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A Report from SABCS Up-to-Date Review of the Treatment of Early Breast Cancer. Maura N. Dickler, MD Assistant Attending Physician Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY. Up-to-Date Review of the Treatment of Early Breast Cancer Overview.

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A Report from SABCSUp-to-Date Review of the Treatment of Early Breast Cancer

Maura N. Dickler, MD

Assistant Attending Physician

Breast Cancer Medicine Service

Memorial Sloan-Kettering Cancer Center

New York, NY


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

  • 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.


RANDOMIZE

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

(N = 1477)

Tamoxifen x 5 yrs

CAF x 6, then

tamoxifen

CAF x 6, with concurrent tam

(N = 361)

(N = 550)

(N = 566)

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

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


SWOG 8814/TBCI 0100 Correlative Science Study

  • 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

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


SWOG 8814/TBCI 0100 Correlative Science StudyMethods - 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.


SWOG 8814/TBCI 0100 Correlative Science StudyMethods - 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

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


SWOG 8814/TBCI 0100 Correlative Science StudySample Size for Analysis

Patients with samples - 666

(45% of parent trial)

RT-PCR obtained - 601 (90%)

Tamoxifen alone 148

CAFT (concurrent) 234

CAF-T (sequential) 219

Final sample for primary analysis

148 + 219 = 367 (40% of parent trial)

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


Disease-Free Survival

1.00

0.75

Disease-free Survival

0.50

Stratified log-rank P-value = 0.054 at 10 years

(adjusted for nodal status)

0.25

Tamoxifen (N=148, 63 events)

CAF-T (N=219, 74 events)

0.00

0

2

4

6

8

10

Years Since Registration

SWOG 8814/TBCI 0100 Correlative Science Study

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

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


SWOG 8814/TBCI 0100 Correlative Science StudyComparative Distribution of RS

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


SWOG 8814/TBCI 0100 Correlative Science Study

Results: Prognosis


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

Overall Survival by Risk Group

(tamoxifen alone)

Disease-Free Survival by Risk Group

1.00

(tamoxifen alone)

1.00

0.75

0.75

Overall Survival

0.50

Disease-free survival

Stratified log-rank p = 0.003 at 10 years

0.50

0.25

Stratified log-rank p = 0.017 at 10 years

Low RS <18 (N=55)

0.25

Intermediate RS 18-30 (N=46)

Low RS <18 (N=55)

High RS ≥31 (N=47)

0.00

Intermediate RS 18-30 (N=46)

High RS ≥31 (N=47)

0

2

4

6

8

10

0.00

Years since registration

0

2

4

6

8

10

Years since registration

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

  • High RS = 43%

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

  • High RS = 51%

SWOG 8814/TBCI 0100 Correlative Science Study

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


SWOG 8814/TBCI 0100 Correlative Science Study

Results: Prediction


Disease-Free Survival by Treatment

  • No benefit to CAF over time if low RS

  • Strong benefit to CAF if high RS

1.00

Low risk (RS < 18)

0.75

0.50

Disease-free survival

Stratified log-rank p = 0.97 at 10 years

0.25

Tamoxifen (N=55, 15 events)

CAF-T (N=91, 26 events)

0.00

0

2

4

6

8

10

Years since registration

Disease-Free Survival by Treatment

Disease-Free Survival by Treatment

1.00

1.00

Intermediate risk (RS 18-30)

High risk (RS ≥ 31)

0.75

0.75

Disease-free survival

Disease-free survival

0.50

0.50

Stratified log-rank p = 0.48 at 10 years

Stratified log-rank p = 0.033 at 10 years

0.25

0.25

Tamoxifen (N=46, 22 events)

Tamoxifen (N=47, 26 events)

CAF-T (N=57, 20 events)

CAF-T (N=71, 28 events)

0.00

0.00

0

2

4

6

8

10

0

2

4

6

8

10

Years since registration

Years since registration


SWOG 8814/TBCI 0100 Correlative Science StudyTen-Year DFS Point Estimates (95% CI)

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

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


DFS hazard ratios adjusted for nodal status

Overall trial

Entire RS sample

Low RS

Trial Subset

Intermediate RS

High RS

Chemotherapy benefit

No chemotherapy benefit

0

.5

1

1.5

2

Hazard Ratio

SWOG 8814/TBCI 0100 Correlative Science Study Comparison of CAF-T to Tamoxifen Alone

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


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

Comparison of CAF-T to Tamoxifen Alone

(DFS adjusted for nodal status)

Low RS

Intermediate RS

First 5 years

Greater than 5 years

High RS

Chemotherapy benefit

No chemotherapy benefit

0

1

2

3

4

Hazard ratio

SWOG 8814/TBCI 0100 Correlative Science Study

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


Overall Survival by Treatment

1.00

High risk (RS ≥31)

0.75

Overall survival

0.50

Stratified log-rank test p = 0.027 at 10 years

0.25

Tamoxifen (N=47, 22 deaths)

CAF-T (N=71, 20 deaths)

0.00

0

2

4

6

8

10

Years since registration

SWOG 8814/TBCI 0100 Correlative Science StudyThe 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%)

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


SWOG 8814/TBCI 0100 Correlative Science StudyConclusions 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.

