Advances in Breast Cancer Detection and Management

Rowan T Chlebowski MD, PhD

Professor of Medicine

David Geffen School of Medicine at UCLA

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

January 7, 2009

DISCLOSURE

• Dr. Chlebowski receives research support from Amgen and is a consultant for Amgen, Astrazeneca, Novartis, Eli Lily and Wyeth.

LEARNING OBJECTIVES

• To become familiar with the Women’s Health Initiative results and impact on breast cancer incidents

• To become familiar with current issues regarding breast cancer detection

• To become familiar with recent results from the San Antonio Breast Cancer Symposium

WHI Hormone Program Design

Prior Hysterectomy

CEE (Conjugated equine estrogens) 0.625 mg/d

CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d

N= 16,608

N= 10,739YES

NO

Placebo

Placebo

* Initially: CEE only (N=331), CEE+MPA, or Placebo

WHI Writing JAMA 2002; 288: 321 Chlebowski JAMA 2003; 289: 3253

Available online @ http://jama.ama-assn.org/

Trial Time(yrs)

HR

(tim

e)

0.1

25

0.2

50.5

12

4

HR=1.62(1.10,2.39)

0 1 2 3 4 5

Post Intervention Time (yrs)

HR=1.26(0.73,2.20)

0 1 2 2.5

P-trend-diff = 0.005

Linear time varying Hazard Ratio during Clinical TrialLinear time varying Hazard Ratio during Post-InterventionHR(95%CI) based on events accumulated in 6 month window

Trial Time(yrs)

HR

(tim

e)

0.1

25

0.2

50.5

12

4

HR=1.62(1.10,2.39)

0 1 2 3 4 5

Post Intervention Time (yrs)

HR=1.26(0.73,2.20)

0 1 2 2.5

P-trend-diff = 0.005

Linear time varying Hazard Ratio during Clinical TrialLinear time varying Hazard Ratio during Post-InterventionHR(95%CI) based on events accumulated in 6 month window

Clinical Trial: Sensitivity Analysis CEE+MPA vs. Placebo Breast Cancer Risk During Intervention and Postintervention

HR=1.62 (1.10, 2.39) HR=1.26 (0.73, 2.20)

P Trend-Diff 0.005

Linear time varying Hazard Ratio during Clinical Trial Linear time varying Hazard Ratio during Postintervention HR (95% CI) based on events accumulated in each 6 month window

WHI Clinical Trial Ppts With Mammograms by Year and Randomization Group

83 82 83 83 80 80 78 78

0

50

100

2 YrsBefore

1 YrBefore

1 YrAfter

2 YrsBefore

CEE+ MPA

Placebo

Intervention End

Pp

t w

ith

Mam

mo

gra

ms

(%)

Chlebowski RT, Kuller L, Prentice R, et al. SABCS 2008, Abstract 64

ConclusionsThe increased breast cancer risk associated with combined estrogen plus progestin use declines markedly after therapy discontinuation and is unrelated to mammography utilization change

These findings support the hypothesis that the recent reduction in breast cancer incidence seen in the United States in certain age groups is predominantly related to a decrease in combined estrogen plus progestin use

Breast Cancer Screening

Early detection of breast cancer is accomplished through screening

Screening is undertaken to evaluate an asymptomatic population in order to detect unsuspected disease at a time when cure is still possible

Breast cancer screening involves: mammography, ultrasound, MRI

Digital Mammography or Standard Testing

• Women under 50 years of age• Women who were premenopausal or

perimenopausal• Women classified as having heterogeneously

dense or extremely dense breast tissue

Digital mammography performed significantly better in the detection of breast cancer

Breast MRI: Screening

• 45 cancers

– 22 seen on MRI only

– 10 seen on MRI and mammography

– 8 seen only on mammography

– 4 interval cancers

– 1 cancer detected on CBE only

Kriege et al NEJM July 2004

Breast MRI: Screening

Saslow et al CA Cancer J Clin 2007;57:75-89

San Antonio Breast Cancer Symposium Update

RANDOMIZE

+ Tamoxifen 20 mg/d

+ Anastrozole 1 mg/d

+ Anastrozole 1 mg/d + Zoledronic acid 4 mg q6m

Goserelin3.6 mg q28d

ABCSG-12:1801 patients, stage I/II< 10 nodes, ER and/or PgR+

No adjuvant chemo

Bone substudy (N = 404)

