Molecular Understanding Informs Breast Cancer Treatment

John R. Mackey, MD, FRCP(C)
TRIO Director
Professor
Division of Medical Oncology
Department of Oncology
University of Alberta
Cross Cancer Institute
Edmonton, Alberta
Canada
Rational Options in Breast Cancer:
How Molecular Understanding Informs
Treatment
This program is supported by educational grants from
In association with Translational
Research in Oncology

clinicaloptions.com/oncology
Translational Research 2012
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Program Faculty
Program Director
Dennis J. Slamon, MD, PhD
TRIO Chairman
Chief, Division of
Hematology/Oncology
David Geffen School of Medicine
at UCLA
Los Angeles, California
Faculty
John R. Mackey, MD, FRCP (C)
TRIO Director
Professor
Division of Medical Oncology
Department of Oncology
University of Alberta
Cross Cancer Institute
Edmonton, Alberta
Canada

Faculty Disclosures
John R. Mackey, MD, FRCP(C), has no significant financial
relationships to disclose.
Dennis J. Slamon, MD, PhD, has disclosed that he has
received consulting fees from Genentech, GlaxoSmithKline,
and Roche.

Outline
 The challenge of molecular complexity in breast cancer
 Where we are today
 Where we need to go
– Defining and addressing the problem in Darwinian terms
– Heterogeneity and selection

Challenge of Early-Stage Breast Cancer
 Despite surgery, cytotoxic chemotherapy, hormonal
therapy, and/or regional radiotherapy, ~ 30% of patients
will eventually experience disease recurrence
 The biologic reasons for recurrence and resistance to
treatment are poorly understood
 Recurrent breast cancer is usually lethal

Breast Cancer Biology in 2012:
A Pragmatic View
ENDO
CHEMO
CHEMO
CHEMO
TRAZ
ENDO
CHEMO
TRAZ
ER
NegativePositive
PositiveNegative
HER2

Why This Pragmatic View Fails . . .
 Early breast cancer is much more complex than we
thought
 MBC is much more complex than early breast cancer

Somatic Rearrangement in Breast Cancer
Genomes
 24 primary breast cancers
– Each show unique pattern of DNA rearrangements
 No recurrent rearrangement identified
 Basal breast cancers (and some others) were genetically
chaotic
– Nature, 2009
Stephens PJ, et al. Nature. 2009;462:1005-1010.

Mutational Evolution in a Lobular Breast
Tumor
 Primary breast cancer had 5 mutations (and
subpopulations with an additional 6 mutations)
 At relapse 9 yrs later, this cancer had 32 mutations
 None of these 32 mutations were seen in a panel of
192 breast cancers (ie, every cancer is unique)
– Nature 2009
Shah SP, et al. Nature. 2009;461:809-813.

Challenge of Intratumor Heterogeneity
 Solid tumors are heterogeneous and evolve to
metastasize and evade drug therapy
 Intratumoral heterogeneity presents substantial challenges
to individualizing treatment
– N Engl J Med, 2012
Gerlinger M, et al. N Engl J Med. 2012;366:889-892.

Single Cancer’s Family Tree: Phylogenetic
Relationships of Tumor Regions
Ubiquitous
Shared primary
Shared metastasis
Private
Normal tissue
VHL
KDM5C (missense and frameshift)
mTOR (missense)
SETD2 (frameshift)
SETD2 (missense)
KDM5C (splice site)
SETD2 (splice site)
?
PreM
R4a
R4b
PreP
R9 R8
R2R1
R3
R5
M2b
M1
M2a

Breast Cancer: The Problem
 Every breast cancer is genetically unique
 Each tumor represents multiple evolving clones
 We need to reduce this complexity!
 What are the commonalities?

Growth factor self-sufficiency
Hanahan D, et al. Cell. 2000;100:57-70.
Cancer
Insensitivity to
anti-growth
signals
Evading apoptosis
Tissue invasion and
metastasis
Sustained angiogenesis
Limitless replication
potential
Hallmarks of Malignancy

How Do Current Standard
Adjuvant Therapies Address
the Problem?

