In TNBC Nanda, et al. J Clin Oncol 34:2460 2016 PMID: 2713858
UNC 2% Other TNBC subtypes TNBC tumor Luminal/Androgen receptor (LAR) Androgen-receptor signaling and PIK3CA mutations LAR 16% BL1 35% Basal-like 1 (BL1) Elevated expression of cell cycle and DNA damage response genes Mesenchymal (M) Trans-differentiation features and growth factor signaling (FGFR, PDGFR, NOTCH, TGFß) M 24% BL2 22% N=767 Basal-like 2 (BL2) Enriched in select growth factors (MET & EGFR) and myoepithelial cell features Lehmann, Chen, Shyr, Pietenpol; PLoS One, June, 2016 Courtesy of J. Pietenpol
Fong, et al. N Engl J Med 361:123 2009 PMID:
Mechanism of action of PARPi. Synthetic Lethal Strategy BRCA Tumors Lack HRR Published by AAAS Christopher J. Lord, and Alan Ashworth Science 2017;355:1152-1158
January 2015 March 2017
HER2+ Mouse Model Goel, et al. Nature 548:471 2017 PMID: 28813415
Why Do Tumors Stop Responding? Breast cancer phenotypes are caused by accumulated genetic abnormalities Exogenous mutagens are not linked to the majority of breast cancers Endogenous source of mutation (APOBECs) frequently expressed in breast cancer
APOBEC family 9 active enzymes in humans! Harris, Petersen-Mahrt & Neuberger, 2002, Mol. Cell Petersen-Mahrt, Harris & Neuberger, 2002, Nature
Burns, et al. Nature 494:366 2013 PMID: 23389445
High A3B Levels Shorten Response To Tamoxifen Law, et al. Sci Adv 2:e1601737 2016 PMID: 27730215
A3B levels associated with overall survival in tamoxifen treatment of advanced breast cancer No Previous Adjuvant/Metastatic Treatment Law, et al. Sci Adv 2:e1601737 2016 PMID: 27730215
What Have We Learned About Breast Cancer? Basic research fuels new ideas New ideas are translated into new therapies, almost always first evaluated in metastatic breast cancer Breast cancer is many diseases one size does not fit all Identifying fuel, drivers, and Achilles heels of disease will result in new strategies and combinations Stopping tumor mutation could enhance duration of response to existing therapies
Thanks! Patients Scientists Clinicians Elected officials Advocates