Hormonally Sensitive Early-Stage Breast Cancer Current Considerations and New Directions Terry...
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Hormonally Sensitive Early-Stage Hormonally Sensitive Early-Stage Breast Cancer Breast Cancer Current Considerations and New Current Considerations and New Directions Directions Terry Mamounas, MD, MPH Terry Mamounas, MD, MPH Professor of Surgery Professor of Surgery Northeastern Ohio Universities College of Medicine Northeastern Ohio Universities College of Medicine Medical Director Medical Director Aultman Cancer Center Aultman Cancer Center Canton, OH Canton, OH Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer
Hormonally Sensitive Early-Stage Breast Cancer Current Considerations and New Directions Terry Mamounas, MD, MPH Professor of Surgery Northeastern Ohio
Hormonally Sensitive Early-Stage Breast Cancer Current
Considerations and New Directions Terry Mamounas, MD, MPH Professor
of Surgery Northeastern Ohio Universities College of Medicine
Medical Director Aultman Cancer Center Canton, OH Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Slide 2
Breast Cancer Mortality in US and UK WHO Mortality and UN
Population Estimates
Slide 3
Factors Associated with Reduction In Breast Cancer Mortality
Early Detection Mammography Adjuvant Systemic Therapy Hormonal
Therapy and Chemotherapy Treatment of Advanced Disease Hormonal
Therapy, Chemotherapy, Trastuzumab LR Therapy Surgery XRT
Slide 4
Overview Analysis: Benefit from Tamoxifen 2005 Overview
Analysis
Slide 5
Current Considerations and New Directions with Endocrine
Therapy Recurrence patterns of ER-positive BCRecurrence patterns of
ER-positive BC Optimal tamoxifen durationOptimal tamoxifen duration
Aromatase InhibitorsAromatase Inhibitors Overview of efficacy data
Remaining questions Combinations of AIs with other promising
agents:Combinations of AIs with other promising agents: EGFR
Inhibitors mTOR Inhibitors Bisphosphonates
Slide 6
Saphner et al. J Clin Oncol. 1996;14:2738. Long-Term Risk of
Breast Cancer Recurrence Remains High in ER+ Patients A substantial
proportion of breast cancer recurrences occur >5 years
postsurgeryA substantial proportion of breast cancer recurrences
occur >5 years postsurgery The annual risk of late recurrence is
higher in ER+ tumorsThe annual risk of late recurrence is higher in
ER+ tumors 0 0.1 0.2 0.3 0123456789101112 Recurrence hazard rate
Years ER (n=1,305) ER+ (n=2,257)
Slide 7
Recurrences Breast Cancer Deaths More Than Half of Breast
Cancer Recurrences and Deaths Occur Post-Tamoxifen Adapted with
permission. Early Breast Cancer Trialists Collaborative Group
Meeting, 2000. Years 85.2 76.1 68.2 73.7 62.7 54.9 68% 55% 0 20 40
60 80 100 051015 TamoxifenControl 15%17% 0 20 40 60 80 100 051015
73% 64% 80.9 73.0 87.8 73.2 64.0 Years TamoxifenControl 9%18% 91.4
% of patients
Slide 8
NSABP B-14 Tamoxifen Duration Years TRT N Events PLAC 569 106
TAM 583 137 p=0.03 Disease-Free Survival 40 60 80 100 01234567
Fisher et al: JNCI, 2001 TAM X 5 yrs TAM X 5 yrs Placebo X 5 yrs
Randomization Node-Negative ER-Positive Registration TAM X 5 yrs
Placebo X 5 yrs
Slide 9
Adjuvant Tamoxifen Longer Against Shorter (ATLAS) RANDOMIZE
Tamoxifen 20 mg PO qd 5 years Postmenopausal women with invasive
tumors Tamoxifen 20 mg PO qd 10 years Peto R, et al. 30th Annual
San Antonio Breast Cancer Symposium. December 13-16, 2007; San
Antonio, TX. Abstract 48. Preliminary Data N = 11,500 Woman Years
Number of Recurrences Annual Rate of Recurrence Years 5 -
942,00013533% Years 10 - 1480002113% Recurrence Annual Event Rate
3.4% 5-yr tamoxifen 2.9% 10-yr tamoxifen Rate Ratio 0.866 SE
(0.048) Breast Cancer Mortality Annual Event Rate 1.5% 5-yr
tamoxifen 1.4% 10-yr tamoxifen Rate Ratio 0.895 SE (0.070)
Slide 10
ATLAS Preliminary Results Partial data suggest About 12% risk
reduction in breast cancer recurrence years 5 - 9 from diagnosis
with continued tamoxifen Limitations Incomplete biomarker testing
59% confirmed ER(+) Adherence ~ 80% Incomplete toxicity profile
Peto R, et al. 30th Annual San Antonio Breast Cancer Symposium.
