Clinical Dilemma:Which Adjuvant

Chemotherapy is Just Right?Dr. Maureen Trudeau

Head, Division of Medical Oncology/HematologyToronto Sunnybrook Regional Cancer Centre

Associate Professor, University of Toronto

June 15, 2007

Systemic Therapy - Chemotherapy

• Overall survival improvement in clinical trials both for standard and newer treatments

• Choice – for patients, for physicians (anthracycline +/- taxanes)

• Better decision making aids– www.adjuvantonline.com

• Molecular profiles – Oncotype Dx, MammoPrint• Improved supportive care

Decision Making in Adjuvant Therapy

Tumour characteristicsT, N, Grade, ER, PgR,

HER2, LVIPatient Characteristics

Age, ComorbiditiesPrior Therapy

Performance Status

Patient PreferenceWork/Family/Self

Clinical Trials,Guidelines

Recent Reports

Molecular Profile

Select Breast Cancer Treatments Based on Tumor Phenotype

• Tumor phenotype defines treatment options

Hormone receptor

Positive Hormonal therapy

Negative Chemotherapy

Positive HER2-targeted

therapy

HER2 HER2

Negative PositiveHER2-targeted

therapy

Negative

BIGBIG--TRANSBIG TRANSBIG SecretariatSecretariat–– Used with permissionUsed with permissionMarch 2005 March 2005 -- ConfidentialConfidential

IMPROVED RISK ASSESSMENT OF EARLY IMPROVED RISK ASSESSMENT OF EARLY BREAST CANCER THROUGH GENE BREAST CANCER THROUGH GENE

EXPRESSION PROFILINGEXPRESSION PROFILING

microarraymicroarray

GeneGene--expression profileexpression profile

Good signature

Poor signature

N Engl J Med, Vol 347 (25), Dec. 2002N Engl J Med, Vol 347 (25), Dec. 2002

Breast Cancer is not ONE Disease

HER-2Basal-like Luminal ALuminal B“Normal”

Sorlie T et al, PNAS 2001

Gene Expression Patterns of Breast Carcinomas

Basal-likeSubgroup

= E

HER2Subgroup

= D

Normalbreast

like

LuminalSubtype

C

LuminalSubtype

B

LuminalSubtype

A

ERGene

expression

ERGene

expression

E

DCB

A

O.S.

months

Adapted from PNAS, 2001, vol 98 no. 19

All Breast Cancer

ER+65-75%

HER2+15-20%

Basaloid15%

Molecular Classifications of Breast Tumors

Luminal A ER +

high

Prolif

-

P53 mutations

16%

Luminal B ER +

low

+ 71%

Basal -like ER - + 75%, also

BRCA1

ERBB2 + ER-/+ -/+ 86%

Normal-like ER - -

Sorlie 2007

The “Triple Negative” Breast Cancer

Estrogen Receptor (ER) negativeProgesterone receptor (PR) negative

Her2neu (HER2) negative

Up to 90% of Triple Negative Breast Cancers are Basal-Like Breast Cancers

ER/PR/HER2 -

Basal like Breast Cancers (BLC)

• BLCs comprise 15% of all invasive cancers

• More common in:– Younger pts– African Americans (40% premenopausal women)– BRCA1 mutation carriers

• BLC are associated with:– high grade– p53 mutations– Increased expression of EGFR– CK5/6 (recent studies in 2006…Vimentin, cKIT, SRC)

Sample

• From the HBBC database, 1601 (80%) of patients had details on hormone receptors/HER2 and were eligible for the study

• 180 (12%) of the 1601 patients were defined as basal-like breast cancers

• Mean follow up was 8.1 years

p = 0.02(54.4)(44.6)

877023

(45.6)(54.4)

510609302

Lymph Node StatusPositiveNegativeMissing or Not Tested

p < 0.0001(9.8)(24.2)(66.0)

1537

101

(19.9)(51.8)(28.3)

237616336

Tumor GradeIIIIIIMissing

p < 0.0001(36.5)(55.6)(7.9)

659914

2

(62.7)(32.8)(4.6)

880461

6416

Tumor SizeT1 (? 2 cm)T2 (>2cm to ? 5cm)T3 (>5cm)Missing

p < 0.00013.0 cm2.1 cmMean Tumor Size

p < 0.00015357.7Mean Age at Diagnosis (yrs)

