10/15/2012

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Chemotherapy in Luminal Breast Cancer: Choice of Regimen

Andrew D. Seidman, MDAttending Physician

Breast Cancer Medicine ServiceMemorial Sloan‐Kettering Cancer Center

Professor of MedicineWeill Cornell Medical College

Question 

• Which of the following chemotherapy regimens are optimal options as adjuvant therapy for a 59 year old woman with a 1.7 cm., ER+, PR+, HER2 negative, node negative breast cancer with an 21‐Gene Recurrence Score of 30?

1. doxorubicin, cyclophosphamide and docetaxel (“TAC”)

2. cyclophosphamide + methotrexate + fluorouracil (CMF)

3. doxorubicin + cyclophosphamide followed by a taxane (AC‐T)

4. docetaxel + cyclophosphamide (“TC”)

5. doxorubicin + cyclophosphamide (AC)

6. FEC or FAC

The Questions: Choice of Chemotherapy for Luminal Breast Cancer

• Chemotherapy or Not?

• Anthracycline or Not?y

• Taxane or Not?

• Does Density Matter?

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It’s All About …The “Talk”

Metastatic Breast Cancer

5

Historical Perspective1985 NIH Consensus Conference: 

Premenopausal, node (+) : Chemotherapy

Premenopausal, node (‐) : treatment not recommended,consider chemotherapy if "high risk"

Postmenopausal, node (+), ER (+) : tamoxifen

Postmenopausal, node (+), ER (‐) : consider chemotherapy,but cannot be recommended as standard practice

Postmenopausal, node (‐) : no routine adjuvant therapy,may be considered for certain "high‐risk" patients

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S1007: A Phase III, Randomized Clinical Trial of Standard S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/Adjuvant Endocrine Therapy +/-- Chemotherapy in Patients Chemotherapy in Patients with 1with 1--3 Positive Nodes, Hormone Receptor3 Positive Nodes, Hormone Receptor--Positive and Positive and

HER2HER2--Negative Breast Cancer with Recurrence Score of 25 Negative Breast Cancer with Recurrence Score of 25 or Lessor Less

Ana M. GonzalezAna M. Gonzalez‐‐Angulo, M.D.Angulo, M.D.

Primary ObjectivePrimary Objective

To determine the effect of chemotherapy in To determine the effect of chemotherapy in patients with node positive breast cancer who patients with node positive breast cancer who do not have high RS by 21do not have high RS by 21--Gene RS AssayGene RS Assay

•• Patients with 1Patients with 1--3 positive nodes and HR+ and HER23 positive nodes and HR+ and HER2--•• Patients with 1Patients with 1--3 positive nodes, and HR+ and HER23 positive nodes, and HR+ and HER2--breast cancer with RS ≤ 25breast cancer with RS ≤ 25

•• DFS for patients treated with chemotherapy compared to DFS for patients treated with chemotherapy compared to no chemotherapy and dependence on the magnitude of no chemotherapy and dependence on the magnitude of RS. RS.

•• Determine the optimal Determine the optimal cutpointcutpoint for recommending for recommending chemotherapy or not.chemotherapy or not.

ChemotherapyChemotherapy

Second Generation RegimensSecond Generation Regimens

Third Generation RegimensThird Generation Regimens

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Biologic Heterogeneity Mandates Individualized 

Treatment Approaches

21‐GeneRecurrence Score (RS) Assay

PROLIFERATIONKi‐67STK15SurvivinCyclin B1

ESTROGENERPRBcl2SCUBE2

16 Cancer and 5 Reference Genes From 3 Studies

RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score + 0.05 x CD68- 0.08 x GSTM1- 0.07 x BAG1Cyclin B1

MYBL2

SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta‐actinGAPDHRPLPOGUSTFRC

CD68 Category RS (0-100)Low risk RS <18

Int risk RS ≥18 and <31

High risk RS ≥31

Paik et al. N Engl J Med. 2004;351:2817‐2826.

0.07 x BAG1

•

Standardized Quantitative 21‐Gene RS Assay: Node ‐, ER + 

15%

20%

25%

30%

35%

40%

Recurr

ence a

t 10 Y

ears

Low Risk Group High Risk Group Intermediate Risk Group

0%

5%

10%

0 5 10 15 20 25 30 35 40 45 50

Recurrence Score

Dis

tant

1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006 3) Paik et al JCO 2006, 4) Gianni et al JCO 2005

Lower RS’s••Lower likelihood of recurrenceLower likelihood of recurrence••Greater magnitude of TAM benefitGreater magnitude of TAM benefit••Minimal, if any, chemotherapy benefitMinimal, if any, chemotherapy benefit

Higher RS’s••Greater likelihood of recurrenceGreater likelihood of recurrence••Lower magnitude of TAM benefitLower magnitude of TAM benefit••Clear chemotherapy benefitClear chemotherapy benefit

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Adjuvant Chemotherapy Regimens

CMF =  AC

AC → P/DCAF/FAC CEF/FEC

DC

ddAC → P

// /

FEC → P/D

Differential Benefits by Subtype?