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


SWOG 8814/TBCI 0100 Correlative Science StudyOther 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

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


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


Doxorubicin 60 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Every 21 days X 4 Cycles

RANDOMI

ZE

AC

Docetaxel 75 mg/m2 IV Day 1

Cyclophosphamide600 mg/m2 IV Day 1

Every 21 days X 4 Cycles

TC

AC vs. TC Adjuvant TrialTrial Design

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


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

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


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

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


AC vs. TC Adjuvant TrialDemographics by Treatment and Age

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


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

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


AC vs. TC Adjuvant TrialDFS by Treatment and Age Group

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


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

*FISH+ = Gene copy ratio of 2.0 or greater

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


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

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


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

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


Overall HR for DFS = 0.74

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

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


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

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


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

Insert graphics here

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


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

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


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

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


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)

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


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

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


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,

MMaerevoet, H Orfeuvre,JM Extra, AC Hardy, AL Martin,

A Kramar, and J Genève


  • Perez et al, ASCO, 2007: abstr # 512

  • Slamon et al, SABCS, 2006: abstr # 1

  • Joensuu et al, N Engl J Med, 2006;354:809-20

  • Piccart et al, N Engl J Med, 2005;353:1659-72

  • Smith et al, Lancet, 2007;369:29-36

  • Romond et al, N Engl J Med, 2005;353:1673-84

PACS-04: BackgroundResults of Adjuvant Trastuzumab Trials


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.


Stratified on:

Center

N (<4 vs.  4)

Trastuzumab (T)

Loading dose 8 mg/kg

Maintenance 6 mg/kg q3w

for 1 year = 18 injections

S

U

R

G

E

R

Y

RT*

HT

6 FEC100 q3w

2nd randomization

performed as soon as

HER2 expression

determined

Trastuzumab

started after

chemotherapy and RT

R1

R2

Observation

6 ED75 q3w

RT*

HT

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

PACS-04: Treatment Protocol

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


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

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


PACS-04: Second Randomization

  • 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

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


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

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


R1 = 3,010

R2 = 528

Obs. = 268

T = 260

Not treated with T

Treated = 234

PACS-04:Study Flow Chart

  • Between February 2001 and August 2004, 3,010 patientsfrom 82 French and Belgian institutions were randomized

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


PACS-04: Exposition to Trastuzumab

18%

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


PACS-04:Cardiac Safety

  • * 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

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


PACS-04:Efficacy Results

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


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

80.9%

72.7 %

77.9%

73.2%

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

P = 0.41

PACS-04:Disease-Free Survival (ITT)

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


HR = 0.57

95%CI (0.30-1.09)

HR = 1.04

No interaction between time

and treatment efficacy (P = 0.22)

PACS-04:Hazard Rates of First EventExploratory Analysis

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


96.5%

93.0%

95.7%

91.5%

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

PACS-04:Overall Survival (ITT)

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


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

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


0

2

1

In favor of T

In favor of Obs.

Summary of Trastuzumab Adjuvant Trials


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

ITT population

N = 3125

Safety population

N = 3092

HR+ subpopulationN = 2618

Anastrozole 5Y

(N = 3125)

Postmenopausal women with invasive breast cancer

(N = 6241)

Randomised

Double blind

ITT population

N = 3116

Safety population

N = 3094

HR+ subpopulationN = 2598

Tamoxifen 5Y (N = 3116)

Commenced July 1996

21 Countries (USA 24%)

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

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


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.

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


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

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


ATAC: Time to Recurrence HR+ Patients

HR

0.76

95% CI

(0.67, 0.87)

P-value

0.0001

30

30

HR+

25

25

21.8%

20

20

Tamoxifen (T)

Anastrozole (A)

Patients (%)

15

15

12.5%

17.0%

10

10

9.7%

5

5

Absolute

Difference 2.8%

Absolute

Difference 4.8%

0

0

1

2

3

4

5

6

7

8

9

Follow-up time (years)

At risk:AT

26182598

25412516

24532400

23612306

22782196

21592075

19951896

18011711

14921396

608547

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


4.0

4.0

HR = 0.75

HR = 0.77

3.0

3.0

Annual hazard rates (%)

2.0

2.0

Tamoxifen (T)

Anastrozole (A)

1.0

1.0

0.0

0.0

0

1

2

3

4

5

6

7

8

9

Follow-up time (years)

ATAC: Time to RecurrenceSmoothed Hazard Estimates for HR+ Patients

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


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

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


30

30

HR

0.84

95% CI

(0.72, 0.97)

P-value

0.022

25

25

HR+

20

20

Tamoxifen (T)

Anastrozole (A)

15.6%

15

15

Patients (%)

