Christy A Russell MD Keck School of Medicine University of Southern California Hazard Rate of Relapse According to Tumor Subtype and Year of Diagnosis British Columbia PopulationBased Data 19861992 ID: 751648
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Slide1
Adjuvant Therapy of Breast Cancer
Christy A Russell, MDKeck School of MedicineUniversity of Southern CaliforniaSlide2
Hazard Rate of Relapse
According to Tumor Subtype and Year of DiagnosisBritish Columbia Population-Based Data
1986-1992
2004-2008
Cossetti
, et al. JCO 2014Slide3
What’s New in Chemotherapy?Slide4
What’s New with Chemotherapy?
ER (+), HER2 (-) Breast CancerWe await the publication of TAILORx to further refine the predictive value of Oncotype Dx (especially in the intermediate RS tumors).We await the publication of MINDACT trial to elicit whether MammaPrint has any predictive value at all over clinical features for chemotherapy benefit.
We await completion of the
RxPonder
trial for ER(+), lymph node (+) patients.Slide5
TAILORx
schema Trial Assigning Individual
ized
O
ptions for Treatment
Patients with node-negative, hormone-positive breast cancer
Onco
type
DX
®
assay
Recurrence Score
®
result ≤ 10
Hormone therapy registry
Recurrence Score result 11-25*
Randomize to either hormone therapy or chemotherapy + hormone therapy
Recurrence Score result > 25Chemotherapy + hormone therapy
Register specimen banking
*
Primary study group
:
Recurrence Score result 11-25 correlates with
a 10-20% risk of distance recurrence at 10 years (upper 95% CI)Slide6
EORTC-BIG MINDACT TRIAL DESIGN
6,000 Node negative and 1-3 + lymph node breast cancer women
Dr Martine Piccart-Gephart JBI, Brussels
Evaluate Clinical-Pathological risk
and
70-gene signature risk
Clinical-pathological and 70-gene both HIGH risk
Discordant cases
Clin-Path HIGH
70-gene LOW
Clinical-pathological and 70-gene both LOW risk
Use Clin-Path risk to decide Chemo or not
Use 70-gene risk to decide Chemo or not
Adjuvant
Chemotherapy
(+ endocrine Tx if ER+)
N=3300 (55%)
N=600 (10%)
Adjuvant Endocrine
therapy only
N=2100 (35%)
Clin-Path LOW
70-gene HIGH
Randomize
The goal of this trial is to show that MammaPrint can
spare 20-30% of patients from adjuvant chemoSlide7
RxPonder
Schema and Patient Flow
Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer
(N= 600)
RS already Available
Physician and patients discuss randomization knowing the RS
(N= 8,800)
Patients consent to study-sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data
RECURRENCE SCORE
(N= 3,800)
Discuss alternative trials for high risk patients
N= 5,600
Physician and patients discuss randomization knowing the RS
N= 1,600
Record chosen therapy and followed for vital status through cancer registry
N= 2,000
Chemotherapy; appropriate endocrine therapy
N= 2,000
No Chemotherapy; appropriate endocrine therapy
STEP 2 REGISTRATION/
RANDOMIZATION
N= 4,000
Randomization
stratified by
1. RS
0-13 vs. 14-25
2. Menopausal status
3. Axillary node dissection vs. Sentinel node biopsy
RS > 25
RS
<
25
Accept
Refuse
STEP 1 REGISTRATION
Tumor tissue submission for RS
STEP 2 RANDOMIZATIONSlide8
What’s New with Chemotherapy?
ER (-), HER2 (-) Early Breast CancerWhat is the best sequence for anthracyclines and taxanes?Weekly or dose-dense paclitaxel?For whom can we avoid anthracyclines (NSABP B49)?Slide9
CONSORT diagram for the original protocol of Southwest Oncology Group S0221 trial.
Budd G T et al. JCO 2015;33:58-64
©2015 by American Society of Clinical OncologySlide10
(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm.
Budd G T et al. JCO 2015;33:58-64
©2015 by American Society of Clinical Oncology
TN
pts
ER+
ptsSlide11
(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm.
Budd G T et al. JCO 2015;33:58-64Slide12
NSABP B49 Schema
Node Positive, or High-Risk Node Negative,HER2 Negative
Stratification
Number of Positive Nodes
Hormone receptor status
Randomization
Arm 1
Anthracycline-based Chemotherapy*
Arm 2
TC x 6
Chemotherapy per Investigator*
TAC x 6
AC
WPddAC
WPddAC ddPSlide13
What’s New for ER (+) Early Breast Cancer in Premenopausal Women?Slide14
Premenopausal HR+ Early Breast Cancer
Adjuvant tamoxifen for > 5 years is recommended.
