a report from sabcs up-to-date review of the treatment of early breast cancer

A Report from SABCS

Up-to-Date Review of the Treatment of Early Breast Cancer

Maura N. Dickler, MDAssistant Attending Physician

Breast Cancer Medicine ServiceMemorial Sloan-Kettering Cancer Center

New York, NY

Up-to-Date Review of the Treatment of Early Breast Cancer

Overview• Chemotherapy

– Genomic profiling using the 21-Gene Recurrence Score Assay in postmenopausal, ER+, LN+ patients

– Update of AC vs. TC

• Trastuzumab for HER2+ Early Breast Cancer: PACS04 Trial • Endocrine Therapy: 100 month update of ATAC• Symptom Management/Supportive Care

– Effects of endocrine therapy on bone health and arthralgias– Prevention of AI-induced bone loss

• Bisphosphonates• Denosumab

Chemotherapy

SABCS Abstract 10

Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in

Postmenopausal, Node-Positive (N+), ER-Positive (ER+) Breast Cancer

SWOG 8814, TBCI 0100

K. Albain, W. Barlow, S. Shak, G. Hortobagyi, R. Livingston, I. Yeh, P. Ravdin, C. Yoshizawa, F. Baehner, N. Davidson, G. Sledge, E. Winer, C.

Hudis, J. Ingle, E. Perez, K. Pritchard, L. Shepherd, C. Allred, K. Osborne, and D. Hayes for The Breast Cancer Intergroup of North America

SWOG 8814/TBCI 0100 Correlative Science Study

Rationale

• The 21-gene Recurrence Score assay (RS) is prognostic for women with node(-), ER+ breast cancer on 5 years of tamoxifen*

• A high RS predicts large benefit from chemotherapy in node(-) disease, but no improvement if the RS is low**

• There are no RS data in a N+ population with a tamoxifen-alone control

• SWOG 8814 is an ideal trial to explore this question

*Paik, et al. NEJM, 2004**Paik, et al. J Clin Oncol, 2006

Albain K, et al. SABCS 2007. Abstract 10.

Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+

RANDOMIZE (N = 1477)

Tamoxifen x 5 yrs

CAF x 6, then tamoxifen

CAF x 6, with concurrent tam

Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years

(N = 361)(N = 550) (N = 566)



• Two co-primary objectives were to determine if the RS:─ Provides prognostic information for women with N+ disease

treated only with tamoxifen, and

─ Allows prediction of a N+ group that does not derive benefit from chemotherapy



Methods - I• NCI correlative science project (#8814A-ICSC) used paraffin-

embedded specimens from optional central banking protocol

• Conducted RT-PCR for 16 genes + 5 reference genes by Genomic Health, Inc; blinded to outcomes

• Calculated RS according to published criteria

• Assessed same endpoints from main trial: DFS and OS (DRFI not available)

• Performed analysis at SWOG Statistical Center using plan finalized before data received

Paik, et al. NEJM 2004.Albain K, et al. SABCS 2007. Abstract 10.


Methods - II

• Limited to tamoxifen and sequential CAF-T arms (eliminated inferior concurrent CAFT)

• Stratified log-rank tests by nodes (1-3 vs. 4+), due to strong prognostic effect in main trial

• Conducted Cox regression analyses on continuous RS and its interaction with treatment– Found violation of the proportional hazards assumption (hazard ratio not

constant over time)

– Therefore, analyses done with a split time axis: ≤ 5 and > 5 years



Sample Size for Analysis

Patients with samples - 666(45% of parent trial)

RT-PCR obtained - 601 (90%)Tamoxifen alone 148CAFT (concurrent) 234CAF-T (sequential) 219

Final sample for primary analysis148 + 219 = 367 (40% of parent trial)


0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

Sur

viva

l

0 2 4 6 8 10Years Since Registration

Tamoxifen (N=148, 63 events)CAF-T (N=219, 74 events)

Stratified log-rank P-value = 0.054 at 10 years (adjusted for nodal status)

Disease-Free Survival

• Outcomes in RS subset mirror those reported in main trial: superiority of CAF-T




Comparative Distribution of RS

StudyLow Risk (RS < 18)

Int. Risk(RS 18-30)

High Risk(RS ≥ 31)

NSABP B14* 51% 22% 27%

NSABP B20* 54% 21% 25%

Kaiser controls* 56% 19% 25%

ECOG 2197** 49% 31% 20%

SWOG 8814*** 40% 28% 32%

*node(-): Paik, et al. NEJM 2004 & JCO 2006; Habel, et al. Breast Ca Res Treat 2006**node(-) or 1-3+: Goldstein, et al. Proc ASCO 2007***node+, postmenopausal: this analysis – no difference by age



Results: Prognosis



0.00

0.25

0.50

0.75

1.00

Ove

rall

Surv

ival

0 2 4 6 8 10Years since registration

Low RS <18 (N=55)Intermediate RS 18-30 (N=46)High RS ≥31 (N=47)

Stratified log-rank p = 0.003 at 10 years

(tamoxifen alone)Overall Survival by Risk Group

0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

sur

viva

l

0 2 4 6 8 10Years since registration

Low RS <18 (N=55)Intermediate RS 18-30 (N=46)High RS ≥31 (N=47)


(tamoxifen alone)Disease-Free Survival by Risk Group

• 10-yr: Low RS = 60%, Int. RS = 49%,High RS = 43%

• 21-Gene recurrence score is prognostic for DFS and OS in tamoxifen arm

• 10-yr: Low RS = 77%, Int. RS = 68%,High RS = 51%


Results: Prediction

• No benefit to CAF over time if low RS

• Strong benefit to CAF if high RS

0.00

0.25

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0.75

1.00

Dis

ease

-free

sur

viva

l

0 2 4 6 8 10

Years since registration



Low risk (RS < 18)

Disease-Free Survival by Treatment0.