Cancer
Insensitivity to
antigrowth
signals
Evading apoptosis
Tissue invasion
and metastasis
potential
Trastuzumab, aromatase inhibitors, tamoxifen
Taxanes
Trastuzumab
Standard Adjuvant Therapy in Breast
Cancer

Addressing Replication With Cytotoxic
Chemotherapy
 We have reached a plateau: TAC = ddAC-P
 “New” cytotoxics have not improved outcomes in breast
cancer
– Capecitabine, vinorelbine, gemcitabine of no proven benefit

Addressing the Hallmark of Growth Factor
Self-Sufficiency
 HER2-directed therapies
– State of the art
– On the horizon

HER2-Positive Breast Cancer
 Decision of adjuvant therapy depends on
– Optimal efficacy
– Optimal safety
– Optimal quality of life
– Which regimen has best
risk-to-benefit ratio?

NCCTG N9831
1 yr of trastuzumab
4 × AC 12 × paclitaxel 90 mg/m2
HER2+
NSABP B-31
HER2+
1 yr of trastuzumab
4 × AC 4 × paclitaxel 175 mg/m2HERA
2 yrs of trastuzumab
HER2+
(IHC or FISH)
Accepted CT:
AC, EC, FAC,
FEC, ET, AT,
CMF
1 yr of trastuzumab
Observation
BCIRG 006
HER2+
4 × AC
60/600 mg/m2
4 × docetaxel
100 mg/m2
6 × T and platinum salts
75 mg/m2
75 mg/m2
or AUC 6
1 yr of trastuzumab
N = 3222
1 yr of trastuzumab
AC → T
AC → TH
TCH
(IHC or FISH)
(IHC or FISH)
(FISH)
4 Positive Adjuvant Trastuzumab Trials

Trastuzumab: Safety
 Only incremental safety concern is cardiotoxicity
 FDA has reviewed each of the registration trials source
documentation and recalculated CHF rates using
standardized criteria

FDA product monograph, May 2008.
Study, % Trastuzumab Control
B-31/NCCTG 2 0.4
HERA 2 0.3
BCIRG 006
AC → TH 2 0.4
 TCH 0.4 0.4
Incidence of CHF in Adjuvant
Breast Cancer Studies

Sequential Trastuzumab Is Inferior to
Concurrent Trastuzumab
 NCCTG N9831 phase III study
 Treatment: AC followed by
– Paclitaxel
– Paclitaxel plus sequential trastuzumab
– Paclitaxel plus concurrent trastuzumab
 DFS superior at 5 yrs with concurrent trastuzumab
– 80.1% with sequential vs 84.4% with concurrent
Perez EA, et al. J Clin Oncol. 2011;29:4491-4497.

What Regimen Provides the Best
Risk-to-Benefit Ratio?
TCH

4 × AC
60/600 mg/m2
4 × T
100 mg/m2
6 × T and carboplatin
75 mg/m2
AUC 6
1 yr of trastuzumab
N = 3222
1 yr of trastuzumab
AC → T
AC → TH
TCH
HER2+
(central FISH)
N+ or high
risk N-
4 × AC
60/600 mg/m2
4 × T
100 mg/m2
Stratified by nodes
and HRS
Slamon D, et al. SABCS 2009. Abstract 62.
Phase III BCIRG 006 Trial: Adjuvant
Trastuzumab in HER2+ Breast Cancer

Slamon D, et al. N Engl J Med. 2011;365:1273-1283.
100
80
60
40
20
0
0 12 24 36 48 60 72 84
Mos
DFS(%)
AC-T plus
trastuzumab
TCH
AC-T
93
87
81
88
78
86
75
8492
87 84 81
BCIRG 006 Trial of Adjuvant Trastuzumab
in HER2+ Breast Cancer: 5-Yr DFS

BCIRG 006 Trial of Adjuvant Trastuzumab
in HER2+ Breast Cancer: Grade 3/4 AEs
AE, % AC-T
(n = 1050)
AC-TH
(n = 1068)
TCH
(n = 1056)
Arthralgia 3.2 3.3 1.4*
Myalgia 5.2 5.2 1.8*
Fatigue 7.0 7.2 7.2
Hand-foot syndrome 1.9 1.9 0.0*
Stomatitis 3.5 2.9 1.4*
Diarrhea 3.0 5.6 5.4
Nausea 5.9 5.7 4.8
Vomiting 6.2 6.7 3.5*
Irregular menses 27.0 24.3 26.5
*Statistically significant AC-TH vs TCH.