Trial ABCSG-12: Endocrine Therapy With orWithout Zoledronic Acid

+ Tamoxifen 20 mg/d + Zoledronic acid 4 mg q6m

Surgery + RT

N = 103

N = 100

N = 96

N = 1051533 centrally reviewedBMD measurements, bothtrochanter and spine

Gnant M, et al. SABCS 2007 (Abstract 26)

Gnant et al. ASCO 2008; abstract LBA4.

ABCSG-12 Trial of Endocrine TherapyWith or Without Zoledronic Acid:

First Efficacy Results

ABCSG-12 Trial of Endocrine TherapyWith or Without Zoledronic Acid:

First Efficacy ResultsTamoxifen

(n = 900)

Anastrozole

(n = 903)HR

P Value

Disease-Free Survival 65 events 72 events 1.096 .593

Recurrence-Free Survival

64 events 72 events 1.116 .529

Overall Survival 15 events 27 events 1.791 .065

ZA

(n = 899)

No ZA

(n = 904)HR

P Value

Disease-Free Survival 54 events 83 events 0.643 .011

Recurrence-Free Survival

54 events 82 events 0.653 .014

Overall Survival 16 events 26 events 0.595 .101

FIRST (Fulvestrant fIRst-line Study Comparing Endocrine Treatments)

Phase II, randomized, open-labeled, multi-center

Advanced breast cancer ER positive First line

Fulvestrant HD (500 mg/mos plus 500 mg D14)

Anastrozole 1 mg/d

Ellis et al SABCS 2008, Abst 6126

Kaplain Meier Plot for Time to Progression (TTP)

d

Integrated meta-analysis on

6634 patients with early breast cancer

receiving neoadjuvant

anthracycline-taxane +/- trastuzumab

containing chemotherapy

von Minckwitz G, Kaufmann M, Kümmel S, Fasching P, Eiermann W,

Blohmer JU, Costa SD, Loibl S, Mehta K, Untch M

for the

andA G A G OO

17.1%

27.7%

5.6%

13.4%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

without Trastuzumab with Trastuzumab

pCR

Treatment Group EffectsUse of Trastuzumab

in Patients with HER2-Positive Tumors

N=736 N=671

* excluding patients with HER2 negative or HER2 unknown tumors

P<0.001ypTis No

ypT0 No

Average number DM1 molecules/monoclonal antibody=3.5

DM1 is conjugated to trastuzumab via a non-reducible thioether bond to a linker molecule (MCC).1

1. Beeram M., et al. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 1028).

A Phase II Study of Trastuzumab-DM1 (T-DM1), a HER2 Antibody-Drug Conjugate, in Patients with

HER2-Positive Metastatic Breast Cancer (MBC): Interim Results

Prior Therapy N=112

Median number of chemotherapy agents for metastatic disease (range)

3 (1–12)

Prior anthracycline, n (%) 76 (67.9)

Median duration of prior trastuzumab therapy, weeks (range)

76.6 (3–660)

Patients on prior lapatinib therapy, n (%) Median duration of lapatinib therapy, weeks (range)

62 (55.4)

26.3 (3–106)

Prior Chemotherapy and Anti-HER2 Therapy

Analysis of Efficacy: Antitumor Activity

Tumor Response as Assessed by Investigators N

Overall ORR†

n (%)

(95% CI)

Confirmed‡ ORR†

n (%)

(95% CI)

All efficacy evaluable patients* 10742 (39.3)

(30.0, 49.0)

29 (27.1)

(19.4, 36.1)

Subset of patients with ≥6 months follow-up or have discontinued study treatment

7633 (43.4)

(32.6, 54.9)

29 (38.2)

(27.3, 50.0)

Median follow-up, 4.4 mo (19 weeks)

* Because of limited follow-up, 19 patients have only had 1 post-baseline tumor assessment† PR+CR‡ Confirmed Objective response: Complete or partial response determined on two consecutive occasions 4 weeks apart

ORR=Objective response rate