000.

250.

500.

751.

00D

isea

se-fr

ee s

urvi

val

0 2 4 6 8 10




High risk (RS ≥ 31)

Disease-Free Survival by Treatment

0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

sur

viva

l

0 2 4 6 8 10




Intermediate risk (RS 18-30)

Disease-Free Survival by Treatment


Ten-Year DFS Point Estimates (95% CI)

Recurrence Score Risk Category

TamoxifenAlone

CAF followed by tamoxifen

Low (< 18)*60%

(40%, 76%)64%

(50%, 75%)

Intermediate (18-30)49%

(32%, 63%)63%

(48%, 74%)

High (≥ 31)43%

(28%, 57%) 55%

(40%, 67%)

*40% event rate over 10 years and resistance to CAF


Low RS

Intermediate RS

High RS

Entire RS sample

Overall trial

Chemotherapy benefit No chemotherapy benefit

Tria

l Sub

set

0 .5 1 1.5 2Hazard Ratio

DFS hazard ratios adjusted for nodal status


Comparison of CAF-T to Tamoxifen Alone



Low RS

Intermediate RS

High RS

Chemotherapy benefit No chemotherapy benefit

0 1 2 3 4Hazard ratio

First 5 years Greater than 5 years

Comparison of CAF-T to Tamoxifen Alone (DFS adjusted for nodal status)

• No CAF benefit DFS either early or late in low RS, but stable impact over time if high RS



The RS is Predictive for Overall Survival

• No benefit to CAF in low RS in first 5-years (HR 1.05) or over entire time period (HR 1.18)

• Strong impact of CAF in high RS:– First 5-years HR 0.43 (0.21, 0.90) – Over entire period HR 0.56 (0.31, 1.01)– 10-year estimates:

Tamoxifen 51% (35%, 65%)CAF-T 68% (51%, 79%)

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Ove

rall

surv

ival

0 2 4 6 8 10


Tamoxifen (N=47, 22 deaths)CAF-T (N=71, 20 deaths)

Stratified log-rank test p = 0.027 at 10 years

High risk (RS ≥31)

Overall Survival by Treatment


SWOG 8814/TBCI 0100 Correlative Science Study Conclusions on Primary Analysis

• The 21-gene RS is prognostic for tamoxifen-treated patients with positive nodes

• Chemotherapy benefit is predicted when the RS is high, dominating in the first 5-years, but carried over long-term

• A low RS may define a group of women with positive nodes who do not appear to benefit from anthracycline-based chemotherapy

• This analysis of SWOG 8814 is just one study to evaluate the predictive impact of RS in ER+, LN+ postmenopausal patients.

• Currently, this data should be used with caution for treatment decisions regarding chemotherapy in LN+ patients.



Other Perspectives

• New strategies in endocrine/biologic therapy are needed if low RS, given event rate of 40% over 10-years

• Biology (not age) should drive treatment decisions, since for high RS chemotherapy is beneficial regardless of age

• These data (both RS and IHC) collectively challenge chemotherapy mandates for patients with N+, ER+ disease: not all benefit from chemotherapy, whereas others derive greater benefit than previously predicted


SABCS Abstract 12

Extended Follow-up and Analysis by Age of the US Oncology Adjuvant Trial 9735:

Docetaxel/Cyclophosphamide is Associated with an Overall Survival Benefit Compared to Doxorubicin/Cyclophosphamide and is Well-

tolerated in Women 65 or Older

Jones SE, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL,

Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Muss HB, Savin MA

AC vs. TC Adjuvant TrialTrial Design

Jones SE, et al. SABCS 2007. Abstract 12.

Doxorubicin 60 mg/m2 IV Day 1Cyclophosphamide 600 mg/m2 IV Day 1Every 21 days X 4 Cycles

Docetaxel 75 mg/m2 IV Day 1Cyclophosphamide 600 mg/m2 IV Day 1Every 21 days X 4 Cycles

RANDOMIZE

AC vs. TC Adjuvant TrialObjectives of this Analysis

• Primary Objective:– To compare disease-free survival (DFS) and overall survival

(OS) of AC vs. TC in early operable breast cancer at a median followup of 7-years

• Secondary Objectives:– To determine outcome by age and treatment regimen– To assess the impact of HER2 status on DFS (limited sample)– To determine toxicity profiles by age and treatment regimen