Adjuvant Trastuzumab in HER2+ Breast
Cancer: Grade 3/4 Hematologic AEs
AE, % AC-T
(n = 1050)
AC-TH
(n = 1068)
TCH
(n = 1056)
Neutropenia 63.3 71.5 65.9
Leucopenia 51.8 60.3 48.2*
Febrile neutropenia 9.3 10.9 9.6*
Neutropenic infection 11.1 11.9* 11.2
Anemia 2.4 3.1* 5.8
Thrombocytopenia 1.6 2.1 6.1
Leukemia, n (%) 6 pts (0.6) 1 pt (0.1) 1 pt (0.1)
*Statistically significant AC-TH vs TCH.

Adjuvant Trastuzumab in HER2+ Breast
Cancer: Mean LVEF Changes Favor TCH
66
65
62
61
59
0
0 12 24 36 48
MeanLVEF(%)
Mos Since Randomization
64
63
60
58
AC-TH (n = 1042)
TCH (n = 1030)
AC-T (n = 1014)

Clinical Event, n (%) AC-T AC-TH TCH
Distant recurrence 188 124 144
Grade 3/4 CHF 7 21 4
Acute leukemia 6 1 1
Total 201 146 149
Adjuvant Trastuzumab in HER2+
Breast Cancer: Risk-to-Benefit Ratio

State-of-the-Art Adjuvant Therapy for
HER2+ Early Stage Breast Cancer
 Nonanthracycline TCH regimen has the most favorable
risk-to-benefit ratio
– Exploits synergistic interaction
– Avoids cardiotoxicity
– No leukemogenicity
– Superior efficacy to sequential trastuzumab strategies
– Equivalent efficacy to anthracycline/trastuzumab/taxane
combinations
– Better quality of life (Au, et al.; submitted)

What Is on the Horizon for HER2+ Early
Breast Cancer?
 Biology informs the new adjuvant trials
 Trastuzumab predominantly restores sensitivity to
apoptosis
 Lapatinib primarily reduces proliferation
 Synergy between trastuzumab and lapatinib
 Synergy between trastuzumab and pertuzumab
 HER2 amplification increases VEGF production

Nucleus
Rb myc
max
PI3K
HER2
ras
raf
MEKMEK
MAPKMAPK
CyclinsCyclins
CdksCdks
p27p27
//p16p16
ER
p53
Akt
mTOR
VEGFVEGF
HER2 Amplification Drives Proliferation
HER2

Nucleus
Rb myc
max
PI3K
HER2
ras
raf
MEKMEK
MAPKMAPK
cyclinscyclins
Cdk’sCdk’s
p27p27
//p16p16
ER
p53
Akt
mTOR
VEGFVEGF
HER2 Amplification Suppresses Apoptosis
HER2

Nucleus
Rb myc
max
PI3K
HER2
ras
raf
MEKMEK
MAPKMAPK
cyclinscyclins
Cdk’sCdk’s
p27p27
//p16p16
ER
p53
Akt
mTOR
HER2
Chang J, et al. SABCS 2008.

Growth factors
Nucleus
Rb myc
max
PI3K
HER2
HER
1,3,4
ras
raf
MEKMEK
MAPKMAPK
cyclinscyclins
Cdk’sCdk’s
p27p27
//p16p16
ER
p53
Akt
mTOR
Chang J, et al. SABCS 2008.

Trastuzumab 4 mg/kg
IV (loading dose) →
2 mg/kg once wkly
× 11 wks ±
Paclitaxel 80 mg/m2
IV once wkly ×
12 wks
ClinicalTrials.gov. NCT00490139.
ALTTO Phase III Study: Lapatinib ±
Trastuzumab in HER2+ Breast Cancer
Women with
centrally
determined
HER2+
invasive breast
cancer
(N = 8000
planned)
Surgery,
(neo)
adjuvant
anthracycline
-based
therapy for
4 cycles;
LVEF ≥ 50
Trastuzumab 8 mg/kg IV (loading dose) → 6 mg/kg
every 3 wks for 1 yr ±
Paclitaxel 80 mg/m2
IV once wkly × 12 wks
Lapatinib 1500 mg/kg PO QD× 51 wks ±
Paclitaxel 80 mg/m2
Trastuzumab 8 mg/kg (loading dose) → 6 mg/kg
every 3 wks for 1 yr
Lapatinib 1000 mg PO QD × 51 wks ±
Paclitaxel 80 mg/m2
Lapatinib
1500 mg orally QD ×
34 wks
6-wk
wash-out

