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RECENT ADVANCES IN BREAST CANCER THERAPY
Dr. Bhuvaneswari Ramaswamy MD MRCPyOhio State University
Breast Cancer – IntroductionIncidence of Invasive Breast cancer in the US
230, 480 (~124.3 per 100,000)
Life time Risk 1 in 8 women
Prevalence 2,747,459
Median Age of Diagnosis 61
Mortality 39,270y ,
Race IncidenceAll Races 124.3/100,000
White 127.3 per 100,000 women
Black 121.2 per 100,000 women
Asian/Pacific Islander 94.5 per 100,000 women
American Indian/Alaska Native 80.6 per 100,000 women
Hispanic b 92.7 per 100,000 women
Based on Survaillance Epidemiology and End Result DatabaseAmerican Cancer Society, Cancer Facts & Figures. 2006
Breast Cancer: Then and NowBreast Cancer: Then and NowThen Now
• ~75% of women survived ≥5 years
• Mastectomy was the only
• ~95% of women survive ≥5 years
• Lumpectomy is availabley ysurgical option
• Single-agent chemotherapy was standard of care
p y• Combination chemotherapy
is the standard of care• Hormonal therapy is widely
• Hormonal therapy with tamoxifen was under investigation only
py yused
• Receptor-based therapy is widely used
• Genes involved in breast cancer development have not yet been identified
• Understanding of genetic components have expanded
National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/cancer-advances-in-focus/breast.
Age-adjusted Cancer Death Rates for F l b Sit US 1930 2005Females by Site, US, 1930-2005
Adapted from American Cancer Society. Cancer Facts and Figures 2009.
BREAST CANCER MORTALITY BY STAGEMORTALITY BY STAGE
Stages of Breast CancergLocalized Disease:
Distribution 60%Metastatic Disease
Distribution 5 7%– Distribution - 60%– 5-Year Survival – 98%
– Distribution 5-7%– 5-year survival 23%
Locally Advanced– Distribution 33%– Distribution 33%– 5-year Survival 84%
Based on Survaillance Epidemiology and End Result Database
Biology of Breast Cancergy
HormoneReceptor (+)
65-75%
Breast Cancer
65 75%
HER2+15 20%15-20%
TN*TN15% *Triple Negative
HER-2Basal-like L i l ALuminal B“Normal”HER-2Basal-like Luminal A
Sorlie T et al, PNAS 2001
Outcomes Based on Molecular Subtype
9Sorlie T et al, PNAS 2001
Molecular-Genetic ProfilingMolecular Genetic ProfilingTissue Patients FDA Validation?
MammoPrint fresh Node neg ER+, ER -
yes MindAct
W d H li f h ERWound Healing fresh ER+ no no
Oncotype DX paraffin Node neg yes TAILORxyp p gER+
y
HOXB 13/ IL 17b Ratio
paraffin ER+ no noIL-17b Ratio
CYP 2D6 blood all yes no
ONCOTYPE DX ASSAYONCOTYPE DX ASSAY
Paik S et al. NEJM 2004
FATHER OF TARGETED THERAPYTHERAPY
Dr. Elwood JensenESTROGEN RECEPTORESTROGEN RECEPTOR
• “A lady with growth neoplastic• A lady with growth neoplasticThought surgical ablation too drastic.She preferred that her illShe preferred that her illCould be cured with a pill,Which today is no longer fantastic ”Which today is no longer fantastic.
ATLAS STUDYATLAS STUDY
6846 women with ER+ Observation
operable breast cancer who had had 5 years of adjuvant (N=6846*) R
Tamoxifen x 5 yrs
Objectives:• Recurrence Rate*Numbers of Patients for the Analysis:
(1) P ti t ith ER ti d ER k • Breast Cancer Mortality(1) Patients with ER negative and ER unknown breast cancer (N=6048) were excluded from the analysis of the study’s primary objectives.(2) All 12,894 patients were included in safety
l ianalysis.