AC vs. TC Adjuvant TrialInclusion Criteria

• Patients with Stage I, II, or operable Stage III invasive breast cancer

• Complete surgical excision of the primary tumor

• Age >18 years

• Adequate renal function

• Adequate hematologic function

• Adequate hepatic function

• Karnofsky PS >80%

• Signed informed consent


AC vs. TC Adjuvant TrialDemographics by Treatment and Age

<65 Years ≥65 Years TC AC TC AC

Number of pts 428 Pts 428 Pts 78 Pts 82 Pts

ER+ 298 (70%) 275 (64%) 52 (67%) 58 (71%) PR+ 268 (63%) 258 (60%) 47 (60%) 49 (60%)

Nodes 0 212 (50%) 217 (51%) 28 (36%) 31 (38%) 1 to 3 174 (41%) 174 (41%) 35 (45%) 38 (46%) 4+ 42 (10%) 37 (9%) 15 (19%) 13 (16%)

Median Age (yrs) 50 49 69 68

Range (27 - 64) (27 - 64) (65 - 77) (65 - 77)


AC vs. TC Adjuvant TrialDFS by Treatment

At Risk TC 506 495 473 454 442 434 425 420 418 AC 510 498 477 442 422 412 401 396 392

0 12 24 36 48 60 72 84 96Months

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Proportion DFS

P = 0.033HR = .74

TC

AC

81%

75%


AC vs. TC Adjuvant TrialDFS by Treatment and Age Group


0 12 24 36 48 60 72 84 96Months

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Proportion DFS

<65TC

<65 AC

65+ TC

65+ AC

AC vs. TC Adjuvant TrialAssessment of HER2 Status by FISH* for 170 Patients

*FISH+ = Gene copy ratio of 2.0 or greater

TC AC Total

# of Patients 83 87 170

Negative 55 69 124 (73%)

Positive 28 18 46 (27%)


AC vs. TC Adjuvant TrialDFS for HER2 Positive Status


At Risk TC 28 27 21 20 17 17 16 16 16 AC 18 17 14 10 9 8 8 8 8

0 12 24 36 48 60 72 84 96Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Proportion DFS

HR = .73

TC

AC

AC vs. TC Adjuvant TrialDFS for HER2 Negative Status


At Risk TC 55 53 49 45 42 42 42 41 40 AC 68 61 51 47 45 44 44 40 38

0 12 24 36 48 60 72 84 96Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Proportion DFS

HR = .56

TC

AC

AC vs. TC Adjuvant TrialDFS Hazard Ratios (CI) for Key Subgroups

Overall HR for DFS = 0.74


AC vs. TC Adjuvant TrialOverall Survival by Treatment

At Risk TC 506 502 495 481 466 461 454 449 448 AC 510 504 493 476 459 448 432 429 427

0 12 24 36 48 60 72 84 96Months

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Proportion Surviving

P = 0.032HR = .69

TC

AC

87%

82%


AC vs. TC Adjuvant TrialOverall Survival by Treatment and Age Group

Insert graphics here

0 12 24 36 48 60 72 84 96Months

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Proportion Surviving

65+TC

65+AC

<65TC

<65AC


AC vs. TC Adjuvant TrialGrade 3/4 Hematologic Toxicity by Treatment & Age (%)


Adverse Event 428 Pts 428 Pts 78 Pts 82 Pts Anemia <1 1 <1 5 Neutropenia 60 54 52 59 Thrombocytopenia <1 1 0 <1 Febrile Neutropenia 4 2 8 4


AC vs. TC Adjuvant TrialGrade 3/4 Nonhematologic Toxicity by Treatment & Age (%)


Adverse Event 428 Pts 428 Pts 78 Pts 82 Pts Asthenia 3 4 6 9 Edema 1 <1 0 <1 Fever 4 3 6 4 Infection 7 10 6 2 Myalgia 2 1 0 <1 Arthralgia 1 1 <1 <1 Stomatitis 1 2 0 <1 Diarrhea 2 1 5 1 Nausea 2 7 3 5 Vomiting 1 6 0 0 Phlebitis <1 <1 <1 0


AC vs. TC Adjuvant TrialLong-term Fatal Toxicities

• 3 additional long-term fatal toxicities all on the AC arm– CHF (45 yrs - AC)

– Myelodysplastic syndrome (63 yrs - AC)

– Myelofibrosis (66 yrs - AC)


AC vs. TC Adjuvant TrialConclusions

• At 7 Years, 4 cycles of TC compared to AC was associated with:– Superior DFS (P = 0.033)

– Superior Overall Survival (P = 0.032)

– Efficacy in HER2+ as well as HER2- disease (limited sample)

• TC was effective in older as well as younger patients

• Numerically, slightly more febrile neutropenia with TC but more anemia with AC in older patients

• Less long-term toxicities (cardiac and bone marrow) with TC


HER2+ Early Breast Cancer

SABCS Abstract 72

Trastuzumab Following Adjuvant Chemotherapy in Node-Positive,

HER2-Positive Breast Cancer Patients4-Year Follow-Up Results of the PACS-04 Trial

M Spielmann, H Roché, JP Machiels, T Delozier, H Bourgeois, D Serin, G Romieu, JL Canon, A Monnier, G Piot,