Genomic profiles are being developed to guide us on which women will benefit from > 5 years of tamoxifen.
The value of ovarian function suppression or ablation for women who receive tamoxifen is uncertain.
Women who develop chemotherapy-induced amenorrhea have a reduced risk of relapse.Slide15
Outcome at 15 years with Tamoxifen
ER+ disease, entry age < 45 years, 79% chemotherapy (n=2614)
EBCTCG, Lancet 2011Slide16
Options for Premenopausal Women
Standard of care has been tamoxifen for 5 years, but > 5 years looks better in some.What is the role of ovarian ablation in women receiving tamoxifen? SOFT
What is the role of ovarian ablation with an AI?
SOFT, TEXT, ABCSG-12Slide17Slide18
SOFT Primary Analysis: DFS
5.6 years median follow-up
> 95%
Overall
survival
Primary analysis in overall population not significant (p=0.10)
Multivariable Cox model HR=0.78 (95% CI 0.62-0.98) p=0.03
Francis, et al. NEJM 2014Slide19
SOFT Secondary Objectives
T + OFS vs T: 19% relative reduction in breast cancer recurrence p= 0.09
E + OFS vs T: 36% relative reduction in breast cancer recurrence CI (0.49-0.83
)
Francis, et al. NEJM 2014Slide20
SOFT: Outcomes by Chemotherapy
No Prior Chemotherapy
Prior Chemotherapy
No chemotherapy cohort selected for low risk features:
90% > age 40yr, 91% node negative, 85% tumor
<
2 cm, 41% grade 1
Francis, et al. NEJM 2014Slide21Slide22
Cost of Treatment: Toxicity
15% stopped OFS by 2 years, 22% by 3 years.Provider-reported, clinical importantDepression reported in
≅
50%, 4% severe, 5% increase with OFS
Increase in menopausal symptoms, osteoporosis, insomnia most marked
Patient reportedNo difference in global QOL with use of OFS in primary analysis
Global QOL indicators do not reflect important endocrine effectsEndocrine differences are less pronounced after 2 yearsCompliance or adjustment to menopause?
Endocrine toxicity overall less in women with prior chemotherapy
Ribi
, et al. SABCS 2014Slide23
TEXT and SOFT Trials: Comparison of Tamoxifen or Exemestane With OFS
Tamoxifen
20 mg/day
+
OFS*
(n = 1328)
Premenopausal
Patients with HR+ BC
≤ 12 wks after surgery
(N = 2672)
Stratified by trial, use of chemotherapy, nodal status
*OFS
TEXT: triptorelin 3.75 mg IM every 28 days for 6 mos, then optional bilateral oophorectomy or irradiation
SOFT: choice of method
TEXT
Exemestane 25 mg/day
+
OFS*
(n = 1014)
Tamoxifen
20 mg/day
Premenopausal
patients with HR+ BC
≤ 12 wks after surgery
(if no chemo) or≤ 8 mos after chemo(N = 3066)
SOFT
Tamoxifen
+ OFS*(n = 2344)
Tamoxifen 20 mg/day+ OFS* (n = 1016)Exemestane + OFS*(n = 2346)
Exemestane 25 mg/day+ OFS* (n = 1332)
Joint Analysis
5 yrs
Pagani
O, et al. ASCO 2014. Abstract LBA1.Slide24
60% of first failures involved distant sites, including soft tissue, bone, and viscera
Patients, n
HR (95% CI)
5-Yr DFS, %
E +
OFS
T +
OFS
E + OFS
T +
OFS
All Patients
2346
2344
91.1
87.3
Cohort
No chemotherapy, TEXT
No chemotherapy, SOFT
Chemotherapy, TEXT
Prior chemotherapy, SOFT
526
470
806
544
527
473
801
543
96.1
95.8
89.8
84.3
93.0
93.1
84.680.6Lymph Node Status
NegativePositive1362984
1350994
95.1
85.6
91.6
81.4
Exemestane With Ovarian Function Suppression Improved DFS
Pagani
O, et al. ASCO 2014. Abstract LBA1.
Reprinted with permission.
