1. D. Lawrence Wickerham, MD,1,17 Norman Wolmark, MD1,17
San Antonio Breast Cancer Symposium - December 6-10, 2016
A Randomized, Double-blinded, Placebo-controlled Clinical Trial of Extended Adjuvant Endocrine Therapy with Letrozole in Postmenopausal Women with Hormone-receptor (+) Breast Cancer who have Completed Previous Adjuvant Tx with an Aromatase Inhibitor: Results from NRG Oncology/NSABP B-42
Eleftherios P. Mamounas, MD,1,2 Hanna Bandos, PhD1,3 Barry C. Lembersky, MD,1,4
Charles E. Geyer, Jr., MD,1,5 Louis Fehrenbacher, MD,1,6 Mark L. Graham, MD,1,7
Stephen L. Chia, MD, FRCPC1,8 Adam M. Brufsky, MD, PhD,1,4 Bryan T. Hennessy, MD,1,9
Gamini S. Soori, MD,1,10 Shaker R. Dakhil, MD,1,11 Thomas E. Seay, MD,1,12 James L. Wade, III, MD,1,13
Edward C. McCarron, MD,1,14 Soonmyung Paik, MD,1,15 Sandra M. Swain, MD,1,16
D. Lawrence Wickerham, MD,1,17 Norman Wolmark, MD1,17
1NRG Oncology/NSABP (NSABP Legacy trials are now part of the NRG Oncology portfolio), Pittsburgh, PA; 2UF Cancer Center at Orlando Health, Orlando, FL; 3University of Pittsburgh, Pittsburgh, PA; 4University of Pittsburgh Cancer Institute, Pittsburgh, PA; 5Massey Cancer Center, Virginia Commonwealth University, Richmond, VA; 6Kaiser Permanente Oncology Clinical Trials Norther California, Vallejo, CA; 7Southeast Cancer Control Consortium, Goldsboro, NC; 8British Columbia Cancer Agency (BCCA),Vancouver, British Columbia, Canada; 9Cancer Trials Ireland (Formerly known as Irish Clinical Oncology Research Group - ICORG), Dublin, Ireland; 10Missouri Valley Cancer Consortium, Omaha, NE; 11CCOP, Wichita Cancer Center of Kansas, Wichita, KS; 12Georgia NCI Community Oncology Research Program, Atlanta, GA; 13CCOP, Central Illinois, Decatur, IL; 14MedStar Franklin Square Medical Center/Weinberg Cancer Institute, Baltimore, MD; 15Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea; 16Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC; 17Allegheny Health Network Cancer Institute, Pittsburgh, PA
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2. NSABP B-42: Background/Rationale
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Background/Rationale
Extended adjuvant endocrine therapy after 5 years of tamoxifen with either an aromatase inhibitor or tamoxifen improves disease-free survival in early-stage breast cancer
Optimal duration of adjuvant aromatase inhibitor therapy beyond 5 years is unknown
NSABP B-42 aimed to determine whether 5 years of letrozole vs. placebo improves disease-free survival in patients who have completed 5 years of hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor
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3. R NSABP B-42: Schema or Stratification:
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Schema
Postmenopausal Pts with ER+ or PR+ Breast Cancer
Stage I, II, or IIIa invasive BC at diagnosis
Disease-free After 5 Years of Endocrine Therapy or
AI X 5 yrs
TAM X < 3 yrs
 AI to Complete 5 yrs
Stratification:
Pathological nodal status (Negative, Positive)
Prior adjuvant TAM (Yes, No)
Lowest BMD T score: spine, hip, femur (>-2.0, ≤ -2.0 SD) R
Letrozole X 5 yrs
Placebo X 5 yrs
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4. San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Endpoints
Primary endpoint:
Disease-free Survival (DFS):
Local, regional, distant recurrence, opposite BC, 2nd non-breast primary cancer, and death from any cause as first event
Secondary endpoints:
Overall survival
Breast Cancer-Free Interval (BCFI):
Recurrence or opposite BC as first event
Distant Recurrence (DR)
Osteoporotic fractures (OF)
Arterial thrombotic events (AT)
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5. NSABP B-42: Patient Population
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Patient Population
From September 2006 to January 2010, 3966 pts were randomized
43 patients excluded: 36 no follow-up; 7 not at risk for the primary endpoint
Median follow-up for 3923 pts included in efficacy analyses was 6.9 years
The required 631 DFS events for definitive analysis occurred by August 2016
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6. NSABP B-42: Patient Characteristics
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Patient Characteristics
No significant differences in the distribution of patient, tumor, and prior treatment characteristics between the two treatment groups:
34-35% <60 years of age
57-58% node-negative
39% received prior tamoxifen
61% breast-conserving surgery
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7. NSABP B-42: Treatment Compliance
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Treatment Compliance