M Maerevoet, H Orfeuvre, JM Extra, AC Hardy, AL Martin, A Kramar, and J Genève

PACS-04: BackgroundResults of Adjuvant Trastuzumab Trials

Study Nr. of patients Median follow-up risk of relapse

HERA (1,2)3,387 1-yr 46 %

3,401 2-yrs 36 %

NSABP B-31

NCCTG 9891 (3,4)

3,351 2-yrs 52 %

3,968 4-yrs 52 %

BCIRG 006 (5) 3,222 3-yrs 39 %

FinHer (6) 231 3-yrs 58 %

(1) Piccart et al, N Engl J Med, 2005;353:1659-72(2) Smith et al, Lancet, 2007;369:29-36(3) Romond et al, N Engl J Med, 2005;353:1673-84

(4) Perez et al, ASCO, 2007: abstr # 512(5) Slamon et al, SABCS, 2006: abstr # 1(6) Joensuu et al, N Engl J Med, 2006;354:809-20

PACS-04: Aim of the Study

• The PACS-04 trial evaluated the efficacy of a one-year trastuzumab therapy following adjuvant chemotherapy in HER2-overexpressing, node-positive breast cancer patients

Spielmann M, et al. SABCS 2007. Abstract 72.

PACS-04: Treatment Protocol

* RT was delivered within 4 weeks after the last chemotherapy cycle

R1

SURGERY

6 FEC100 q3w RT*

Stratified on: Center N (<4 vs. 4)

RT*6 ED75 q3w

HT

HT

Trastuzumab (T)Loading dose 8 mg/kg

Maintenance 6 mg/kg q3wfor 1 year = 18 injections

Observation

R22nd randomization

performed as soon asHER2 expression

determined

Trastuzumabstarted after

chemotherapy and RT


PACS-04: Major Inclusion CriteriaFirst Randomization

• Histologically proven unilateral breast cancer with complete resection (T1-T2-T3)

• Axillary node-positive

• M0 (bone scan, liver ultrasonography, chest X-ray)

• Age > 18 years and 65 years

• Left ventricular ejection fraction (LVEF) 50% as measured by MUGA scan or echocardiography


• Performed as soon as results of HER2 assessment available

• HER2-positive status defined by following:– HER2 3+ (IHC) i.e. > 10% stained cells

– HER2 2+ and FISH positive (cut-off: 2.2 copies)

• HER2 status reviewed by central reference centers

• The median time between R1 and R2 was 2.6 months

PACS-04: Second Randomization


PACS-04: StatisticsSecond Randomization

• Primary endpoint = 3-year DFS

• Hypothesis: Trastuzumab decreases by 33% the risk of relapse

• Based on an expected 3-year DFS of 70% for the observation arm– = 5% and 1 - = 80%

– Number of events required = 118

– Number of patients required = 540

• Intent-to-treat analysis

• Overall number of patients required at R1 = 3,000


PACS-04: Study Flow Chart• Between February 2001 and August 2004, 3,010 patients from 82 French

and Belgian institutions were randomized

Not treated with T

R1 = 3,010

R2 = 528

Treated = 234

T = 260Obs. = 268

Reasons N = 26Refusal 17

Cardiac toxicity under CT 5

Progression 2

Second cancer 1

Other reason 1


19 (8%) 23 (10%) 16 (7%)

176 (75%)

0

20

40

60

80

100

120

140

160

180

1 to 5 6 to 10 11 to 15 16 to 18Number of injections

PACS-04: Exposition to Trastuzumab

18%

Reason for discontinuation

N 1 to 5 6 to 10 11 to 15 16 to 18

Cardiac events 15 17 9 1

Progression 2 4 4 0


PACS-04: Cardiac Safety

Obs. T

Number of patients 268 260

T discontinued due to cardiac events*, all grade NA 42

Cardiac death 0 0

CHF 1 4

LVEF < 45% without symptoms 6 11

* Stopping rules of trastuzumab in case of cardiac toxicity were as follows:• LVEF <45% or [45%-50%] + relative decrease 15%• LVEF [50%-55%] or [45%-50%] + relative decrease < 15% → cardiologist decision


PACS-04: Efficacy Results

Median follow-up from the initiation of adjuvant chemotherapy = 48 months

PACS-04: Disease-Free Survival (ITT)

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

260 251 221 149 78 10Trastuzumab268 250 225 168 93 21Observation

Number at risk

0 12 24 36 48 60Months

Observation Trastuzumab p=0.41

HR=0.86: 95%CI [0.61-1.22]

Kaplan-Meier survival estimatesKaplan-Meier curves, and log-rank test stratified on N

80.9%

77.9%72.7 %

73.2%

HR = 0.86; 95%CI [0.61-1.22]P = 0.41


PACS-04: Hazard Rates of First EventExploratory Analysis

.002

.004

.006

.008

.01

.012

Haz

ard

rate

0 6 12 18 24 30 36 42 48Months

ObservationTrastuzumab

HR=1.04HR=0.57: 95%CI [0.30-1.09]

Smoothed hazard estimates

HR = 0.5795%CI (0.30-1.09) HR = 1.04

No interaction between time and treatment efficacy (P = 0.22)


PACS-04: Overall Survival (ITT)