Significancep value *

Basal-like(N=180)

number (percent)

Non Basal(N=1421)

number (percent)

Characteristic

Characteristics of Basal-like versus Non basal-like Breast Cancers

* p values were calculated with the use of the chi-square test

Hazard Rate of Distant Recurrence

Survival

Novel Therapies for TN

• BRCA1 involved in repair of double stranded DNA breaks– Mutations implicated in breast/ovarian susceptibility

• BRCA1 cancers appear to closely resemble sporadic triple negative breast cancers on molecular level

• in vitro chemo-sensitivity studies have found that basal-like breast cancers may be particularly sensitive to cisplatin and to other drugs that cause double-strand breaks in DNA

• Agents such as cisplatin and carboplatin may be more effective treatment than other types of chemotherapy for the basal like group

Oncotype DX• A multigene assay to predict recurrence of

Tamoxifen-treated, node-negative breast cancer (Paik NEJM 204)

• 21 genes - proliferation (5), invasion (2), HER 2 (2), Estrogen (4) , 3 others and 5 reference genes with a Recurrence Score (RS) algorithm

• For node negative, tam treated (JCO 2007): –Luminal A = low risk oncotype DX–Luminal B = mod/high risk

Program for the Assessment of Clinical Program for the Assessment of Clinical Cancer Tests (PACCTCancer Tests (PACCT--1):1):

TTrial AAssigning IIndividuaLLized OOptions for TRReatment (TAILORxTAILORx)

Participating Groups:Participating Groups:ECOG, North American Breast Cancer Intergroup ECOG, North American Breast Cancer Intergroup

(CALBG, SWOG, NCCTG, NCIC, & ACOSOG) (CALBG, SWOG, NCCTG, NCIC, & ACOSOG)

& NSABP& NSABP

Background:Background:Management of ER-Positive, Lymph-

Node Negative Breast Cancer

• ~ 137,000 diagnosed annually in North America• ~ 80-85% are adequately treated with

• surgery +/- irradiation• hormonal therapy

• Adding chemotherapy recurrence by ~ 25%• absolute benefit is small (~3-5% or less)

• Current practice guidelines • chemotherapy recommended for most

• Approved diagnostic test by regulatory agencies in the United States (CLIA)

• No special processing required - may be performed on routinely collected and processed formalin-fixed, paraffin embedded tissue

• Extensive post-marketing experience and familiarity in U.S. oncology community

• Increasing precedent for third party reimbursement• Prior successful collaboration between NCI-

sponsored groups and industry partner

Background:Background:Practical Considerations Practical Considerations for Selectingfor Selecting

Oncotype DX AssayOncotype DX Assay

Background:Background:Scientific Rationale for Selecting Oncotype DX Scientific Rationale for Selecting Oncotype DX

AssayAssay1. Validated prognostic test for tamoxifen treated patients

– predictive of distant distant recurrence – may be used as dichotomous or continuous variable– (Paik et al. NEJM, 2004)(Paik et al. NEJM, 2004)

2. Also validated in population based Kaiser study –– (Habel et al. SABCS 2004, abstr 3109)(Habel et al. SABCS 2004, abstr 3109)

3. Lower RS predictive of tamoxifen benefit –– (Paik et al. ASCO 2005, abstr(Paik et al. ASCO 2005, abstr 510)

4. Higher RS predictive of chemotherapy benefit–– (Paik et al. SABCS 2004, abstr 21)(Paik et al. SABCS 2004, abstr 21)

5. Correlates more strongly with outcome than Adjuvant! –– (Bryant et al. St. Gallen, 2005)(Bryant et al. St. Gallen, 2005)

6. Predictive of locallocal recurrence in tam treated patients – (Mamounas, SABCS 2005, abstr 29)

T A I L O R xT A I L O R xS t u d y D e s i g nS t u d y D e s i g n

ARM AHormona l Therapy

A lone

Secondary S tudy Group 1RS < 11

~29% of P opulation

ARM BHormona l Therapy

A lone

ARM CChemotherapy P lusHormona l Therapy

RANDOMIZEStratification Factors :

