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Breast Cancer and Endocrinology: Where Are We In 2014? Douglas Yee, MD Director Masonic Cancer Center University of Minnesota
Targeted Therapy - 1896
Beatson GT Lancet 2:104-107 1896
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Inhibition of ERa Function LHRH LHRH Agonists/Antagonists Leuprolide Goserelin
LH, FSH SERM Tamoxifen Torimefene Raloxifene Fulvestrant
Ovary
Co-Repressor
Oopherectomy
E2
Adrenal Peripheral
NCo-R SMRT
ERa
Aromatase Inhibitor E1
Anastrazole Letrozole Exemestane
ERE
Breast Cancer Mortality
Source: WHO Mortality Database
Jemal et al, Breast Can Epidemiol Biomarkers Prev; 2010; 19:1893-1907
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Targeting ERα Lowers Recurrence
Davies, et al. Lancet 378:771 2011 PMID: 21802721
Success of ERα Targeting • Multiple strategies are effective – Receptor disruption – Ligand deprivation
• ERα is a validated biomarker • Clinical benefits of ERα targeting extend across breast cancer spectrum – Risk reduction (prevention) – Adjuvant therapy (invasive and non-invasive breast cancer) – Metastatic disease
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Clinical Endocrine Resistance • Estrogen receptor α (ERα) expressing breast cancers that: – Never respond/benefit from ERα targeting strategies • Primary resistance (de novo) - < 6 months clinical benefit
– Initially respond/benefit but then progress • Secondary (acquired) - > 6 months clinical benefit
• Therapeutic targeting of ERα function by – Ligand disruption strategies (SERMs, AIs) – Disruption of signaling pathways that affect ERα function • Directly affect ERα function • Indirectly affect ERα mediated biology
Post-Translational Modifications of ERα
Green = activation Red = inhibition
Le Romancer M et al. Endocrine Reviews 2011;32:597-622
©2011 by Endocrine Society
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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
Other Growth Regulatory Pathways In Cancer?
Diane Arbus's photograph of Eddie Carmel in “A Jewish giant at home with his parents, in the Bronx, N.Y., 1970”.
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IGF1R Signaling Activates ERα Function Via PI3K/Akt/mTOR/S6K
Becker, et al. Mol Endocrinol 25:516 2011 PMID: 21292829
Anti-IGF Drugs Tyrosine kinase inhibitor BMS-754807 Insm-18 (NDGA) XL-228 OSI-906 (linsitnib) GSK 1904529A ABDP A-928605 AXL1717 (PPP) KW-2450
BMS Insmed Exelixis OSI GSK AZ Abbott Alexar Kyowa Kirin
d/c Phase III Preclinical halted Preclinical Preclinical Preclinical Phase II Phase I/II
Pfizer ImClone sanofi-aventis Schering Merck Amgen Roche Biogen Idec Genentech
Phase III-d/c d/c d/c d/c (Merck) Phase II Phase III d/c Phase I Preclinical
FH IgG2 FH IgG1 Hum IgG1 FH IgG1 Hum IgG1 FH IgG1 FH IgG1 FH IgG4 Hum IgG1
MedImmune Boehr Ingle
Phase I//II Phase I
FH IgG2 FH
Monoclonal antibodies CP 751,871 (figitumumab) A12 (cixutumumab) AVE1642 Sch717454 (robatumumab) MK 0646 (dalotuzumab) AMG 479 (ganitumumab) R 1507 (teprotumumab) BIIB022 h10H5
Neutralizing antibody MEDI-573 BI 836845
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Ganitumab (AMG479) In Endocrine Resistant Breast Cancer Arm A (Blinded) Planned n = 100 R A N D O M I Z A T I O N
AMG 479 12 mg/kg IV Q2W + Exemestane or Fulvestranta
Arm B (Blinded) Planned n = 50 AMG 479 Placebo IV Q2W + Exemestane or Fulvestranta aInvestigator
decision
Stratification: 1. Exemestane or Fulvestrant 2. Extent of disease
• • • •
Exemestane: 25 mg PO QD Fulvestrant: 500 mg IM on Day 1, 250 mg IM Day 15 and 29, and then Q4W CT or MRI Q8 weeks Bone scan Q12 weeks