DAC(Tac)

AC ‐> wkly P

The Anthracyclines Have Been a Mainstay:  Clear Benefits in Unselected Patients

3.7%

4.6%

EBCTCG, Lancet 2005

OS

Gennari  A et al,  JNCI 2008

OS

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Anthracycline sensitivity in HER2‐positives

TOP2Deleted

TOP2Normal

DiLeo SABCS 2008 (abs 705)

Normal

TOP2Amplified

Anthracycline for Luminals?

• Unique, serious, potential late toxicities (cardiac, AML, MDS)

• Total/near total alopecia

• Increased likelihood of nausea

• Some evidence of effectiveness in all subgroups

• Limited prospective, reproducible data demonstrating a lack of differential benefit in any subset

• Mixed retrospective, data demonstrating effectiveness limited to subsets

• Biomarker identification and testing is evolving

Adjuvant CMF or AC vs Capecitabine in women >65Capecitabine Alone for Selected Luminals?

Muss et al, NEJM 2009

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Meta‐analysis: Adjuvant taxane vs no taxane: DFS

Copyright © American Society of Clinical OncologyDe Laurentiis, M. et al. J Clin Oncol; 26:44‐53 2008

Meta‐analysis: Adjuvant taxane vs no taxane:  OS

Copyright © American Society of Clinical Oncology

De Laurentiis, M. et al. J Clin Oncol; 26:44‐53 2008

Disease-free Survival among Patients Treated with or without Paclitaxel According to

Estrogen-Receptor Status and HER2 Expression

21Hayes DF et al. N Engl J Med 2007;357:1496-1506

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No paclitaxelbenefit

Each of these 3 subsets shows a statistically significant benefit from paclitaxel with small sample size

E1199: Best Taxane for Luminal BC?

Secondary Comparisons:Docetaxel Paclitaxel

q3w q1w q3w q1w

5-Year DFS 81.2% 77.6% 76.9% 81.5%

d t lit l 3HR: 1.23 HR: 1.09 HR: 1.0 HR: 1.27

Primary Comparisons:Paclitaxel vs. Docetaxel: HR: 1.032; P = 0.61

q3w vs. q1w: HR: 1.062; P = 0.33

compared to paclitaxel q3wP = 0.02 NS NS P = 0.006

Hormone Receptor Positive*

HR: 1.28

P = 0.03

HR: 1.15

NS

HR: 1.0

NS

HR: 1.20

NS

Hormone Receptor Negative*

HR: 1.08

NS

HR: 0.96

NS

HR: 1.0

NS

HR: 1.40

P = 0.02

5-Year OS 87.3% 86.2% 86.5% 89.7%

compared to paclitaxel q3wHR: 1.13

NS

HR: 1.02

NS

HR: 1.0

NS

HR: 1.32

P = 0.01

* Exploratory analysis

Meta‐analysis of disease‐free survival (DFS) according to ER status for Taxanes

Copyright © American Society of Clinical Oncology De Laurentiis, M. et al. J Clin Oncol; 26:44‐53 2008

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Meta‐analysis of disease‐free survival (DFS) according to HER‐2 status

Copyright © American Society of Clinical Oncology

De Laurentiis, M. et al. J Clin Oncol; 26:44‐53 2008

Weekly Paclitaxel was “equally superior” to every 3 Week Paclitaxel in Luminal or Triple Negs in E1199

HRHR HER2HER2 No. No. DFSDFS OSOS

Pos Neg 1213 1.31 1.36

(0.97, 1.72) p=0.05

(0.92, 2.00)

p=0.12

Neg Neg 462 1.37

(0.98, 1.93

P=0.07

1.33

(0.91, 1.94)

P=0.14

Taxane OR Anthracycline for Luminal BC?: US Oncology 9735 

AC x 4 q3w

Doxorubicin  (60 mg/m2)Cyclophosphamide  (600 mg/m2)

n=510

• N=1016• 71% ER+• 48% N–

TC x 4 q3w

Docetaxel  (75 mg/m2) Cyclophosphamide  (600 mg/m2)

n=506

Eligibility: Stage I, II, or III disease

R

Jones et al. J Clin Oncol. 2006;24:5381‐5387.