9.1%

13.2%

10

10

5

7.8%

5

1.3%

2.4%

0

0

0

1

2

3

4

5

6

7

8

9

Follow-up time (years)

At risk:AT

26182598

25512533

24702440

2393

2363

23202263

22012151

20421982

18541809

15361484

636591

ATAC: Time to Distant RecurrenceHR+ Patients

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


5

5

HR

0.60

95% CI

(0.42, 0.85)

P-value

0.004

4.2%

HR+

4

4

3

3

Tamoxifen (T)

Anastrozole (A)

2.5%

Patients (%)

1.8%

2

2

1.0%

1

1

0.8%

1.7%

0

0

0

1

2

3

4

5

6

7

8

9

Follow-up time (years)

At risk:AT

26182598

25412516

24532400

2361

2306

22782196

21592075

19951896

18011711

14931396

608547

ATAC: Contralateral Breast CancerHR+ Patients

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

AD, absolute difference


Favoursanastrozole (A)

Favourstamoxifen (T)

Hazard ratio(95% CI)

P-value

0.85 (0.76-0.94)

0.003

Disease-free survival

Time to recurrence

0.76 (0.67-0.87)

0.0001

Contralateral breast cancer

0.60 (0.42-0.85)

0.004

Time to distant recurrence

0.84 (0.72-0.97)

0.022

Death after recurrence

0.90 (0.75-1.07)

0.2

Death: all causes

0.97 (0.86-1.11)

0.7

0.2

0.4

0.6

0.8

1.0

1.2

1.5

2.0

Hazard ratio (A / T) and 95% CI

ATAC: Endpoints HR+ Patients

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


On-treatment

Off-treatment

SAE

Anastrozole

Tamoxifen

Anastrozole

Tamoxifen

Treatment-related

153

284

49

57

4

Endometrial cancer

12

1

12

Myocardial infarction

33

26

28

34

Cerebrovascular accident

34

22

20

20

375

Fracture episodes*

234

146

143

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

*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.

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


4

Anastrozole (A)Tamoxifen (T)

3

2

Annual fracture episode rates (%)

1

RR = 1.55

P < 0.0001

RR = 1.03

P = 0.79

0

0

1

2

3

4

5

6

7

8

9

Time since randomization (years)

At risk:

AT

2984

2976

2859

2824

2745

2699

2640

2572

2496

2419

2306

2208

2077

2000

1713

1645

702

659

ATAC: Fracture Episode Rates Throughout Study

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


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)

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


ATAC: ConclusionsSafety

  • After completion of 5-years treatment with anastrozole:

    • No excess fracture rate

    • No new morbidity or mortality concerns

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


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 TrialTrial 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 TrialResults

  • 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 Studies

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.


R

A

N

DO

M

I

Z

E

D

  • Eligibility

  • ER+/PgR+ BCa

  • PMW withT score ≥ -2

  • Stratification

  • Adjuvant Chemo(yes or no)

  • T score (> -1 or between -1 and -2 )

Zoledronic acid 4 mg IV q 6 mo UPFRONT

+ Letrozole (2.5 mg/d)a

Zoledronic acid 4 mg IV q 6 mo DELAYEDb

+ Letrozole (2.5 mg/d)a

5-yearsFinal analysis

1-year

3-years

0

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.

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


Zoledronic Acid Initiation in Delayed Group

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

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


N = 189

N = 204

N = 251

N = 189

N = 206

N = 251

Percentage Change in Bone Mineral Density

N = 256

N = 256

N = 199

N = 188

N = 197

N = 187

P < .0001

P < .0001

Month 12

Month 12

Month 24

Month 24

Month 36

Month 36

Lumbar Spine

Total Hip

Mean (SEM) Percentage Change in Bone Mineral Density

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

SEM, standard error of the mean.


P = .0024a

Patients (%)

Upfront Group (N = 140)

Delayed Group (N = 133)

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

aP value corresponds to INTERGROUP comparison at 36 mo.

LS, lumbar spine.

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


P = .0011a

Patients (%)

Upfront Group (N=47)

Delayed Group (N=52)

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

aP value corresponds to INTERGROUP comparisons at 36 mo.

LS, lumbar spine.

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


Fracture Rates

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


Disease Recurrence

CI, confidence interval; CNS, central nervous system.

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


Adverse Events Occurring in > 10% of Patients

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


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

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


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

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


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


Denosumab*

60 mg SC every 6 mos. x 4

(N = 127)

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

    • Evidence of bone loss

    • No osteoporosis (T score < -2.5)

  • (N = 252)

Placebo*

60 mg SC every 6 mos. x 4

(N = 125)

  • Primary endpoint: percent change in lumbar BMD at 12-months

  • Stratify: duration of AI therapy (≤ 6 vs. > 6 mos.)

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

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

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


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

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


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

  • 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 months

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


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

  • 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.


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

  • 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

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


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

      • Final results pending

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

      • Active and well tolerated non-anthracycline option

      • Final results pending


Treatment of Early Breast CancerClosing Comments

Maura N. Dickler, MD


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