Adjuvant Endocrine Therapy: How Long is Long...
Transcript of Adjuvant Endocrine Therapy: How Long is Long...
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Adjuvant Endocrine Therapy: How Long is Long Enough?
Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute
Harvard Medical School Boston, Massachusetts
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• I have no conflicts to disclose.
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Early vs Late Recurrence
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Jatoi I et al. JCO 2011;29:2301-2304
Time Dependence of Breast Cancer Recurrence in
Subsets Defined by Genomic Assays
Intrinsic/
PAM50
MammaPrint
OncotypeDX
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It is tautological to say, but the sine qua non for a late
recurrence is not having an early recurrence
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Coates, A. S. et al. J Clin Oncol; 25:486-492 2007
BIG 1-98 DFS OS
Predictors of Early Recurrence
(first 2 years)
Mauriac Ann Oncol 2007:18:859
T stage
N stage
LVI
HER2+
ER or PR neg
Grade
Note: lots of these correlate with
ER expression
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• Just because patients are at jeopardy for late recurrence does not necessarily mean that additional treatment will help
• Examples:
• HERA (2 vs 1 year of trastuzumab)
• Adjuvant Chemo (12 m vs 6 m)
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Tamoxifen
Why did we stop at 5 years anyway?
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Tamoxifen 5 yrs vs. Not
EBCTG
Overview
2000
Tam
Nil
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Duration of Tamoxifen: NSABP B-14
Placebo
Placebo
n=579
Tamoxifen x 5 years
n=593
Disease Free at 5 yrs
n=1172
Tamoxifen x 5 yrs
NSABP B-14
ER+, LN neg
Fisher, et al. JNCI 2001
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Duration of Tamoxifen: NSABP B-14 Fisher, et al. JNCI 2001;
median f/u 7 years post-rerandomization
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Scottish Trial of Extended Tamoxifen
Stewart HJ, et al. Brit J Cancer 1996;74:297-299.
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ECOG Trial of Extended Tamoxifen Beyond 5 Years
Tormey DC, et al. JNCI 1996;88:1828-33.
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TAM
AI
TAM
AI
Plac
AI
TAM
TAM
0 5 2 3 10
Years After Diagnosis
Upfront
ATAC
BIG 1-98
ABCSG 12
TEAM
Sequential
BIG 1-98
IES
ITA
NSAS BC-03
ARNO 95
ABCSG 8*
Extended
MA.17
ABCSG 6a
NSABP B-33
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ER+ Breast Cancer
What happens in years 6 to 10?
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MA 27: Letrozole or Placebo after 5 years of Tamoxifen
Goss PE et al. N Engl J Med 2003;349:1793-1802.
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Late Introduction of AI Therapy in MA17
Goss P E et al. JCO 2008;26:1948-1955
DFS
DDFS
Late switchers were:
Younger
Higher stage (N+, T2/T3)
Had more adj chemo
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MA17: DFS by treatment and menopausal status (at time of diagnosis).
Goss P E et al. Ann Oncol 2013;24:355-361
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NSABP B-33:
disease-free survival with exemestane versus placebo (intent-to-treat)
Mamounas E P et al. JCO 2008;26:1965-1971
©2008 by American Society of Clinical Oncology
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Sites of first event with exemestane versus placebo.
Mamounas E P et al. JCO 2008;26:1965-1971
©2008 by American Society of Clinical Oncology
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Cumulative incident plots of contralateral breast cancers according to initial randomization to
letrozole or placebo on MA.17.
Ingle J N et al. Ann Oncol 2008;19:877-882
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ATLAS population
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Disease-free Survival Overall Survival
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Richard Gray, Daniel Rea, Kelly Handley & 17 others
on behalf of the
aTTom Collaborators
aTTom: Long-term effects of continuing adjuvant
tamoxifen to 10 years versus stopping at 5 years in 6,953
women with early breast cancer
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10 vs 5 years of tamoxifen: Recurrence by treatment ASCO 2013
580 vs 672 recurrences RR=0.85 (95%CI 0.76-0.95)
p=0.003
An additional 143 vs 216 recurrences since 2008
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10 vs 5 years of Tamoxifen: Breast Cancer Death by Treatment Allocation
404 vs 452 breast cancer deaths
RR=0.88 (95%CI 0.77-1.01; p=0.05) p=0.06
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10 year EFS by stage, grade, and age for ER+ breast cancers not relapsing by year 5 from diagnosis:
British Columbia Data. Lohrisch et al. SABCS 2013 Stage
and
grade
Age > 50 years at Diagnosis Age
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Late recurrence in endocrine-treated cancers. Cuzick et al. SABCS 2013 ATAC
N=9366 ABCSG-8 N=3714
PAM50 N=1007
Excluded: -Insufficient residual RNA -Failed PAM50 QC
PAM50 N=1478
Excluded: -Insufficient residual RNA -Failed PAM50 QC
Excluded: -Not recurrence free at 5 years (N=145)
Excluded: -Not recurrence free at 5 years (N=203)
Combined dataset N=2137
N=862 N=1275
Excluded: -Combination arm -Chemotherapy -No blocks received -Insufficient tumour material
transATAC* N=1125
Tissue database N=1620
Excluded: -No tissue specimen -No consent
*RNA extracted by GHI
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Luminal A vs Luminal B HR (95% CI) P-value
Luminal A (N=1530 (71.6%)) - -
Luminal B (N=542 (25.4%)) 2.89 (2.07- 4.02)
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WHY NOT JUST TREAT EVERYONE FOREVER, ANYWAY?
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Patient-reported Reasons for Stopping Endocrine Therapy (N = 77)
%
Patient-related
Side effects
Concern about adverse effects from therapy
Cost
Dislike of having to be on medications
Wanted to move on from the cancer
27
16
18
17
11
Doctor-related
Told to stop by doctor
Completion of recommended course of treatment
16
9
(Not mutually exclusive)
Pini, ASCO 2011
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Persistent Risks of Therapy
• Tamoxifen
• Uterine cancer
• Thromboembolism
• Aromatase Inhibitors
• Osteoporosis
• Myalgias/arthralgias
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ATAC: annual bone fracture rates
ATAC Trialists, Lancet Oncology 2008;9:45
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Real Choices I
• Premenopausal
• Start with tamoxifen
• At 5 years
– If premenopausal, continue tamoxifen
– If postmenopausal (for sure), continue tamoxifen or switch to an AI
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Real Choices II
• Postmenopausal
• Start with tamoxifen or an AI
• If starting with tamoxifen, option of extended adjuvant treatment with either tamoxifen or an AI
• If starting with an AI, data may be available in 5 years to guide your choice at that timepoint
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Real Choices III
• Patients can usually tell you their preference
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The spectrum of patients on tamoxifen
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Real Choices III
• Patients can usually tell you their preference
• Benefits of extended adjuvant therapy are relatively modest, and baseline risk probably is relevant
• Low threshold for discontinuing treatment if not well tolerate
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Final Point
• After decades, we are still optimizing adjuvant endocrine therapy
• There is a movement to minimize the relationship between oncologists and breast cancer “survivors” by shifting care to other clinicians or survivorship clinics
• Ironically, in the largest population of cancer survivors, we are still amending treatment plans 5+ years out from diagnosis.