Nucleus
Rb myc
max
PI3K
HER2
HER
1,3,4
ras
raf
MEKMEK
MAPKMAPK
cyclinscyclins
Cdk’sCdk’s
p27p27
//p16p16
ER
p53
Akt
mTOR
Growth factors

Nucleus
Rb myc
max
PI3K
HER2
HER
1,3,4
ras
raf
MEKMEK
MAPKMAPK
cyclinscyclins
Cdk’sCdk’s
p27p27
//p16p16
ER
p53
Akt
mTOR
(neo) ALTTO rationale
Growth factors

ALTTO in Perspective
 Promising results in combination arm
– In M1 disease, lapatinib plus trastuzumab active as salvage
therapy
– Neoadjuvant potential
 Due to pharmacokinetic interaction with paclitaxel, 43%
of patients receiving lapatinib/trastuzumab discontinued[1]
1. Hudis, et al. ASCO 2008.
2. Dieras V, et al. ASCO 2010. Abstract 1049.

Addressing the Hallmark of Sustained
Angiogenesis
 Angiogenesis: physiologic process of new blood vessel
formation
 Principally driven by interactions between VEGFs
and 3 high-affinity VEGFRs

VEGFR-3VEGFR-2VEGFR-1
Endothelial cell
VEGF antibody
P
P
P
P P
P
P
P
P
P
P
P
Anti-VEGF
antibodies
(bevacizumab)
Anti-VEGFR2
antibodies
(ramucirumab)
Small-molecule inhibitors of VEGFR
(vatalanib, cediranib, motesanib,
sunitinib, sorafenib, axitinib, others)
Soluble
VEGFRs
(aflibercept)
Agents Targeting the VEGF Pathway

Antiangiogenic Agents: Class Toxicities
 Hypertension
 Clotting
 Bleeding
 CHF (when combined with anthracyclines)
 Financial
 Agent-specific toxicities
– Motesanib: cholecystitis
– Sunitinib, pazopanib: pigmentation changes
– Tyrosine kinase inhibitors: fatigue

Ramucirumab
 Fully humanized antibody directed against VEGFR2
 Potential for immune-mediated destruction of
angiogenic vessels
 Circumvents insoluble VEGF activation of VEGFR2

TRIO-012 Ramucirumab Study
 Patient population
– Women with HER2-negative, unresectable, locally recurrent, or MBC with or without
measurable lesions
– No previous chemotherapy for metastatic or locally recurrent and inoperable breast
cancer
 Study plan
RANDOMIZ
Follow-up
Progressive
disease
or
unacceptable
toxicity
or
withdrawn
consent
Docetaxel 75 mg/m² IV q3w
Blinded ramucirumab
10 mg/kg IV q3w
…..
…..
2/3
1/3
Docetaxel 75 mg/m² IV q3w
Blinded placebo IV q3w
Mackey J, et al. Clin Breast Cancer. 2009;9:258-261.

Adjuvant Antiangiogenic
Therapy?

HER2 Biology
Nucleus
PI3K
HER2HER
1,3,4
ras
raf
MEKMEK
MAPKMAPK
Akt
mTOR
Survival
Proliferation
VEGFVEGF
Growth factors

BETH: Bevacizumab With Trastuzumab
Adjuvant Therapy in HER2+ Breast Cancer
 CIRG/TRIO 011: phase III translational study (planned
N = 3509) based on the following
– Adjuvant trastuzumab is effective
– Preclinical observations that HER2 transfection leads to VEGF
overexpression and increased angiogenesis
– HER2 and VEGF are independent prognostic factors
– Clinical efficacy of the 2 antibodies trastuzumab and bevacizumab from
phase I and II studies
– The ability to add bevacizumab to the noncardiotoxic backbone (TCH)
from the BCIRG 006 study
– Averel trial showed efficacy of this combination in MBC
 Fully accrued, results expected in 2013