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

260 256 244 177 96 11Trastuzumab268 264 255 203 115 26Observation

Number at risk

0 12 24 36 48 60Months

Observation Trastuzumab

HR=1.27: 95%CI [0.68-2.38]

Kaplan-Meier survival estimates

95.7%

96.5%

91.5%93.0%

HR = 1.27; 95%CI [0.68-2.38]


PACS-04: Conclusions

• After 4-years of follow-up and the occurrence of the required number of events, the present study did not detect any significant difference between T and non-T arms

• Trend to have a better efficacy of trastuzumab during the first 18 months of follow-up

• The risk of cardiac toxicity remains low


Summary of Trastuzumab Adjuvant Trials

Study FU, yrs N

HERA1 3,387

2 3,401

NSABP B-31/

NCCTG 9891

2 3,351

4 3,968

BCIRG 006 3 3,222

FinHer 3 231

PACS 04 4 528

HR

0.54

0.64

0.48

0.48

0.61

0.42

0.86

0 1 2In favor of T In favor of Obs.

Endocrine Therapy

SABCS Abstract 41

ATAC: 100 Month Median Follow-Up (FU) Shows Continued Superior Efficacy and No

Excess Fracture Risk for Anastrozole (A) Compared With Tamoxifen (T) After Treatment

Completion

Forbes JF, Cuzick J, Buzdar A, Howell A, Baum M, on behalf of the ATAC Trialists' Group

ATAC: Trial Design

Forbes JF, et al. SABCS 2007. Abstract 41.

ITT: intent-to-treat; HR+: hormone receptor-positive

Tamoxifen 5Y (N = 3116)

ITT population N = 3116

Safety populationN = 3094

HR+ subpopulationN = 2598

ITT population N = 3125

Safety populationN = 3092

HR+ subpopulationN = 2618

Anastrozole 5Y (N = 3125)

Postmenopausal women with invasive

breast cancer (N = 6241)

RandomisedDouble blind

Commenced July 199621 Countries (USA 24%)

ATAC: Background

• Previous reports1 at a median FU of 33 and 68 months showed that anastrozole is more effective, has fewer serious side effects and is better tolerated than tamoxifen during the active treatment period

• It is not known whether efficacy benefits or side effects persist long term after treatment completion

1ATAC Trialists’ Group: Lancet 2002; 359: 1832-33; Lancet 2005; 365: 60-62.


ATAC: UpdateMedian follow-up 100 months

• All treatments completed prior to this analysis

• Total follow-up: 46,292 women years (increment 38%)

• Total events: 1704 (increment 39%)

• Compliance on treatment: A 88%, T 87%

• Blinding maintained post treatment

• Mean age at this analysis: 72 years


ATAC: Time to Recurrence HR+ Patients

26182598

25412516

24532400

23612306

22782196

21592075

19951896

18011711

14921396

608547

At risk:AT

AbsoluteDifference 4.8%

Pat

ient

s (%

)

30

25

20

15

10

5

00 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

12.5% 17.0%

21.8%

Follow-up time (years)

HR+HR0.76

95% CI(0.67, 0.87)

P-value0.0001

9.7%

Tamoxifen (T)Anastrozole (A)

AbsoluteDifference 2.8%


ATAC: Time to RecurrenceSmoothed Hazard Estimates for HR+ Patients

Ann

ual h

azar

d ra

tes

(%)

4.0

3.0

2.0

1.0

0.0

4.0

3.0

2.0

1.0

0.00 1 2 3 4 5 6 7 8 9


HR = 0.77 HR = 0.75



ATAC: Time to RecurrenceCarryover Effect, Post-treatment Period, HR+ Patients

• Recurrence rates continue to be lower with anastrozole after treatment completion

• The absolute difference in recurrence increased from 2.8% after 5-years to 4.8% after 9-years

• Statistically significant larger carryover effect for anastrozole vs. tamoxifen years 5-9: HR = 0.75 (95% CI 0.61-0.94), P = 0.01

• Carryover effect (risk reduction) in years 5-9:

─ Tamoxifen: 33%, (EBCTCG overview1)

─ Anastrozole (est): 50%

1Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005; 365: 1687-1717


ATAC: Time to Distant RecurrenceHR+ Patients

26182598

25512533

24702440

23932363

23202263

22012151

20421982

18541809

15361484

636591

At risk:AT

Pat

ient

s (%

)

30

25

20

15

10

5

00 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0

7.8%

9.1% 13.2%

15.6%


1.3% 2.4%

HR+HR0.84

95% CI(0.72, 0.97)

P-value0.022



ATAC: Contralateral Breast CancerHR+ Patients

AD, absolute difference

Pat

ient

s (%

)

5

4

3

2

1

00 1 2 3 4 5 6 7 8 9

5

4

3

2

1

0

1.0%

1.8%2.5%

4.2%


0.8% 1.7%

26182598

25412516

24532400

23612306

22782196

21592075

19951896

18011711

14931396

608547

At risk:AT


HR+HR0.60

95% CI(0.42, 0.85)

P-value0.004


ATAC: Endpoints HR+ Patients

Disease-free survival

Time to recurrence

Time to distant recurrence

Contralateral breast cancer

Death: all causes

Death after recurrence

Favoursanastrozole (A)

Favourstamoxifen (T)

0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0

Hazard ratio (A / T) and 95% CI

0.76 (0.67-0.87)

0.84 (0.72-0.97)

0.60 (0.42-0.85)

0.97 (0.86-1.11)

0.90 (0.75-1.07)

0.85 (0.76-0.94)

Hazard ratio(95% CI)

0.0001

0.022

0.004

0.7

0.2

0.003

P-value


*A fracture episode comprised one or more fractures on the same day based on adverse events and serious adverse event report. A patient may have had more than one episode.