December 13-16, 2007; San Antonio, TX. Abstract 48.
Slide 11
Adjuvant Tamoxifen To Offer More (aTTom) RANDOMIZE Discontinue
Tamoxifen 20 mg PO qd Postmenopausal women with invasive tumors who
received 2 years of tamoxifen N = 6934 Tamoxifen 20 mg PO qd 5
additional years Gray R, et al. J Clin Oncol. 2008;26(15S):
Abstract 513. Preliminary Data N = 6952 Discontinued Tamoxifen
Continued Tamoxifen Relative RiskP Value Disease
Recurrence4474450.95NS Median Follow-up 4.2 Years of 15-Year
Analysis
Preliminary aTTom Results Limitations Confirmed ER(+) = 40%
Various durations of tamoxifen use Adherence ~ 80% Incomplete
toxicity profile Statistically, only 68% of the true effect of
10-year tamoxifen will be observed Gray R, et al. J Clin Oncol.
2008;26(15S): Abstract 513.
Slide 14
Adjuvant Aromatase Inhibitors Replacing 5 Years of Tamoxifen as
the Gold Standard AIs as Initial Therapy AIs After 2-3 Yrs of TAM
AIs After 5 Years of TAM TAM X 5 Yrs AI X 5 Yrs TAM X 2-3AI X 2-3
TAM X 5 Yrs PLAC X 5 Yrs AI X 5 Yrs Three Strategies
Slide 15
Relative Reductions in DFS Event in 8 Reported AI Adjuvant
Trials Percent IES 55 m ITA 52 m MA.17 30 m Up-Front After 2-3 yrs
of TAM After 5 yrs of TAM ATAC 68 m 13% 58% 42% 24% 0 10 20 30 40
50 60 70 19% BIG 26 m 40% ABCSG/ARNO 28 m Coombs et al. ASCO 2006
Boccardo et al. ASCO 2005 Jakesz et al. Lancet 2005.
AnastrozoleLetrozoleExemestane ABCSG-6 60 m 36% Howell A, et al:
SABCS 2004 Thurlimann et al. N Engl J Med 2005. Goss et al. JNCI
2005 Jakesz et al. ASCO 2005 Mamounas et al. SABCS 2006 32% B-33 30
m
Slide 16
75% Reductions in Contralateral BC in 7 Reported AI Adjuvant
Trials Percent IES 37 m ITA 36 m MA.17 30 m Up-front After 2-3 y of
TAM After 5 y of TAM ATAC 68 m 42% 50% (ns) 46% 50% 0 10 20 30 40
50 60 70 25% ABCSG/ARNO 28 m Jakesz et al. SABCS 2004. Goss et al.
JNCI 2005. Mamounas et al. SABCS 2006 Howell et al. SABCS 2004.
Coombs et al. SABCS. 2004. Boccardo et al. JCO 2004
AnastrozoleLetrozoleExemestane 42% (ns) Thurlimann et al. ASCO
2005. BIG 1-98 26 m B-33 30 m
Slide 17
Aromatase Inhibitors Remaining Questions Are there significant
differences in efficacy and toxicity between different AIs?Are
there significant differences in efficacy and toxicity between
different AIs? What is the proper time to initiate AIs?What is the
proper time to initiate AIs? What is the optimal duration of
AIs?What is the optimal duration of AIs? What is the role of AIs in
premenopausal women who undergo ovarian function suppression?What
is the role of AIs in premenopausal women who undergo ovarian
function suppression? What is the role of AIs in patients with
DCISWhat is the role of AIs in patients with DCIS
Slide 18
NCIC MA.27 Trial: Anastrozole vs. Exemestane Anastrozole 5
years Celecoxib 3 years Celecoxib 3 years Exemestane 5 years
Placebo 3 years Placebo 3 years Postmenopausal ER+ and/or PgR+
Chemo or not Activated: 6/03 Accrual: 6,830
Slide 19
NCIC MA.27 Trial: Anastrozole vs. Exemestane Anastrozole 5
years Celecoxib 3 years Celecoxib 3 years Exemestane 5 years
Placebo 3 years Placebo 3 years Postmenopausal ER+ and/or PgR+
Chemo or not Activated: 6/03 Accrual: 6,830
Slide 20
Primary end point:Disease-free survival Secondary end points:
Safety, overall survival, time to distant mets, time to CBC, BC-
specific survival Early Breast Cancer Postmenopausal ER+ and/or
PgR+ Node-positive Anastrozole 1 mg/d RANDOM
RRAANNDDOOMMIZEIZERRAANNDDOOMMIZEIZE Letrozole 2.5 mg/d N=4,000 De
Boer et al. J Clin Oncol. 2006;24(18S):582s. Abstract 10672.
