CCO Rational Options in Breast Cancer : How Molecular Understanding Informs Treatment

John R. Mackey, MD, FRCP(C)TRIO DirectorProfessor Division of Medical OncologyDepartment of OncologyUniversity of AlbertaCross Cancer InstituteEdmonton, AlbertaCanada

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/oncologyTranslational Research 2012

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Program Faculty

Program DirectorDennis J. Slamon, MD, PhDTRIO ChairmanChief, Division of Hematology/OncologyDavid Geffen School of Medicine at UCLALos Angeles, California

FacultyJohn R. Mackey, MD, FRCP (C)TRIO DirectorProfessor Division of Medical OncologyDepartment of OncologyUniversity of AlbertaCross Cancer InstituteEdmonton, AlbertaCanada


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

ENDOCHEMO

CHEMO

CHEMOTRAZENDO

CHEMOTRAZ

ERNegativePositive

Po

siti

veN

egat

ive

HE

R2


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

UbiquitousShared primaryShared metastasisPrivate

Normal tissue

VHL

KDM5C (missense and frameshift)mTOR (missense)

SETD2 (frameshift)

SETD2 (missense)KDM5C (splice site)

SETD2 (splice site)

?

PreM

R4a

R4b

PreP

R9 R8R2R1

R3R5

M2bM1

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

signalsEvading apoptosis




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 × AC60/600 mg/m2

4 × docetaxel100 mg/m2

6 × T and platinum salts75 mg/m2 75 mg/m2 or AUC 6

1 yr of trastuzumab

N = 32221 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 BestRisk-to-Benefit Ratio?

TCH


4 × AC60/600 mg/m2

4 × T100 mg/m2

6 × T and carboplatin75 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 × AC60/600 mg/m2

4 × T100 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

00 12 24 36 48 60 72 84

Mos

DF

S (

%)

AC-T plustrastuzumab

TCHAC-T

93

8781

88

78

86

75

849287 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 AEsAE, % 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 AEsAE, % 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

00 12 24 36 48

Mea

n L

VE

F (

%)

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


NucleusNucleus

RbRb myc

maxmyc

max

PI3KPI3K

HER2HER2

rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK

CyclinsCyclinsCyclinsCyclins

CdksCdksCdksCdks

p27p27//p16p16p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR

VEGFVEGFVEGFVEGF

HER2 Amplification Drives Proliferation

HER2HER2


NucleusNucleus

RbRb myc

maxmyc

max

PI3KPI3K

HER2HER2

rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK

cyclinscyclinscyclinscyclins

Cdk’sCdk’sCdk’sCdk’s

p27p27//p16p16p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR

VEGFVEGFVEGFVEGF

HER2 Amplification Suppresses Apoptosis

HER2HER2


NucleusNucleus

RbRb myc

maxmyc

max

PI3KPI3K

HER2HER2

rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK



p27p27//p16p16p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR

HER2HER2

Chang J, et al. SABCS 2008.


Growth factorsGrowth factors

NucleusNucleus

RbRb myc

maxmyc

max

PI3KPI3K

HER2HER2HER 1,3,4HER 1,3,4

rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK



p27p27//p16p16p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR

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 withcentrally

determinedHER2+

invasive breastcancer

(N = 8000planned)

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 IV once wkly × 12 wks

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 IV once wkly × 12 wks

Lapatinib 1500 mg orally QD ×

34 wks

6-wkwash-out


NucleusNucleus

RbRb myc

maxmyc

max

PI3KPI3K


rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK



p27p27//p16p16p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR



NucleusNucleus

RbRb myc

maxmyc

max

PI3KPI3K


rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK



p27p27//p16p16p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR

(neo) ALTTO rationale



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

PP

PP P

PPP

PP

PP

Anti-VEGFantibodies

(bevacizumab)

Anti-VEGFR2antibodies

(ramucirumab)

Small-molecule inhibitors of VEGFR (vatalanib, cediranib, motesanib,

sunitinib, sorafenib, axitinib, others)

SolubleVEGFRs

(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

RA

ND

OM

IZA

TIO

N

Follow-up

Progressivedisease

or unacceptable

toxicityor

withdrawnconsent

Docetaxel 75 mg/m² IV q3w

Blinded ramucirumab 10 mg/kg IV q3w

…..

…..

2/3

1/3Docetaxel 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

NucleusNucleus

PI3KPI3K


rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK

AktAkt

mTORmTOR

Sur

viva

l

Prol

ifera

tion VEGFVEGFVEGFVEGF



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 2013ClinicalTrials.gov. NCT00625898.


Growth factor

Growth factor

NucleusNucleusRbRb myc

maxmyc

max

PI3KPI3K

HER2HER2HER1,3,4HER1,3,4

rasras

rafraf

MEKMEKMEKMEK

MAPKMAPKMAPKMAPK


Cdk’sCdk’sCdk’sCdk’sp27p27//p16p16

p27p27//p16p16

ERER

p53p53

AktAkt

mTORmTOR

VEGFVEGFVEGFVEGF

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)

ClinicalTrials.gov. NCT00625898.


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






Lapatinib, neratinib, pertuzumab, T-DM1

BevacizumabDenosumab

EverolimusMetformin

Hallmarks of Malignancy

What Will Future Adjuvant Therapies Look Like?



Cancer






Src inhibitors, PI3K/Akt inhibitorsT-DM1, lapatinib

DenosumabAnti-integrin therapies

ASA

Telomerase inhibitors

PARP inhibitorsRb inhibitors

Dichloroacetate

RamucirumabBevacizumab

Physical exerciseMetforminEverolimusEntinostat

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

Go Online for More CCO Coverage of Chicago 2012!

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http://www.clinicaloptions.com/oncology

CCO Rational Options in Breast Cancer : How Molecular Understanding Informs Treatment

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