Download Continued Clinical Benefit: The Extended Adjuvant Treatment Strategy

Preventing Relapse Beyond 5 Years:
The MA.17 Extended Adjuvant Trial
Paul E. Goss, MD, PhD
Director of Breast Cancer Research
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Antagonizing Estrogen-Dependent
Breast Cancer Growth
Postmenopausal
Fat tissue
Tumor and peritumoral cells
Ovaries
Aromatase
inhibitor
LH/FSH
inhibitor
Estrogen
Exogenous
estrogen
Tamoxifen
X
LH/FSH = luteinizing hormone/
follicle/stimulating hormone;
DVT/PE = deep vein
thrombosis/pulmonary embolism.
 Resistance develops
 Growth can be stimulated
by tamoxifen
 Endometrial cancer
 DVT/PE
More Than Half of Breast Cancer
Recurrences and Deaths Occur
Post-Tamoxifen
Recurrence
Recurrence (%)
50
45.0
38.3
40
30
26.5
33.2
24.7
20
15.1
10
15-year gain 11.8% (SE 1.3)
Logrank 2p<0.00001
0
0
5
10
Years
15
Breast Cancer Mortality
60
Breast Cancer Mortality (%)
60
50
40
34.8
30
25.7
25.6
20
11.9
17.8
10
8.3
15-year gain 9.2% (SE 1.2)
Logrank 2p<0.00001
0
0
Control
About 5 years of tamoxifen
5
10
Years
Early Breast Cancer Trialists Collaborative Group. The Lancet. Vol 365 May 14, 2005.
15
Greater Absolute Risk Reduction With
Tamoxifen in Node + vs Node - Disease
Early Breast Cancer Trialists Collaborative Group Lancet 2005; 365:168
Proportion disease-free
Relapse-Free Survival Decreases
Consistently Regardless of ER/PgR Status
N- and N+ Patients
1.0
0.9
ER/PgR– (n=430)
0.8
0.7
0.6
ER+ and/or PgR+ (n=778)
0.5
P<0.001
0.4
5
10
15
20
Years postdiagnosis
 Late recurrences (>5 years) were more frequent in ER+ and/or
PgR+ tumors
Hortobagyi et al. Proc Am Soc Clin Oncol. 2004;23:23. Abstract 585.
NSABP B-14: No Benefit of Extending
Tamoxifen for 7 Years Beyond the
Initial 5 Years
Survival
100
100
90
90
82%
80
P=0.03
78%
70
Placebo
Tamoxifen
60
50
5
10
12
Years
% Surviving
% Surviving
disease-free
Disease-Free Survival
94%
91%
80
P=0.07
70
Placebo
Tamoxifen
60
50
5
10
12
Years
 Tamoxifen demonstrated higher rates of endometrial cancer, ischemic heart
disease, and cerebrovascular disease.
Fisher et al. J Natl Cancer Inst. 2001;93:684.
Letrozole vs Tamoxifen in First-line
Metastatic Breast Cancer
Letrozole better
Tamoxifen better
Subgroup
Viscera
Bone
Soft tissue
Rec. unknown
Rec. positive
No antiestrogen
Post Tam
Whole study
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6
Hazard ratio
Mouridsen et al. J Clin Oncol. 2003;21:2101.
Extended Adjuvant Therapy: Letrozole
(LET) Following 5 Years of Tamoxifen
 >5 y of tamoxifen believed to add no benefit
 Recurrence after tamoxifen is ~2% and ~4% per
annum in node –ve and +ve pts, respectively
 Late recurrences (>5 years) were more frequent in
ER+ and/or PgR+ tumors
 LET after tamoxifen shrinks existing tumors/
prevents tumors in animal models
 LET after tamoxifen induces remissions in
advanced breast cancer
MA.17: Trial Design
Randomization
(all patients disease-free)
0-3
months
Letrozole 2.5 mg qd*
n=2582
Tamoxifen
Placebo qd†
n=2586
Approx. 5 years adjuvant
5 years extended adjuvant
Primary end point: DFS
Secondary end points: OS/safety/QOL/rate of contralateral breast cancer
Substudies: BMD/bone markers, lipid profile
*n=2582 (efficacy), 2563 (safety); †n=2586 (efficacy), 2573 (safety).
QOL = quality of life; BMD = bone mineral density.
Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation; and N Engl J Med. 2003;349:1793.
MA.17: Primary End Point
 Disease-free survival
– Recurrence in