Head-to-Head Adjuvant Phase IIIb Trial: Femara vs Anastrozole
Clinical Evaluation (FACE)
Sequential Treatment Comparisons Median Follow-up 71 months Tam
Let vs. LetLet Tam vs. Let Mouridsen HT, et al: SABCS 2008, Abstr.
13
Slide 23
Breast Cancer Events Tam Let vs. Let OverallBy Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Slide 24
Breast Cancer Events Let Tam vs. Let OverallBy Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Slide 25
TEAM Exemestane vs. Tamoxifen TEAM Trial Amendment: TEAM
Exemestane 5 y Tamoxifen 5 y Completed accrual: 5,700 pts (1,600
pts from US) EXE 5 y TAM 2-3 yEXE 2-3 y TEAM
Slide 26
MA.17: Disease-Free Survival Hazard Ratios of Letrozole to
Placebo Hazard ratio Months after randomization Upper 95% CL Lower
95% CL Ratio estimate P
Gefitinib in Breast Cancer Previous clinical trials in breast
cancer studies showed mainly negative results 1-3 Osborne et al 4
recently reported the first randomized, placebo controlled phase II
study of tamoxifen and gefitinib: A modest improved PFS in patients
with hormonal-nave disease or who had completed adjuvant tamoxifen
>1 year (10.9 vs. 8.8 months, P=0.31) 1 Albain KS, et al SABC
2002 2 Dennison SK, et al Breast Cancer Res Treat 2007 3 Smith IE,
et al J Clin Oncol,2007 4 Osborne CK, SABC 2007
Slide 34
Anastrozole +/- Gefitinib Randomized Phase II Trial
Cristofanilli et al, ASCO 2008, Abstract 1012 Gefitinib 250 mg /
day + Anastrozole 1 mg / day Placebo + Anastrozole 1 mg / day 1:1
randomization Patients Postmenopausal women Age 18 years Newly
diagnosed ER and / or PgR positive metastatic breast cancer No
prior hormonal therapy, or development of metastatic disease during
/ after adjuvant tamoxifen Measurable or non- measurable disease
(via RECIST) Primary Progression-free survival Secondary Objective
response rate Clinical benefit rate Overall survival Safety and
tolerability Response variables Trial closed early due to poor
accrual 94 patients randomized
Neoadjuvant Letrozole +/- RAD001 (Everolimus) Study designStudy
design Phase II, randomized double-blind placebo-controlled trial
Postmenopausal women with >T2 tumors Tumor samples (surgery)
RANDOMIZERANDOMIZE Letrozole 2.5 mg/d Everolimus 10 mg/d Letrozole
2.5 mg/d Placebo n = 138 16 weeks Surgery Tumor biopsies
(pretreatment) Tumor biopsies (day 15) SCREENSCREEN n = 132 Baselga
et al, ASCO 2008, Abstract 530
Slide 38
Higher response with combinationHigher response with
combination PE: 68.1% vs. 59.1%, P = 0.062 US: 58% vs 47%, P =
0.035 Greater decrease in Ki67Greater decrease in Ki67 Increased
toxicityIncreased toxicity Hyperglycemia, stomatitis, infections,
interstitial lung disease Neoadjuvant Letrozole +/- RAD001
(Everolimus)
Slide 39
ABCSG-12 Trial Design Accrual 1999-2006Accrual 1999-2006 1,803
premenopausal breast cancer patients1,803 premenopausal breast
cancer patients Endocrine-responsive (ER and/or PR
positive)Endocrine-responsive (ER and/or PR positive) Stage I &
II,