SABC 2012, Abstract S1-2; Lancet. 2012 Dec 4 [ahead of print]
ATLAS StudyATLAS Study
• After mean of 7 4 woman years of followAfter mean of 7.4 woman years of follow up (30,000 w-y in years 5-9, 16,000 in years 10-14 2000 later)years 10 14, 2000 later)
• Compliance was 80%
SABC 2012, Abstract S1-2; Lancet. 2012 Dec 4 [ahead of print]
BREAST CANCER MORTALITY BY STAGEMORTALITY BY STAGE
Survival Improvement in Metastatic Breast Cancer Patients
100
Cancer Patients
75
al, %
Censored events
P<0.001
Period 1994-2000Period 1987-1993
25
50
Surv
iva
00 12 24 36 48 60
MonthsMonths
• Survival of breast cancer patients presenting with metastases at diagnosis has improved over time, strongly suggesting that improvement is related to treatment
Andre F, et al. J Clin Oncol. 2004; 22(16):3302-3308.
Survival Improvement in Metastatic B t C P ti tBreast Cancer Patients
• A recent study from M.D. Anderson Cancer Center that compared length of survival of metastatic breast cancer patients treated at their institution in five-year incrementsincrements
• Median survival had doubled to 51 months (range 33-69 months) in 1995-2000 from a median survival of 27
h ( 21 33 h ) l fi limonths (range 21-33 months) only five years earlier, 1990-1994.
• Five years after their diagnosis with metastatic diseaseFive years after their diagnosis with metastatic disease, 40 percent of these patients were still alive, as compared with 29 percent during 1990-1994.
Metastatic Breast Cancer – Systemic Therapy Options Depend on Tumor BiologyTherapy Options Depend on Tumor Biology
Metastatic Breast CancerCancer
Hormone Receptor Positive
HER-2/neuPositive Triple Negative
Endocrine Therapy Chemotherapy
Anti-HER-2/neuAgents with
chemotherapy or ChemotherapyTherapy py chemotherapy or endocrine therapy
py
20
Bone Modifying Therapy (Patients with Skeletal Metastases)
Denosumab (RANKL Inhibitor)Denosumab (RANKL Inhibitor)
21
Taken from Robert G. Josse,MD 2009 CGS Annual Scientific Meeting
Denosumab 322 centers:E
Stage IV
•Europe•North & South America,•Japan•Australia•India
Zoledronic Acid 4 mg IV Q28D
+gBreast CancerSkeletal
•South Africa
RPlacebo SQ Q28D
The primary end point:•Time to 1st on-study SRE (non-i f i it t t)Metastases
N=2046
RDenosumab 120
mg SQ Q28D
inferiority test).
Secondary end points:•Time to 1st on study SRE (superioritymg SQ Q28D
+Placebo IV Q28D
•Daily supplementation with calcium (>500 mg) and
•Time to 1st on-study SRE (superiority•test)•Time to 1st and subsequent SREs.•Safety
•Daily supplementation with calcium (>500 mg) and vitaminD (>400U) was strongly recommended. •Chemotherapy and hormonal therapy were allowed (except for oral or intravenous bisphosphonates or unapproved investigational agents).
Exploratory end points:•Overall Survival•Disease ProgressionS
22
•Skeletal Morbidity Rate•Chage from baseline to week 13 in uNTx and BSAP
Stopeck et al. J Clin Oncol 2010; 28:5132-9
Time to First Skeletal Related Event
23
Stopeck et al. J Clin Oncol 2010; 28:5132-9
Time to First and Subsequent Sk l t l E tSkeletal Event
24
Stopeck et al. J Clin Oncol 2010; 28:5132-9
HER Family: Receptors and Ligands
HR
G(N
RG
1)
Ligandbindingdomaindomain
Transmembrane
Tyrosinekinase
HER1 HER2 HER3 HER4domain
H b t I t J R di t O l Bi l Ph 2004 59( l) 21 R k ki Bi h Bi h R C 2004 319 1Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21; Roskoski. Biochem Biophys Res Commun. 2004;319:1;Rowinsky. Annu Rev Med. 2004;55:433.