100
80
60
40
20
0
0
Percent Alive and Disease Free
1
2
3
4
5
6
Yrs Since Randomization
Median follow-up: 5.7 yrs
Difference 3.8% at 5 yrs
Exemestane + OFS (n = 2346)
Tamoxifen + OFS (n = 2344)
E + OFS
T + OFS
Events
216
298
HR
0.72
95% CI
0.60-0.85
P
Value
.0002
5-yr DFS
91.1%
87.3%
.25
.50
.72
1.0
2.0
4.0
Favors E + OFS
Favors T + OFSSlide25
Joint Analysis of TEXT and SOFT
Outcome
HR (95% CI)
p value
DFS
0.72 (0.60-0.85
0.0002
BCFI
0.66 (0.55-0.80)
<0.0001
DDFI
0.78 (0.62-0.97)
0.02
OS
1.14 (0.86-1.51)0.37Exemestane + OFS vs Tamoxifen + OFSMedian Follow-up of 5.7 years
Pagani et al. NEJM 2014Slide26
TEXT and SOFT: Selected Adverse Events
CTCAE
v3.0,
%
Exemestane + OFS
(N = 2318)
Tamoxifen + OFS (N = 2325)
Grades 1-4
Grades
3/4
Grades 1-4
Grades
3/4
Depression
50
3.8
50
4.4
Musculoskeletal
89
11
76
5.2
Osteoporosis
(%
T
score < -2.5)
39 (13)0.425 (6)0.3
Fracture
6.81.35.2
0.8Hypertension236.5
227.3Cardiac ischemia/infarction0.70.3
0.30.1Thrombosis/embolism1.00.8
2.21.9CNS ischemia0.7
0.30.30.1CNS bleeding
0.6< 0.10.90.1Hot flushes/flashes
92109312
Sweating55NR59 NR
Vaginal dryness
52
NR
47
NR
Libido decrease
45
NR
41
NR
Dyspareunia
31
2.3
26
1.4
Urinary incontinence
13
0.3
18
0.3
Pagani
O, et al. ASCO 2014. Abstract LBA1.
Reprinted with permission.Slide27Slide28
Final Analysis of ABCSG 12
HR vs Tam
1.13 (0.88-1.45)
p=0.33
HR vs Tam
1.63 (1.05-2.52
p=0.03
DFS
OS
Gnant, et al Ann Oncol 2014Slide29
Adjuvant Endocrine Therapy for Premenopausal Women
Several evidence-based choices now available:Tamoxifen x 5-10 yrTamoxifen x 5 yr to AI x 5 yr (MA-17)OFS + Tamoxifen
OFS + AI
Davidson N, Commentary SABCS 2014Slide30
Adjuvant Endocrine Therapy for Premenopausal Women
Tamoxifen alone x 5-10 years sufficient for low riskConsider use of OFS + Tam or OFS + AI for higher risk womenChemotherapy recipientsMultiple positive nodes
Age < 35
Optimal duration of OFS-based therapy uncertain
Long-term follow-up for both benefit and toxicity
Davidson N, Commentary SABCS 2014Slide31
Rugo
H. Commentary at 2014 SABCSSlide32
Challenges in Optimal Endocrine Therapy
Predictive markers beyond ER, PRUnderstanding pathways of resistance and when they come into playOptimizing the host environment – BMI?Monitoring the long-term benefit and toxicityCompliance and adherence of the patient (and their health care provider)
Davidson N, SABCS 2014 CommentarySlide33
Obesity in Breast Cancer
Early Breast Cancer Trialists’ Collaborative Group collected data on 80,000 patients with early breast cancer to analyze independent effects of BMI on patient outcomeObesity independently associated with BC-related mortality in premenopausal pts
with ER+ BC
In premenopausal obese (BMI ≥ 30) vs normal-weight women with ER+ disease (N = 20,000): 10-yr BC-relate mortality: 21.5% vs 16.6% (RR = 1.34; 95% CI: 1.22-1.47; 2P < .00001)
Little effect in premenopausal women with ER-negative disease or in postmenopausal women
Postmenopausal ER+ (N = 40,000): RR = 1.06 (95% CI: 0.99-1.14)
Pre- or postmenopausal ER-negative (N = 20,000): RR: 1.00 (95% CI: 0.93-1.08)
Pan H, et al. ASCO 2014. Abstract 503.Slide34Slide35Slide36
BMI: Impact on Efficacy of Endocrine Therapy in ABCSG-12
Pfeiler
, et al. JCO 2011Slide37
BMI: Impact on Efficacy of Endocrine Therapy in ABCSG-12
Pfeiler
, et al. JCO 2011Slide38
BMI: Impact on Efficacy of Endocrine Therapy in ABCSG-12
ConclusionsThese data are hypothesis generating secondary to the retrospective analysis.However, it does suggest that BMI influences the efficacy of OFS+ Anastrozole in premenopausal women when compared to tamoxifen +OFS.
Because over 1/3 of premenopausal women who develop breast cancer are overweight or obese, consideration should be given regarding selection of endocrine therapy.
Pfeiler
, et al. JCO 2011Slide39
Conclusions
Very little practice-changing data in the use of adjuvant chemotherapy.SOFT may present a new paradigm for young high-risk women with ER (+) early breast cancer.The role of BMI may need to be considered when selecting endocrine therapy for our patients.