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TC vs AC: DFS and OS

Copyright © American Society of Clinical Oncology

From: Jones, S. et al. J Clin Oncol; 27:1177‐1183 2009

Summary of unplanned, exploratory analyses of disease-free survival hazard ratios (HR) and CI

Docetaxel/cyclophosphamide (TC) is favored left of 1.

Jones S et al. JCO 2009;27:1177-1183

©2009 by American Society of Clinical Oncology

US Oncology 06090TC versus TAC in HER2 (‐):

(Relative Contribution of A added to to T in Luminals?)

N = 2000

From: http://www.usoncology.com/portal/page/portal/PubWeb/2CancerCareNetwork/03USOncologyResearch/X_ClinicalResearch/X_ClinicalTrialsDetail?PSTUDYNUM=06090PI: J. Blum

80% power to detect a 3.4% DFS advantage for the anthracycline

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If AC or Paclitaxel, 4 = 6

Rx

Paclitaxel    vs            ACD

PI: L. Shulman

6vs    4

URATION

Does Dose Density Matter in Luminal Breast Cancer?

1,000,000,000,000

10,000,000,000

ConventionalSchedule

Dose‐DenseSchedule

10,000,000,000

100,000,000

1,000,000

10,000

100

1

0 10 20 30 0 10 20 30

Weeks

Cell number

ChemoRx Benefit as Function of ER Status: 20‐Year Experience of CALGB & U.S. IntergroupChemoRx Benefit as Function of ER Status: 20‐Year Experience of CALGB & U.S. Intergroup

•Average hazard reduction (confidence interval)

ER8541

Lo Hi9344

No Tax Tax9741

q3 q2Overall

Lo q2

Neg36%

(15 to 52%)25%

(11 to 36%)23%

(0 to 42%)63%

(43 to 76%)

*After adjusting, no significant differences

Berry DA, et al. JAMA 2006.

Neg (15 to 52%) (11 to 36%) (0 to 42%) (43 to 76%)

Pos14%

(-18 to 37%)12%

(-4 to 25%)10%

(-19 to 33%)

32%(-7 to 56%)

Neg29%

(3 to 48%)25%

(11 to 37%)22%

(-5 to 43%)59%

(34 to 74%)

Pos8%

(-27 to 36%)10%

(-10 to 26%)1%

(-44 to 32%)

18%(-41 to 52%)

DFS

OS

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R Negative

20‐Year Experience of CALGB & U.S.  Intergroup20‐Year Experience of CALGB & U.S.  Intergroup

DFS    CALGB 8541

DFSCALGB 9344

DFSCALGB 9741

ChemoRx Benefit as Function of ER Status:

ERER

 Positive

Years Years Years

Berry DA, et al. JAMA 2006

Ultimately, It May Be What Comes AFTER ChemoRx That Matters Most in Luminal BCs!

COMPARISON OF TAILORX AND MINDACT TRIALS

TAILORx MINDACT

Groups TBCI BIG

Population Node‐neg, ER+ Node‐neg, ER+/‐

Assay 21 gene  RS™ 70 gene Prognostic Signature

Utility Scale & Level of Evidence

+ or ++II

+ or ++IIILevel of Evidence II III

Tissue FPET Fresh or frozen

Accrual Goal ~10,500 ~6,000

Randomized group RS 11‐25 (40%) Discordant risk (32%)

RandomizationTreat with hormones+/‐ chemotherapy

Treat by clinical vs. genomic risk

Non‐randomized groupsRS < 11: HormonesRS > 25: Chemo+ hormones

Both low risk (13%):HormonesBoth high risk (55%): Chemo 

hormones

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Question 

• Which of the following chemotherapy regimens are optimal options as adjuvant therapy for a 59 year old woman with a 1.7 cm., ER+, PR+, HER2 negative, node negative breast cancer with an 21‐Gene Recurrence Score of 30?

1. doxorubicin, cyclophosphamide and docetaxel (“TAC”)

2. cyclophosphamide + methotrexate + fluorouracil (CMF)

3. doxorubicin + cyclophosphamide followed by a taxane (AC‐T)

4. docetaxel + cyclophosphamide (“TC”)

5. doxorubicin + cyclophosphamide (AC)

6. FEC or FAC

My Choice:

CMF

Take Home Points:Adjuvant Chemotherapy for Luminal A Breast Cancer

• Relative benefit of chemotherapy in this intrinsic subset is modest

• Anti‐estrogen therapy plays a (the) major role in risk reductionreduction

• Incremental differences in efficacy between 1st, 2nd, and 3rd generation regimens are negligible while differences in early and late toxicities may not be

• “First do no harm”, or at least “first do as little harm as possible”

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It’s Our Time