Median duration of treatment was 59.8 months in both groups
Overall, 62.5% of placebo patients and 60.3% of letrozole patients completed 5 years of therapy
Main reasons for letrozole treatment discontinuation:
Patient withdrawal/refusal: 13.8%
Adverse Event: 9.6%
Disease Progression: 4.1%
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8. San Antonio Breast Cancer Symposium - December 6-10, 2016
Results
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9. NSABP B-42: Disease-Free Survival
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Disease-Free Survival
Letrozole
Placebo
100 80 60 40 20
Years After Randomization
Disease-Free Survival
Letrozole
Placebo
HR=0.85 ( ) P = 0.048
84.7%
81.3%
# Events
292
339
*P-value did not reach statistical significance level of
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10. NSABP B-42: DFS First Events by Treatment
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: DFS First Events by Treatment
Placebo (n=1964)
Letrozole (n=1959)
First event # %
Distant Recurrence 87
4.4 61
3.1
Local Recurrence 33
1.7 36
1.8
Second Primary Ca
171
8.7
134
6.8
Opposite Breast 59
3.0 30
1.5
Non-Breast
112
5.7
104
5.3
Death 48
2.4
Total First Event
339
17.3
292
14.9
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11. NSABP B-42: Cumulative Incidence of BCFI Event
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Cumulative Incidence of BCFI Event
Letrozole
Placebo
Cumulative Incidence
of BCFI Event 12 10 8 6 4 2
Years After Randomization
10.0%
6.7%
HR=0.71 ( ) P=0.003
# Pts # Events
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12. NSABP B-42: Cumulative Incidence of Distant Recurrence
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Cumulative Incidence of Distant Recurrence
Letrozole
Placebo
Cumulative Incidence of DR 12 10 8 6 4 2
5.8%
3.9%
HR=0.72 ( ) P=0.03
Years After Randomization
# Pts # Events 73
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13. NSABP B-42: Overall Survival
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Overall Survival
Letrozole
Placebo
100 80 60 40 20
Years After Randomization
Disease-Free Survival
Letrozole
Placebo
Overall Survival
92.3%
91.8%
HR=1.15 ( ) P=0.22
# Deaths
164
146
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14. NSABP B-42: Cumulative Incidence of Osteoporotic Fx
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Cumulative Incidence of Osteoporotic Fx
Letrozole
Placebo
Cumulative Incidence of
Osteoporotic Fx 12 10 8 6 4 2
5.4%
HR=1.19 ( ) P=0.27
Years After Randomization
4.8 %
# Events 91 78
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15. NSABP B-42: Cum. Inc. of Arterial Thrombotic Events
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Cum. Inc. of Arterial Thrombotic Events 12 10 8 6 4 2
# Events 71 59
Letrozole
Placebo
HR=1.21 ( ) P=0.29
Cum. Inc. of Arterial
Thrombotic Events
4.0%
3.4 %
Years After Randomization
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16. San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Summary
The beneficial effect of extended letrozole therapy on DFS did not reach statistical significance (15% reduction)
No significant difference in overall survival
Extended letrozole provided:
Statistically significant improvement in BCFI (29% reduction in BCFI event)
Statistically significant reduction in the rate of DR (28% reduction in DR)
Letrozole did not significantly increase risk of osteoporotic fractures but risk of arterial thrombotic events was elevated for letrozole after 2.5 years
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17. NSABP B-42: Conclusions and Perspective
San Antonio Breast Cancer Symposium - December 6-10, 2016
NSABP B-42: Conclusions and Perspective
Our findings suggest that careful assessment of potential risks and benefits is required before recommending extended letrozole therapy in patients with early-stage BC, including:
Patient and tumor characteristics (age, nodal status)
Existing co-morbidities
Information on bone mineral density
Tolerance of the AI in the initial 5 years
Genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may help to further individualize the recommendation for extended aromatase inhibitor therapy
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18. San Antonio Breast Cancer Symposium - December 6-10, 2016
Acknowledgements
The 3,966 patients who participated in the trial
The NSABP Investigators/Coordinators
Hanna Bandos and Barry Lembersky
The NSABP Operations and Biostatistics Center staff
NCI CTEP and Novartis
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