Ipsilateral breast

Chest wall

Locoregional nodal

Metastatic sites
– Occurrence of contralateral new primary breast cancer
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Secondary End Points
 Overall survival
 Rate of contralateral breast cancer
 Long-term safety/tolerability
– Lipid profile
– Cardiovascular morbidity/mortality
– Bone fractures/BMD
– Clinical/laboratory
 QOL SF-36/MENQOL
SF-36 = 36-item short-form health survey;
MENQOL = menopause-specific quality of life questionnaire.
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Eligibility Criteria
 Patients enrolled
– Postmenopausal
– ER+ and/or PgR+ or both unknown
– Node–, node+, or node-unknown
– Completed 4.5-6 years of initial tamoxifen
– No evidence of recurrent cancer
– ECOG PS 0-2
ER = estrogen receptor; PgR = progesterone receptor;
ECOG = Eastern Cooperative Oncology Group; PS = performance status.
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Statistical Assumptions
 Primary end point (DFS)
– To detect an improvement in DFS of 22%, equivalent to
reducing the estimated risk of relapse at 4 years by 2.5%
(12%-9.5%)
 Interim analyses
– Prospectively planned at 171 and 342 events
– Stopping boundary nominal significance, P=0.0008
5 Preplanned Subset Analyses
1. Tumor receptors +ve, unknown
2. Lymph node status +ve, –ve, unknown
3. Prior chemo Y/N
4. Menopausal status at start of tamoxifen
5. Prior tamoxifen < or > 5 years
MA.17: Final Analysis
Toxicity - Efficacy
2003
1998
 Interim Analysis (NEJM)
March
Aug Oct
2003
2004
 Final Analysis (Publication Pending)
– DFS events: 207
– DFS events: 247
– Deaths: 73
– Deaths: 113
– No. of pts at 40 months: 384
– No. of pts at 40 months: 1115
– Median follow-up: 2.4 y
– Median follow-up: 2.5 y
MA.17: Patient Demographics
Letrozole
Placebo
Median age (y)
62
62
ER+ and/or PgR+ (%)
98
98
ECOG 0 (%)
90
90
T1 (%)
58
58
Node –ve
50
49
Breast-conserving surgery
57
57
Radiotherapy
60
59
Chemotherapy
46
46
Disease-Free Survival in All Patients:
Significant 42% Reduction in Relative Risk
100
Percent
80
60
P=0.00004
Letrozole
Placebo
40
20
0
0
No. at risk:
Letrozole 2583
Placebo 2587
10
20
30
40
50
60
541
519
176
164
6
8
Months
2497
2489
1905
1874
1110
1075
Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: DFS by Treatment Duration—
Increasing Benefit With Treatment Duration
% of Patients
Year
Letrozole
(n=2582)
Placebo
(n=2586)
1
98.5
97.9
2
96.9
95.4
3
95.7
92.2
4
94.35
89.84
Abs diff (%)
4.5
(CI, 2.1-6.9)
Node –
96.3
93.6
2.7
Node +
92.3
84.8
7.5
Overall P=0.00004
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Total Recurrences
of Breast Cancer
175
155
Node+
No. of events
150
Node–
125
100
94
102
92
75
57
50
63
50
39
18
28
0
74
33
25
Distant
Locoregional
New primary only
17
20
23
14
14
14
10
18
12
13
3
7
Placebo Letrozole Placebo Letrozole Placebo Letrozole
Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Distant DFS—Letrozole Significantly
Reduced the Risk of Distant Metastases by 40%
Distant DFS: All Patients
% Disease-free
100
80
P=0.002
60
Letrozole
Placebo
40
20
0
0
No. at risk:
Letrozole 2583
Placebo
2587
10
20
30
40
50
60
541
519
176
164
6
8
Months
2497
2489
1905
1874
1110
1075
Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Overall Survival—All Patients
% Surviving
100
80
P=0.30
60
Letrozole
Placebo
40
20
0
0
No. at risk:
Letrozole 2583
Placebo
2587
10
20
30
40
50
60
556
559
182
175
6
8
Months
2523
2522
1937
1928
1138
1130
Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Overall Survival—Letrozole Decreased
Mortality by 39% in Node-Positive Patients
Node+
100
80
80
60
% Surviving
% Surviving
Node–
100
P=0.04
40
Letrozole
Placebo
20
60
P=0.24
40
Letrozole
Placebo
20
0
0
0
10
20
30
40
50
60
0
10
Months
20
30
40
50
60
Months
While OS was not improved in node– patients, a similar reduction in local recurrences, new primaries,
and distant recurrences occurred as in the node+ patients
Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
Summary of Key End Points in
Nodal Subgroups
HR=0.45
(0.27-0.75)
Node*
–ve
Node
–ve
Distant
DFS
DFS*
HR=1.52
(0.76-3.06)
HR=0.63
(0.31-1.27)
Node
–ve
OS
Node*
+ve
Node*
+ve
Node*
+ve
HR=0.61
(0.45-0.84)
HR=0.53
(0.36-0.78)
HR=0.61
(0.38-0.98)
*Statistically significant.
Letrozole: Effects on Women’s Health
1. Breast cancer
Estrogen
2. End-organ and QOL
Pmol/L
800
ERT/HRT
200
Normal levels
Aromatase inhibition
Premenop
Postmenop
Bone metabolism
Lipid metabolism/CVD
Thromboembolism/CVD
Cognitive function
Endometrial cancer