ATAC: Serious Adverse Events (SAEs)On- and Off-Treatment (safety population)

SAE

On-treatment

Anastrozole

Off-treatment

Tamoxifen Anastrozole Tamoxifen

Treatment-related 153 284 49 57

Endometrial cancer 4 12 1 12

Myocardial infarction 34 33 26 28

Cerebrovascular accident 20 34 22 20

Fracture episodes* 375 234 146 143


ATAC: Fracture Episode Rates Throughout Study

At risk:AT

RR = 1.03P = 0.79

29842976

28592824

27452699

26402572

24962419

23062208

20772000

17131645

702659

Time since randomization (years)

Ann

ual f

ract

ure

epis

ode

rate

s (%

) Anastrozole (A)Tamoxifen (T)

0 1 2 3 4 5 6 7 8 90

2

3

4

1 RR = 1.55P < 0.0001


ATAC: ConclusionsEfficacy

• At 100-month median follow-up, anastrozole is significantly superior to tamoxifen in preventing breast cancer recurrence

• The absolute difference in recurrence rates continues to increase after treatment completion

• First demonstration of significant long-term carryover effect for an AI:− HR+ population: 2.8% at 5-years to 4.8% at 9-years− HR = 0.75 for A vs. T (years 5-9) (P = 0.01)


ATAC: ConclusionsSafety

• After completion of 5-years treatment with anastrozole:− No excess fracture rate

− No new morbidity or mortality concerns


SABCS Abstract 2071

Risk Factors for Joint Symptoms in the ATAC Trial

Sestak I, on Behalf of the ATAC Trialists' Group

Risk Factors for Joint Symptoms: ATAC Trial Trial Design

• Current study examined risk factors for joint symptoms among women randomized in ATAC trial– No joint symptoms at baseline

• Joint symptoms occurring during treatment or within 14-days of stopping therapy– Arthralgia– Arthritis– Arthrosis– Joint disorder

• 2,095 joint symptoms were reported at 5-years– 1,128 (36.5%) anastrozole vs. 957 (30.9%) tamoxifen

Sestak I, et al. SABCS 2007. Abstract 2071.

Risk Factors for Joint Symptoms: ATAC Trial Results

• Joint symptoms were more frequent with anastrozole vs. tamoxifen– 36.5% vs. 30.9% (OR: 1.28, P < 0.001)

• Most joint symptoms were mild to moderate and decreased with increased time on treatment

• Major risk factors for developing joint symptoms were:– Prior HRT (OR: 1.52, P < 0.001)– Anastrozole treatment (OR: 1.31, P < 0.001)– Prior chemotherapy (OR: 1.20, P = 0.01)– Obesity (BMI ≥ 30 (OR: 1.36, P < 0.001)

• There was no clear indication of any interaction between factors

Sestak I, et al. SABCS 2007. Abstract 2071.

Supportive Care

SABCS Abstract 27

The Effect of Zoledronic Acid on Aromatase Inhibitor-Associated Bone Loss in

Postmenopausal Women With Early Breast Cancer Receiving Adjuvant Letrozole: The Z-FAST Study 36-Month Follow-up

Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H, Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group

Aromatase Inhibitor-Associated Bone Loss

• Aromatase inhibitors (AIs) rapidly and profoundly suppress estrogen production,1,2 resulting in– Increased rate of bone turnover2-6

– Accelerated bone loss2-4,6-8

• Bone loss is more rapid than in postmenopausal women

• Fracture rate increases with AI use

1. Lǿnning P, et al. Semin Oncol. 2003;30:23-32; 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127; 3. Eastell R, et al. J Bone Miner Res. 2006;21:1215-1223; 4. Geisler J, et al. Eur J Cancer. 2006;42:2968-2975; 5. Gonnelli S, et al. Bone. 2007;40:205-210; 6. Perez EA, et al. J Clin Oncol. 2006;24:3629-3635; 7. Coleman RE, et al. J Clin Oncol. 2006;24:5s. Abstract 511; 8. Asmar L, et al. Breast Cancer Res Treat; 2006;100:S115. Abstract 2102.

Adjuvant AI Breast Cancer StudiesMedian

follow-up AI Tamoxifen

Study N (mos) % Fx % Fx P-valueATAC1 6,186 68 11.0 7.7 < .0001BIG 1-982 8,028 51 8.6 5.8 < .001IES3 4,724 56 7.0 4.9 .003ARNO4 3,224 28 2.0 1.0 .015

Placebo% Fx

MA.175 5,187 30 5.3 4.6 .25

ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG 1-98, Breast International Group 1-98 Collaborative Group; IES, Intergroup Exemestane Study; ARNO, Arimidex, Nolvadex 95 Study; Fx, fracture; MA.17, National Cancer Institute of Canada Clinical Trials Group.1. Howell A, et al. Lancet. 2005;365:60-62; 2. Coates AS, et al. J Clin Oncol. 2007;25:486-492; 3. Coombes RC, et al. Lancet. 2007;369:559-570; 4. Jakesz R, et al. Lancet. 2005;366:455-462; 5. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.