Tumor S ize , Menopausal S tatus ,P lanned Chemo, P lanned Radiation

Primary S tudy GroupRS 11-25

~44% of P opulation

ARM DChemotherapy P lusHormona l Therapy

Secondary S tudy Group 2RS > 25

~27% of P opulation

REGISTERSpecimen Banking

ONCOTYPE DX ASSAY

Pre-REGISTER

Background:Background:Definition of Risk Groups for TAILORxDefinition of Risk Groups for TAILORx

•• Risk groups originally defined as (NEJM, 2004):Risk groups originally defined as (NEJM, 2004):– < 18 “Low Risk”– 18-30 “Intermediate Risk”– > 30 “High Risk”

•• Definitions modified for Definitions modified for TAILORxTAILORx::– 11-25 “Primary Study Group”– < 11 “Secondary Study Group 1”– > 25 “Secondary Study Group 2”

•• Rationale for selecting RS 11 as the lower bound for Primary StuRationale for selecting RS 11 as the lower bound for Primary Study Group:dy Group:– RS predicts distant and local recurrence– RS 11: ~ 10% local & distant recurrence rate at 10 years– 10% threshold is typically used for recommending adjuvant chemotherapy

•• Rationale for selecting 25 as upper bound for Primary Study GrouRationale for selecting 25 as upper bound for Primary Study Group:p:– RS 30 associated with 20% risk of distant recurrence– Lowering threshold to 25 reduces risk for undertreatment– When viewing chemotherapy and tamoxifen benefit as a continuous

variables, 95% Confidence Intervals overlap in the 11-25 RS range (shown in next slides)

Adapted by Dr. Maureen E. Trudeau, MD

Anthracycline-based Regimens Superior To CMF/AC

Regimen Trials Group DFS / OS

(1) CEF (NCIC-CTG)

(2) dd (EC) CEF (NCIC/EORTC/SAKK) -- --

(3) FEC100 > FEC50 (FASG)

FEC50 CMF (ICCG) -- --

(4) CAF (SWOG)

(5) E CMF (NEAT/SCTBG)

(6) AV CF (MISSET)

(7) TC (Jones) --

Taxane Regimens Superior To AC-type Regimens

Regimen Trials Group DFS / OS(1) AC P (CALGB) (2) AC P (NSABP) --(3) P FAC (MDACC) -- --(4) DAC (BCIRG) (5) FEC D (PACS 01) (6) A(C) D CMF (BIG 2-98) --

Regimens superior to AC P(1) dd AC P (CALGB)

or dd A P C(2) CEF or dd (EC) P - -

Adjuvant Chemotherapy Options – A Growing List

2007 Options

CEF (CMF)

FEC 100 (FEC 50)

AC Taxol (AC)

TAC (FAC)

FEC 100 Docetaxel

(FEC 100)

Dose-dense AC Taxol

(AC Taxol)

Dose-dense

(EC) Taxol(AC Taxol)

CEF (AC Taxol)

1998 1998 OptionsOptions CMFCMF (1970’s)(1970’s)

(F) AC(F) AC (1980’s)(1980’s)

TAXANES AS ADJUVANT THERAPYTAXANES AS ADJUVANT THERAPYSECOND GENERATION OF CLINICAL TRIALSSECOND GENERATION OF CLINICAL TRIALS

Taxane ± Herceptin®

Best taxane

Dose & schedule

Sequence vs combination N5000

Best taxane

ECOG 1199 (intergroup trial)

AC x 4 P x 4

P weekly x 12

D x 4

D weekly x 12

2800 pts

AC x 4

AC x 4

AC x 4

Are There Factors that May Predict Response or Suggest

which Therapy to Use?

TAXANES AS ADJUVANT THERAPYTAXANES AS ADJUVANT THERAPYSECOND GENERATION OF CLINICAL TRIALSSECOND GENERATION OF CLINICAL TRIALS

Taxane ± Herceptin®

Best taxane

Dose & schedule

Sequence vs combination

N8700

Taxane ± Herceptin®

• HERA: any chemo Herceptin: 0 vs 1 vs 2 yr

• AC D vs AC D + H 1 yr vs DCH x 6 H 1 yr

• AC P vs AC P + H 1 yr

• AC P weekly x 12 vs AC P weekly x 12 H 1 yr vs AC P weekly x 12 + H 1 yr

Trastuzumab DFS

Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005

0 1 2

HERA 1 year

Combined analysis 2 years

Median follow-up

FavorsTrastuzumab

Favors noTrastuzumab

HR

BCIRG 006 DCarboH 2 years

2 yearsBCIRG 006 AC DH

FinHER VH / DH CEF 3 years

Adjusted for pos nodes, T size, menopausal status

Average hazard reduction (Confidence interval)