D I S E A S E
D I S E A S E
P R O G R E S S I O N
P R O G R E S S I O N
Roll-Over Treatment (Open Label) AMG 479 12 mg/kg IV Q2W + Exemestane or Fulvestrantb bEndocrine therapy as originally prescribed
• 156 patients randomized (2:1) between March 2008 and July 2009 • Previous endocrine therapy required
IGF1R Inhibition Leads To Worse Outcomes In Combination With ERα Targeting
• •
Previous endocrine treatment for MBC required Phase II randomized to exemestane/fulvestrant with or without ganitumab (1:2) Robertson, et al. Lancet Oncol 2013 PMID: 23414585
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Multiple Effectors For Multiple Ligands IGF-II
Ins
InsR-B
InsR-A
InsR-A/ IGF1R
InsR-A/ IGF1Rs
IGF-I
InsR-B/ IGF1R
InsR-B/ IGF1Rs
IGF1R
IGF1R splice (s)
Yee J Natl Cancer Inst 2012 PMID: 22761272
Multiple Effectors For Multiple Ligands IGF-II
Ins
InsR-B
InsR-A
Holo
InsR-A/ IGF1R
InsR-A/ IGF1Rs
IGF-I
InsR-B/ IGF1R
Hybrid
InsR-B/ IGF1Rs
IGF1R
IGF1R splice (s)
Holo
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Effects Of Targeting One Receptor? IGF-II
Ins
InsR-B
InsR-A
Holo
InsR-A/ IGF1R
InsR-A/ IGF1Rs
IGF-I
InsR-B/ IGF1R
InsR-B/ IGF1Rs
Hybrid
IGF1R
IGF1R splice (s)
Holo
More Holoreceptor? Ins
InsR-B
InsR-A
IGF-II
InsR-A
IGF-I
InsR-B
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IGF1R siRNA Increases Insulin Binding
Zhang, et al. Cancer Res 67:391 2007 PMID: 17210722
Ganitumab (AMG479) In Endocrine Resistant Breast Cancer Arm A (Blinded) Planned n = 100 R A N D O M I Z A T I O N
AMG 479 12 mg/kg IV Q2W + Exemestane or Fulvestranta
Arm B (Blinded) Planned n = 50 AMG 479 Placebo IV Q2W + Exemestane or Fulvestranta aInvestigator
decision
Stratification: 1. Exemestane or Fulvestrant 2. Extent of disease
• • • •
Exemestane: 25 mg PO QD Fulvestrant: 500 mg IM on Day 1, 250 mg IM Day 15 and 29, and then Q4W CT or MRI Q8 weeks Bone scan Q12 weeks
D I S E A S E
D I S E A S E
P R O G R E S S I O N
P R O G R E S S I O N
Roll-Over Treatment (Open Label) AMG 479 12 mg/kg IV Q2W + Exemestane or Fulvestrantb bEndocrine therapy as originally prescribed
• 156 patients randomized (2:1) between March 2008 and July 2009 • Previous endocrine therapy required
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Tamoxifen Resistant Cells Lose IGF1R and Retain Insulin Receptor MCF-7L Ins (10 nM) IGF-I (5 nM) IGF-II (20 nM) -
TamR
+ - - + -
-
+ - +
-
-
-
-
+
-
+
-
IGF1R qRT-PCR IGF1R 1.5 Fold change (normalized to GUSB)
IGF1Rβ
pAkt
pMAPK
IGF1R
1.0
0.5
0.0 MCF-7L
TamR
IRβ
ERα Fagan, et al. Cancer Res 2012 PMID: 22573715
TamR Cells Are More Sensitive To Insulin MCF-7L Insulin (nM) 0
0.5
1
2
5
TamR 10
20
0
0.5
1
2
5
10
20
IR IGF1R
p-AKT
p-P70S6K
p-MAPK
t-MAPK
Jie Ying Chan
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Insulin Receptor Staining In TamR
MCF-7L
TamR
SFM
IGF-I 10 min
Insulin 10 min
InsR shRNA Blocks TamR Signaling TamR
MCF-7L shGFP Insulin (nM)
shIR#4
2 5
shIR#6
shGFP
shIR#6
2 5 2 5 2 5
shIR#4
2 5 2
5
IRβ IGF1R p-IRS-1 (Y1222)
p-IRS-1 (Y895)
p-AKT p-P70S6K p-MAPK t-MAPK Jie Ying Chan
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TamR Cells Are Sensitive To Low Concentrations Of Insulin % Serum-Free Media
3
TamR scram 2
MCF7 Scr TamR sh4 MCF7 sh4
1
0 0.0
0.5
1.0
Insulin (nM) Jie Ying Chan
IGF1R moAB (Figitumumab) Upregulates Growth Hormone and Insulin 20mg/kg dose
glucose
insulin
GH
Haluska, et al. Clin Cancer Res 13:5834 2007
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IGF1R Inhibition Effective with Exemestane for HgBA1C < 5.7% - normal insulin?