Z-FAST Study Design

ER, estrogen receptor; PgR, progesterone receptor, IV, intravenously; PMW, postmenopausal women.aPlus daily calcium (1,000–1,200 mg) and vitamin D (400–800 IU)bInitiation of zoledronic acid determined by postbaseline T score < -2.0, any clinical fracture, or any asymptomatic fracture at 36 mo.

0 5-yearsFinal analysis

Zoledronic acid 4 mg IV q 6 mo Zoledronic acid 4 mg IV q 6 mo DELAYEDDELAYEDbb

+ Letrozole (2.5 mg/d)a

Zoledronic acid 4 mg IV q 6 mo Zoledronic acid 4 mg IV q 6 mo UPFRONTUPFRONT+ Letrozole (2.5 mg/d)a

RANDOMIZED

3-years1-year

Eligibility• ER+/PgR+ BCa• PMW with

T score ≥ -2

Stratification• Adjuvant Chemo

(yes or no)• T score (> -1 or

between -1 and -2 )

Brufsky A, et al. SABCS 2007. Abstract 27.

Zoledronic Acid Initiation in Delayed GroupDelayed Group Patients Who Initiated Zoledronic Acid No. of Patients (%)

12-mo visit All patients Per protocola

24-mo visit All patients Per protocola 36-mo visit All patients Per protocola

44 (14.7) 28 (9.3)

54 (18.0) 37 (12.3)

62 (20.7) 45 (15.0)

First Zoledronic Acid Infusion in Delayed Group Time to Initiation, mo

Mean (SD) Median Range

13.5 (10.2)11.5

0.03–37.1

aInitiation of zoledronic acid determined by postbaseline T score < -2.0, any clinical fracture, or any asymptomatic fracture at 36 mo.


Lumbar SpineMonth 12 Month 24 Month 36

Total Hip Month 12 Month 24 Month 36

Perc

enta

ge C

hang

e in

Bon

e M

iner

al

Den

sity

-5

-4

-3

-2

-1

0

1

2

3

4

5UpfrontgroupDelayedgroup

P < .0001 P < .0001

N = 251

N = 256

N = 204

N = 199

N = 206

N = 187

N = 189

N = 189

N = 251

N = 256

N = 188N = 197

Mean (SEM) Percentage Change in Bone Mineral Density

SEM, standard error of the mean. Brufsky A, et al. SABCS 2007. Abstract 27.

Shift in LS T Score in Patients with Normal Baseline T Score (T Score > -1)

0

20

40

60

80

100

T Score > - 1 T Score between - 1 and - 2

Upfront Group (N = 140)

Delayed Group (N = 133)

Pat

ient

s (%

) P = .0024a

aP value corresponds to INTERGROUP comparison at 36 mo.LS, lumbar spine.


Shift in LS T Score in Patients With Low Baseline T Score (T Score Between -1 to -2)

0

20

40

60

80

100

T Score > - 1 T Score between -1 and -2 T Score < - 2

Upfront Group (N=47)

Delayed Group (N=52)

Pat

ient

s (%

) P = .0011a

aP value corresponds to INTERGROUP comparisons at 36 mo.LS, lumbar spine.


Fracture Rates

No. of Patients (%)Type of Fracture Upfront Group

(N = 300)

Delayed Group

(N = 300)Clinical Significant trauma

Minimal or no trauma

Asymptomatic

Other

Radiological spine

11 (3.7)

2 (0.7)

2 (0.7)

1 (0.3)

1 (0.3)

12 (4.0)

3 (1.0)

1 (0.3)

2 (0.7)

1 (0.3)Total 17 (5.7) 19 (6.3)


Disease RecurrenceNo. of Patients (%)

Upfront Group

(N=300)

Delayed Group

(N=300)

P-value

Kaplan-Meier percent (95% CI) 3.5 (1.2, 5.7) 6.9 (3.5, 10.2) 0.1266

Site of recurrence

Bone

Breast

CNS

Liver

Lung

2 (0.7)

2 (0.7)

0 (0.0)

1 (0.3)

3 (1.0)

4 (1.3)

2 (0.7)

2 (0.7)

2 (0.7)

2 (0.7)

Other

Number of patients

1 (0.3)

9 (3.0)

7 (2.3)

16 (5.3)

CI, confidence interval; CNS, central nervous system.