Growth
factor
Nucleus
Rb myc
max
PI3K
HER2HER
1,3,4
ras
raf
MEKMEK
MAPKMAPK
cyclinscyclins
Cdk’sCdk’s
p27p27
//p16p16
ER
p53
Akt
mTOR
VEGFVEGF
BETH Phase III Study of Trastuzumab +
Bevacizumab in Breast Cancer: Rationale

6 × TC
1 yr of trastuzumab
TCHB
(Group 1B)
1 yr of bevacizumab
RT
6 × TC
1 yr of trastuzumab
TCH
(Group 1A)
RT
BETH Phase III Study: Chemotherapy +
Trastuzumab ± Bevacizumab
 Primary endpoint: IDFS
 Secondary endpoints: DFS, OS, RFI, DRFI, toxicity
HER2+, N+,
or high-risk N-
Stratified by Ns
and HRS
(N ~ 3500)

Take-Home Messages: HER2+ Research
 New approaches in the adjuvant setting
– Double-hit HER2 pathway (ALLTO; APHINITY)
– Inhibit both HER2 and angiogenesis (BETH)
 TRIO is launching new trials exploring synergistic agents
– TRIO 016: panobinostat (HDAC inhibitor)
– TRIO 019: everolimus (mTOR inhibitor)
– TRIO 0xx: T-DM1

How Are Ongoing Adjuvant Trials
Addressing the Problem?

Cancer
Insensitivity to
antigrowth
signalsEvading apoptosis
Tissue invasion
and metastasis
potential
Lapatinib, neratinib, pertuzumab, T-DM1
Bevacizumab
Denosumab
Everolimus
Metformin
Hallmarks of Malignancy

What Will Future Adjuvant
Therapies Look Like?

Cancer
Insensitivity to
antigrowth
signalsEvading apoptosis
Tissue invasion
and metastasis
potential
Src inhibitors, PI3K/Akt inhibitors
T-DM1, lapatinib
Denosumab
Anti-integrin therapies
ASA
Telomerase inhibitors
PARP inhibitors
Rb inhibitors
Dichloroacetate
Ramucirumab
Bevacizumab
Physical exercise
Metformin
Everolimus
Entinostat
My Predictions for Adjuvant Therapy

 Breast cancer
– A collection of multiple
clones of malignant cells
with divergent genotypes
and phenotypes expected
to demonstrate Darwinian
evolution under the
selection pressure of
systemic therapy
The Molecular Reality of Breast Cancer

Prediction-Based Adjuvant Treatment
Algorithm
 Molecular diagnosis (full genome, epigenome, and
quantitative transcriptome sequencing)
– Bioinformatic identification of post-alteration targets
 Pick from the menu: “à la carte” hallmark inhibitors
 Iteration: on relapse and after each progression, repeat
biopsy and repeat the process

July 1, 2031
Dear Dr. Mackey:
Ultigenomics has determined your patient’s T2N1 primary breast cancer
has the following phenotype, and intervention is recommended:
 Tumor
– PI3K-activating mutation:
PiKtrimicin
– HER2 pathway activation:
T-DM1
– Telomerase activation:
Tipglu
This will reduce your pt’s estimated 10-yr risk of recurrence from 63% to 4%
 Stroma
– VEGFR pathway activation:
ramucirumab
– Bone tropism: denosumab

How Do We Get There From Here?

Making Progress . . .
 Progress in adjuvant therapy will require greater
understanding of disease biology and subsequent
development of targeted therapies
 Ongoing and planned adjuvant trials are likely to make
major improvements in breast cancer survival—please
discuss participation with your patients
 Please contribute to the design and conduct of
biology-based breast cancer trials

Take-Home Messages
 Every breast cancer is genetically unique
 MBCs are more complex than primary breast cancers
 Breast cancer is heterogeneous and evolves in response
to treatment – we are pitted against Darwinian selection
 There are commonalities among this complexity
 Understanding the molecular biology of a specific breast
cancer informs treatment in 2012

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Molecular Understanding Informs Breast Cancer Treatment

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