Ryan, et al. Cancer Res 71(24 Suppl.):239s
Schematic of the phosphatidyl inositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway.
Rugo H S , and Keck S JCO 2012;30:2707-2709
©2012 by American Society of Clinical Oncology
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mTOR Inhibition (Everolimus) Enhances ER Targeting Strategies Exemestane
Tamoxifen 1oResistance
2oResistance
BOLERO 2 • Phase 3 randomized to exemestane with or without everolimus (1:2) • Previous treatment for MBC with nonsteroidal AI required Baselga, et al. N Engl J Med 366:520 2012 PMID: 22149876
TAMRAD • Phase 3 randomized to tamoxifen with or without everolimus (1:1) • Previous AI treatment required Bachelot, et al. J Clin Oncol 30:2718 2012 PMID: 22565002
Toxicity of mTOR Inhibition (≥grade 2) Stomatitis
Pneumonitis
Hyperglycemia/Diabetes >160mg/dl
Fatigue
Rugo, et al. Ann Oncol 25:808 2014 PMID: 24615500
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Targeting IGF/Insulin Signaling with Metformin
Dowling R J O et al. J Mol Endocrinol 2012;48:R31-R43 © 2012 Society for Endocrinology
Diabetics Taking Metformin Have Improved Cancer Outcomes
Landman G W et al. Dia Care 2010;33:322-326
Copyright © 2011 American Diabetes Association, Inc.
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Diabetics Taking Metformin Have Improved Response To Chemotherapy
Jiralerspong S et al. JCO 2009;27:3297-3302 ©2009 by American Society of Clinical Oncology
NCIC MA.32 – Metformin vs. Placebo
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MAPK and PI3K Signaling Co-Exist In Cancer Cells
Foster D A et al. Genes & Cancer 2011;1:1124-1131 Copyright © by SAGE Publications
Regulation Of Cell Cycle Progression By CyclinD-CDK4/6
Lange C A , and Yee D Endocr Relat Cancer 2011;18:C19C24 © 2011 Society for Endocrinology
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The RAS-RAF-MEK-ERK signaling pathway.
Pratilas C A , Solit D B Clin Cancer Res 2010;16:3329-3334
©2010 by American Association for Cancer Research
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Abstract S1-6
Results of a Randomized Phase 2 Study of PD 0332991, a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole vs Letrozole Alone for First-Line Treatment of ER+, HER2– Advanced Breast Cancer (TRIO-18) RS Finn,1 JP Crown,2 I Lang,3 K Boer,4 IM Bondarenko,5 SO Kulyk,6 J Ettl,7 R Patel,8 T Pinter,9 M Schmidt,10 Y Shparyk,11 AR Thummala,12 NL Voitko,13 A Breazna,14 ST Kim,15 S Randolph,15 DJ Slamon1 1University
of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research Group, Dublin, Ireland; Onkologiai Intezet, Budapest, Hungary; 4Szent Margit Korhaz, Onkologia, Budapest, Hungary; City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine; 6Municipal Treatment-andProphylactic Institution, Donetsk, Ukraine; 7Technical University of Munich, Munich, Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA, USA; 9Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary; 10University Hospital Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV, USA; 13Kyiv City Clinical Oncology Center, Ukraine; 14Pfizer Oncology, New York, NY, USA; 15Pfizer Oncology, La Jolla, CA, USA 3Orszagos
5Dnipropetrovsk
Presented at SABCS 2012; December 5, 2012; San Antonio, TX, USA
38
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San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Progression-Free Survival Probability
Progression-Free Survival PD 991 + LET (n = 84)
LET (n = 81)
1.0
Number of Events (%)
21 (25)
40 (49)
0.9
Median PFS, months (95% CI)
26.1 (12.7, 26.1)
7.5 (5.6, 12.6)
0.8
Hazard Ratio (95% CI)
0.7
P value
0.37 (0.21, 0.63)