Adverse Events Occurring in > 10% of Patients

Adverse EventNo. of Patients (%)

Upfront Group (N = 300)

Delayed Group (N = 300)

Arthralgia 109 (36.3) 111 (37.0)

Hot flashes 92 (30.7) 99 (33.0)

Fatigue 78 (26.0) 67 (22.3)

Myalgia 49 (16.3) 36 (12.0)

Bone pain 39 (13.0) 20 (6.7)

Nausea 33 (11.0) 27 (9.0)

Extremity pain 32 (10.7) 23 (7.7)

Headache 30 (10.0) 32 (10.7)

Back pain 28 (9.3) 32 (10.7)

Depression 26 (8.7) 35 (11.7)


Additional Adverse Events

• Renal disorders– Grade 1-2 renal failure

• Upfront group, 2 patients• Delayed group, 0 patients

– Both suspected to be related to zoledronic acid• Atrial fibrillation

– Grade 1-2• Upfront group: 3 patients• Delayed group: 0 patients

– Grade 3-4• Upfront group: 4 patients• Delayed group: 4 patients

– None suspected to be related to study drugs• Osteonecrosis of the jaw

− No confirmed cases


Conclusions

• Upfront administration of zoledronic acid (4 mg IV every 6 months) is effective in preventing bone loss in postmenopausal women on AI therapy– Increased lumbar spine and total hip bone mineral density

– Trend towards lower fracture rate

– Bone-specific alkaline phosphatase effectively suppressed

• Trend towards lower disease recurrence with upfront therapy

• Zoledronic acid was safe and well tolerated


SABCS Abstract 47

A Phase 3 Study of the Effect of Denosumab Therapy on Bone Mineral Density in Women

Receiving Aromatase Inhibitors for Non-Metastatic Breast Cancer

Ellis G, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S

Effect of Denosumab Therapy on BMD in Women Receiving AI for Non-Metastatic Breast Cancer

Study Design

Ellis G, et al. SABCS 2007. Abstract 47.

Women with HR+ non-metastatic breast cancer receiving adjuvant AI therapy

• Evidence of bone loss• No osteoporosis (T score < -2.5)

(N = 252)

• Primary endpoint: percent change in lumbar BMD at 12-months• Stratify: duration of AI therapy (≤ 6 vs. > 6 mos.)

Denosumab*60 mg SC every 6 mos. x 4

(N = 127)

Placebo*60 mg SC every 6 mos. x 4

(N = 125)

*All patients were instructed to take calcium and vitamin D daily.


Baseline Characteristics


Denosumab

(N = 127)

Placebo

(N = 125)

Mean age, yrs 59.2% 59.7%

% white 91% 95%

≥ 10 yrs since last menstrual period 50% 50%

AI therapy at randomization

Anastrozole 56% 54%

Letrozole 33% 31%

Exemestane 11% 14%

Previous AI > 6 mos. 63% 63%

Previous chemotherapy 65% 62%

Previous tamoxifen 46% 42%


Results

• There was greater preservation (> 0% change from baseline) of lumbar spine BMD with denosumab vs. placebo

– 97% vs. 36% (P < 0.0001) at 12 months

– 95% vs. 34% (P < 0.0001) at 24 months

• Lumbar spine BMD increased with denosumab vs. placebo– 5.5% (P < 0.0001) at 12 months

– 7.6% (P < 0.0001) at 24 months

• Hip BMD increased with denosumab vs. placebo– 3.7% (P < 0.0001) at 12 months

– 4.7% (P < 0.0001) at 24 months

• Distal 1/3 radius increased with denosumab vs. placebo– 3.8% (P < 0.0001) at 12 months

– 6.1% (P < 0.0001) at 24 monthsEllis G, et al. SABCS 2007. Abstract 47.


Toxicities• Treatment-related AEs were similar between denosumab and placebo

– Any AEs: 91% vs. 90%

– AEs (grade 3,4,5): 23% vs. 23%

• SAEs occurred in 15% of denosumab treated patients vs. 9% of placebo patients– None of the SAEs were considered treatment-related

– No specific type of AE accounted for the slight imbalance

– One death in each arm due to metastatic disease

• Most frequent AEs:– Arthralgia: 24% vs. 25%

– Extremity pain: 15% vs. 12%

– Back pain: 14% vs. 13%

– Fatigue: 13% vs. 14%

– Constipation: 12% vs. 9%

– Cough: 10% vs. 4%

– Insomnia: 9% vs. 12% Ellis G, et al. SABCS 2007. Abstract 47.


Conclusions

• In women with non-metastatic breast cancer who had low bone mass and were receiving adjuvant AI therapy, twice yearly administration of denosumab consistently increased BMD over 24-months at trabecular and cortical bone sites

• Overall AE rates were similar to placebo


Oral Chemotherapy for Early Disease

Neoadjuvant Trials – Capecitabine

• Three ongoing trials evaluating the potential benefit of adding capecitabine into neoadjuvant therapy

– Abstract 79, von Minckwitz: EC→T vs. EC→TX vs. EC→T→X

• More non-hematologic toxicity in capecitabine arms

• Final results pending

– Abstract 5057, Roché: CEX vs. FEC (oral vs. IV 5-FU)

• Improved pCR with CEX without compromising toxicity


– Abstract 5059, Tripathy: XT ± H with p53 mutation analysis

• Active and well tolerated non-anthracycline option


Treatment of Early Breast Cancer

Closing Comments

Maura N. Dickler, MD

a report from sabcs up-to-date review of the treatment of early breast cancer

Documents

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