Urogenital function
Vasomotor symptoms
Other cancers
Other
MA.17: Incidence of Adverse Events*
(All Grades)
% of Patients
Letrozole
Placebo
P Value
Hot flashes
58
54
0.003
Arthritis/arthralgia
25
21
<0.0001
Muscle pain
15
12
0.04
6
8
0.005
Hypercholesterolemia
16
16
0.79
Cardiovascular events
6
6
0.76
Osteoporosis
8
6
0.003
Discontinuations due to adverse events
5
4
0.02
Discontinuations for other reasons
4
5
0.1
Vaginal bleeding
*90% of AEs grade 1 or 2.
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
MA.17: Number of Patients Who Experienced
Osteoporosis or Bone Fractures
209
200
Letrozole
Placebo
No. of patients
(8%)
155
150
(6%)
100
137
119
(5.3%)
(4.6%)
50
0
New osteoporosis*
(P=0.003)
*Patient-reported.
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
Bone fractures*
(P=0.25)
MA.17: Bone Companion Trial Design
(N=226)
BMD
Bone biomarkers
Serum bone ALK phos
Serum C-telopeptide
Urine N-telopeptide
0
1
2
3
Year
Tamoxifen
0-3
months
Letrozole
n=113
Placebo
n=113
Perez et al. SABCS, 2004. Abstract 404.
4
5
MA.17 Bone Companion Trial:
2-Year Results
 Percent change from baseline BMD in LS and TH after 2 y;
osteoporosis documented by DEXA scan (unlike MA.17)
 LS BMD, LET vs PLC: −5.35% vs −0.7% (P=0.008)
– Reported osteoporosis (3.3% vs 0%; P=0.126)
 TH BMD, LET vs PLC: −3.60% vs −0.71% (P=0.044)
– No patient went below the absolute threshold for osteoporosis
(≤−2.5 SD below peak bone mass)
 Documented osteoporosis less than patient-reported (MA.17)
 Difference in fracture rates not significant
(LET: 1.65%; PLC: 6.73%; P=0.08)
 Urine N-telopeptide significantly higher with LET at 1 and 2 years
LS = lumbar spine; TH = total hip
LET = letrozole; PLC = placebo.
Update of Perez et al. Breast Cancer Res Treat. 2004;88(suppl 1):S36. Abstract 404.
MA.17 Lipid
Substudy (MA.17L) Trial Design
Randomization
(All patients disease-free)
0-3
months
Letrozole 2.5 mg qd*
n=183
Tamoxifen
Placebo qd†
n=164
~5 years adjuvant
5 years extended adjuvant
 347 patients enrolled
 37 ineligible patients – (33 hyperlipidemic at baseline, 4 protocol violations)
 Closed for accrual May 2002
Wasan et al. Ann Oncol. Epub ahead of print, April 7, 2005.
MA.17L: Results
 Letrozole did not significantly alter serum
cholesterol, HDL cholesterol, LDL cholesterol,
triglycerides, or lipoprotein (a) compared with
placebo in patients treated for up to 36 months
following approximately 5 years of adjuvant
tamoxifen
Wasan et al. Ann Oncol. Epub ahead of print, April 7, 2005.
MA.17: Efficacy Conclusions
 LET significantly reduced the risk of recurrences (43%)
regardless of nodal status and prior chemotherapy
 LET significantly reduced the risk of distant metastases by
40% compared with placebo
 LET reduced occurrences (37.5%) of new contralateral
breast cancers
 LET significantly improved OS in node-positive patients
 OS was not improved in node-negative patients but a similar
degree of reduction in local recurrences, new primaries, and
distant recurrences occurred as in the node-positive
patients
MA.17: Safety and Tolerability
Conclusions
 Predictable but mild E2 deficiency symptoms occurred
 Global QOL was unaffected; mild QOL changes were noted
related to reported menopausal symptoms and joint and
muscle pains
 Bone metabolism was affected by LET as indicated by a
minimal increase in osteoporosis detected over 4 years,
but no significant difference in clinical fractures occurred
 Evaluation of longer-term toxicities will be determined from
MA.17 follow-up and re-randomization including sub-studies
2004 ASCO Guidelines on AIs in
Postmenopausal Women With
HR+ Breast Cancer
 Optimal adjuvant therapy should include an AI as initial
therapy or after treatment with tamoxifen in order to lower
the risk of tumor recurrence
– AIs are appropriate as initial treatment for women with
contraindications to tamoxifen
– For all other postmenopausal women, treatment options include 5
years of AI treatment or sequential therapy consisting of tamoxifen
(for either 2-3 years or 5 years) followed by AIs for 2-3, to 5 years
 Women with breast cancer and their physicians must weigh
the risks and benefits of all therapeutic options
Winer et al. J Clin Oncol. 2004. Epub ahead of print.
MA.17 Rerandomization Trial
Tamoxifen
Letrozole
Placebo
(n=900)
(n=900)
MA.17
0
5
MA.17
Extension
10
15
Years
 As of May 2005, 81 patients have been re-randomized to MA.17R
Goss et al. ASCO, 2004. Abstract 847 and slide presentation.
Questions and Answers