ER 8541

LoHi

9344

Tax

9741

q3q2

Overall

Loq2

Neg 36%

(15 to 52%)

25% (11 to 36%)

23% (0 to 42%)

63% (43 to 76%)

DFS

Pos 14%

(-18 to 37%)

12% (-4 to 25%)

10% (-19 to 33%)

32% (-7 to 56%)

Neg 29%

(3 to 48%)

25% (11 to 37%)

22% (-5 to 43%)

59% (34 to 74%)

OS

Pos 8%

(-27 to 36%)

10% (-10 to 26%)

1% (-44 to 32%)

18% (-41 to 52%)

Courtesy: Berry et al SABCS 2004

PACS 01DFS by Age, ITT

Kap

lan-

Mei

er E

stim

ate

Log-rank P-Value = 0.690HR (Cox model) = 0.98 [0.77-1.25]

0.00

0.25

0.50

0.75

1.00

Survival Time (years)

0 1 2 3 4 5 6 7 8

6FEC100

3FEC100-3D

Age < 50 yrs

Log-rank P-Value = 0.001HR (Cox model) = 0.67 [0.51-0.88]

Kap

lan-

Mei

er E

stim

ate

0.00

0.25

0.50

0.75

1.00

Survival Time (years)0 1 2 3 4 5 6 7 8

6FEC100

3FEC100-3D

Age 50 yrs

Multivariate Interaction Test HR: 0.66 [0.46-0.95] P-value = 0.026

HR = 0.76 P = 0.046

0 6 12182430364248546066

100

90

80

70

60

50

FAC

TAC

Negative

0 6 12182430364248546066

90

80

70

60

50

FAC

TAC

HR = 0.60 P = 0.0088

Positive

Time to First Event

100

TAC vs FACDFS by HER2 Status

Time to First Event

% A

live a

nd

Dis

ease-F

ree

(Centrally reviewed, FISH centrally reviewed)

Ratio of HRs 0.85 p= 0.4122 NEJM 2005

Topoisomerase II

• Topoisomerase II is essential for DNA replication and recombination

• Anthracyclines target topoisomerase II• Increased sensitivity to HER2 due to co-

amplification of TOP2A?

A pooled analysis on the interaction A pooled analysis on the interaction between HER-2 expression and between HER-2 expression and responsiveness of breast cancer responsiveness of breast cancer

to adjuvant chemotherapyto adjuvant chemotherapy

Alessandra Gennari, Maria Pia Sormani, Matteo Puntoni and Paolo Bruzzi

National Cancer Research Institute - Genoa

and University of Genoa - Italy

SABCS 2006

Characteristics of studies - ICharacteristics of studies - I

Study ComparisonHER2 status

determined (%)

NSABP B11 PF vs PAF 638/682 (94%)

NSABP B15 CMF vs AC 2.034/2.295 (89%)

GUN 3 CMF vs CMF/EV 123/220 (56%)

Brussels CMF vs HEC/EC 354/777 (46%)

Milan CMF vs CMF→ A 506/552 (92%)

DBCCG - 89 - D CMF vs FEC 805/980 (82%)

NCIC MA5 CMF vs CEF 628/710 (88%)

SABCS 2006

Total (available/randomised)Total (available/randomised) 5.088/6.216 (82%)5.088/6.216 (82%)