HER2 Overexpression in Breast CancerHER2 is overexpressed in ~ 18-25% of breast cancers
N l (1 )Normal (1x)~ 25,000-50,000 HER2 receptors
Overexpressed HER2 (10-100x)Up to ~ 2,000,000 HER2 receptors
1. Excessive cellular division2. Increased ability to form
tumors in experimental mice3. Increased ability to form
metastasesPegram MD et al Cancer Treat Res 2000;103:57-754. Secretion of vascular
endothelial growth factors
Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182.
0.8
1.0
Disease F0 4
0.6
0.8
Free Survival
0.4
0.2
0.8
1.0
Overall Survival
0.6
0.4 Survival0.2
Slamon DJ et al. Science 1987;239: 177-235
Months
Efficacy in Early Breast Cancer: SummaryTrial/ Trial/ NN Med Med HR HR HR HR Absol. % Absol. % Absol %Absol %a /a /
Experimental Experimental RegimenRegimen
ededf/uf/u DFSDFS
pp--valuevalueOSOS
pp--valuevalue
bso %bso %diff DFSdiff DFS
bso %bso %diff OSdiff OS
NSABP/N9831NSABP/N9831 396396 2 92 9 0 480 48 0 650 65 12 8 @ 412 8 @ 4 3 2 @ 4 y3 2 @ 4 yNSABP/N9831NSABP/N9831AC→THAC→TH
39639688
2.9 2.9 yy
0.480.48<0.0000<0.0000
11
0.650.65<0.0007<0.0007
12.8 @ 4 12.8 @ 4 yy
3.2 @ 4 y3.2 @ 4 y
HERAHERA 340340 2 y2 y 0.640.64 0.660.66 6.3 @ 3 y6.3 @ 3 y 2.7 @ 3 y2.7 @ 3 yMultiple→HMultiple→H 11 <0.0001<0.0001 <0.0115<0.0115
BCIRG 006BCIRG 006AC→DHAC→DH 322322 2 y2 y
0.610.61<0.0001<0.0001
0.590.590.0040.004
6 @ 3 y6 @ 3 y 4 @ 3 y4 @ 3 yAC→DHAC→DH 322322
222 y2 y
BCIRG 006BCIRG 006DCaH (aka DCaH (aka TCH)TCH)
0.670.670.00030.0003
0.660.660.0170.017
5 @ 3 y5 @ 3 y 2 @ 3 y2 @ 3 y
TCH)TCH)FinHerFinHerD/V+H→CEFD/V+H→CEF
232232 3 y3 y 0.420.420.010.01
0.410.410.070.07
11.7 @ 3 11.7 @ 3 yy
6.6 @ 3 y6.6 @ 3 y
Perez E et al. ASCO 2007; Smith I et al. Lancet 2007; Slamon D et al. SABCS 2006; Joensuu H et al. NEJM 2005; Spielmann M. et al SABCS2007
RESISTANCE TO THERAPY
LEVEL OF CROSS TALK FOR ONE PATHWAY
The 6 degrees of separation in drug resistance.
Trusolino L , and Bertotti A Cancer Discovery 2012;2:876-880
©2012 by American Association for Cancer Research
I IHER2 HER3
Pertuzumab
III
II
III
II
HER2 HER3
DimerizationIV
III
IVIII
E t ll l
DimerizationarmsTrastuzumab
TDM1
RTKRTKIntracellular
ExtracellularTDM1
RAS PI3K PTENRTKactivationRAF
MEK
PI3K
AKT
PTEN
TranscriptionNucleus
MAPK mTORTKI
32
Transcription
Cell proliferation Cell survivalOlson. J Clin Oncol. 2012;30:1712-4.
Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopesp p
Pertuzumab-HER2 Complex
Trastuzumab-HER2 Complexp p
Pertuzumab Dimerization d i
III
Idomain
TrastuzumabIII
IIIII
II
IV IVIV IV
Inhibits HER2 dimerization with other HER family receptors (particularly HER3)
Activates ADCC Inhibits multiple HER mediated signaling
Activates ADCC Inhibits HER-mediated signaling pathways Prevents HER2 domain cleavage
Hubbard SR. Cancer Cell. 2005;7:287-288.
Inhibits multiple HER-mediated signaling pathways
CLEOPATRAPlacebo
Trastuzumab 6mg/kg q
CLEOPATRA
Trastuzumab 6mg/kg q 3 weeks
Docetaxel 75 mg/m2 q 3 k
RANHER2 MBC
P t b 420 3
weeksNDOM
HER2+ MBC1st linen =808
1:1
Pertuzumab 420 mg q 3 weeks
Trastuzumab 6mg/kg q
I ZE
3 weeksDocetaxel 75 mg/m2 q 3
weeksweeks
Baselga NEJM 2011
CleopatraCleopatra
Baselga NEJM 2011
CleopatraCleopatra
Baselga NEJM 2011
SMART BOMBSMART BOMB
Trastuzumab-DM1: Novel Antibody-Drug ConjugateConjugate
Monoclonal antibody: Trastuzumab
Target expression: HER2
Trastuzumab
Cytotoxic agent: DM1
Highly potent cytotoxic agent MCCDM1
Systemically stable
Linker: SMCCT-DM1Average drug:antibody ratio 3.5:1
MCC (Non-reducible thioether bond to a linker molecule)Meeream M., et al. J clin Oncol. 2008; 26 (May 20 suppl; abstract
EMILIA (TDM4370g) Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBCLapatinib/Capecitabine in HER2 MBC
Stratification:World RegionNumber of Previous Chemotherapy
PD or unacceptable toxicityType of prior regimensLocally advanced breast cancerPresence of visceral disease
Patients with HER2+ locally advanced or metastatic breast cancer
T-DM1 3.6 mg/kg q3w(n = 495)
following treatment with a taxane and trastuzumab
(N = 980)
Lapatinib 1250 mg daily+Capecitabine 1000 mg/m2 2x/dayDays 1-14 every 3weeks(n = 496)
Primary endpoint: PFS by IRF, OS, safetySecondary endpoints: QoL (FACT B), DOR, PFS by investigator
assessmentJ Clin Oncol 30, 2012 (suppl; abstr LBA1)
40
Verma et al. N Engl J Med. 2012 (Published online on October 1)
Endocrine Therapy Resistance
Aromatase Inhibitors
Tamoxifen
Everolimus
a o eFulvestrant
Johnston S R Clin Cancer Res 2010;16:1979-1987
BOLERO-2BOLERO 2
PlaceboExemestane
RAN
Postmenopausal ER/PR+ Advanced
Breast Cancer NDOM
Breast Cancer
Progression on nonsteroidal AI in the
2:1
EverolimusExemestane
I ZE
adjuvant or metastatic setting
n =724
Baselga NEJM 2011
Bolero2Bolero2
• Insert exemestane + mTOR Bolero2 trialInsert exemestane mTOR Bolero2 trial
Baselga NEJM 2011
BOLERO-2
Baselga NEJM 2011
WHY???WHY???
• WHY are we still dealing with failures???WHY are we still dealing with failures???• WHY do not we cure 100% of patients
with breast cancer?with breast cancer?
Russens et al, JCI, 2011
STUDY DESIGNS FOR ARRAY-BASED GENE EXPRESSIONSTUDUES
Russens et al, JCI, 2011
Planned approachesFuture DirectionsMolecular Characterization
Courtesy of N. Wagley g
NEW SUBTYPES OF BREAST CANCER
Russens et al, JCI, 2011
MULTILEVEL APPROACH FOR DYNAMIC CLASSIFICATION
Russens et al, JCI, 2011