Disease Free SurvivalDisease Free Survival

Test for interaction 2 = 13.7 p < 0.001

non anthra better

0.34 - 0.800.71 - 1.17

0.520.91NCIC MA-5

0.61 - 0.830.90 - 1.11

0.53 - 1.06 0.60 - 1.05

0.46 - 1.490.91 - 1.64

0.65 - 1.080.86 - 1.20

0.44 - 0.820.75 - 1.23

0.711.00

Overall

0.750.79DBCCG-89-D

0.831.22Milan

0.34 - 1.270.93 - 1.97

0.651.35Brussels

NSABP B15

0.600.96

NSABP B11

0.841.02

heterogeneity 25 = 5.3, p = 0.38

heterogeneity 25 = 7.6, p = 0.18

Study HR 95% CI anthra better

0.6 1 2 50.4

p < 0.0001

p = 1.0

0.9

HER2 positive HER2 negative

SABCS 2006

0.82 - 0.980.90Total p = 0.01

Efficacy summaryEfficacy summary

• Risk of relapse

29%

HR 0.71 (0.61-0.83) (p < 0,0001)

•Risk of death

27%

HR 0.73 (0.62-0.85) (p < 0,0001)

HER2 positiveHER2 positive

• Risk of relapse

anthra ≈ non anthra

HR 1.00 (0.90-1.11) (p = 1,0)

•Risk of death

anthra ≈ non anthra

HR 1.03 (0.92-1.16) (p < 0,86)

HER2 negativeHER2 negative

SABCS 2006

Hierarchy of Chemotherapy Regimens

Appropriate high Appropriate high riskrisk

populationpopulation

Older, no Older, no GCSFGCSF

Younger, Younger,

+ GCSF+ GCSF

Younger,Younger,

+/- GCSF+/- GCSF

Younger, Younger,

+ GCSF+ GCSF

Younger, Younger,

+ GCSF+ GCSF

# of cycles# of cycles 6 cycles6 cycles 10 cycles10 cycles6 cycles6 cycles

(12 visits)(12 visits)8 cycles8 cycles 6 cycles6 cycles

High riskHigh risk FECFECDD dd(EC)dd(EC)PP CEFCEF dd(AC)dd(AC)PP TACTAC

is better thanis better than

Moderate riskModerate risk FEC 100FEC 100CEFCEF

(MA 5)(MA 5)ACACPP

ACACPP

ACACDD

is better thanis better than

Low RiskLow Risk FEC 50FEC 50 CMFCMF ACAC DCDC ADAD

No TherapyNo TherapyP = paclitaxelP = paclitaxel

D = docetaxelD = docetaxel

CAF FAC

The choice of chemotherapy

Depends on the following:

• Tumour characteristics and risk of relapse

• Patient comorbidities

• Patient age

• Social determinants

• Drug availability / costs

• Physician or patient preference

Cost of common regimens

Regimen N+ Study Total Treatment Costs USD

(drug acquisition + incidental + administration)

DAC BCIRG001 $8,226

AC ->P CALGB9344 $4,340

AC->P CALGB9741 $11,741

CE120F MA-5 $4,852

FE100C FASG-5 $3,557

FE100C->D PACS-01 ~ $6,200

Convenience of common regimens

Regimen N+ Study Visits Chair time (h)

TAC BCIRG001 6 14

AC ->T CALGB9344 8 21.6

AC->T CALGB9741 8 21.6

CE120F MA-5 12 5.4

FE100C FASG-5 6 9

FE100C->D PACS-01 6 8

Adapted by Dr. Maureen E. Trudeau, MD

Where are we going?

Cases

A 68-year old woman presents with an infiltrating duct carcinoma

• 1.2 cm in size

• ER 80% PR 60%

• HER 2 -

• Sentinel node negative

A 68-year old woman presents with an invasive ductal carcinoma

A 59-year old postmenopausal woman with invasive ductal carcinoma

• 1.9 cm in size

• ER 30% PR 0%

• HER 2+ (3+ by IHC)

• Grade 3

• Sentinel node negative

A 59-year old postmenopausal women with invasive ductal carcinoma

A 49-year old premenopausal woman with invasive lobular carcinoma

• 2.5 cm in size

• ER 70% PR 30%

• HER 2-

• Grade 2

• 2/10 positive lymph nodes

A 49-year old premenopausal woman with invasive lobular carcinoma

A 39-year old premenopausal woman with invasive ductal carcinoma

• 2.8 cm in size

• ER 0% PR 0%

• HER 2 -

• Grade 3

• 5 nodes positive

A 44-year old premenopausal woman with invasive ductal carcinoma

• 2.0 cm in size

• ER 100% PR 100%

• HER 2 -

• Grade 2

• 1/17 nodes positive

• 2 other smaller lesions, grade 1