F. Cardoso, MD - European Society for Medical Oncology€¦ · F. Cardoso, MD Director, Breast...
Transcript of F. Cardoso, MD - European Society for Medical Oncology€¦ · F. Cardoso, MD Director, Breast...
F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal
ESO Breast Cancer Program CoordinatorESMO Board of Directors & NR Committee Chair
EORTC Breast Group Past-Chair
(Neo-) adjuvant endocrine therapy
DISCLOSURES
Consultant/Ad Board:
Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo,
Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics,
Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer,
Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva
St. Gallen 2017Escalating and de-escalating treatment in Early Breast Cancer across subtypes
and treatment modalities
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (“Oxford Overview”)
ESMO Early Breast Cancer Guidelines 2015 (new version to
be published in 2018!)
EARLY BREAST CANCER: WHO NEEDS ADJUVANT ET?
(almost) All ER+ EARLY BREAST CANCER patients!
Until the early 90’s: decision was based on menopausal status:
All post-menopausal: YesAll pre-menopausal: No
EBCTCG, The Lancet 2011
• HR the only predictive factors
• Levels of positivity also important
PREDICTIVE MARKERS FOR ENDOCRINE THERAPY
ER (Tam and AIs)
PgR (Tam and AIs)
HER-2
PROLIFERATION (Ki67)
Bcl-2 (Tam)
AIB-1 (Tam)
ER-beta (Tam)
MTA1s (Tam)
Cyclin E (Tam)
Intratumoral Aromatase (AIs)
Genomic signatures
ESR1 mutations
• HR are the only predictive factors with Level 1 evidence for ET
• NO BIOMARKER CAN HELP DECIDE BETWEEN TAM & AI
Efficacy of 5 years Tam
WHICH TYPE OF ENDOCRINE THERAPY?
Messages from the EBCTCG overview & individual trials
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
Study Treatment arms/ Population (n)
MedianFU
Recurrence Mortality
Tamoxifen 5 yearsOverview 2011[76]
TAM 5 y vs no TAM10 645 ER+
15 y RR 0.53 [SE 0.03] years 0–4
RR 0.68 [SE 0·06] years 5–9
2p<0·00001RR 0.97 [SE 0.10] years
10–14
RR 0.71 [SE 0.05] years 0–4,
RR 0.66 [SE 0.05] years 5–9
RR 0.68 [SE 0.08] years 10–14
p<0·0001
CARRY-OVER EFFECT
9% ABSOLUTE BENEFIT
MCBS: A
Time to recurrence: smoothed hazard estimates
HR+ patients
Annual
hazard
rates
(%)
4.0
3.0
2.0
1.0
0.0
4.0
3.0
2.0
1.0
0.0
0 1 2 3 4 5 6 7 8 9
Follow-up time (years)
Tamoxifen (T)
Anastrozole (A)
In the HR+ subgroup, the absolute difference in recurrence
increased from 2.8% after 5 years to 4.8% after 9 years
There is a statistically significant larger carryover effect for
anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01)
Efficacy of Aromatase Inhibitors: Upfront
WHICH TYPE OF ENDOCRINE THERAPY?Messages from the EBCTCG overview & individual trials
Study Treatment arms/Population (n)
MedianFU
Recurrence Mortality
AIs 5 years ATAC TAM 5y vs ANA 5y
3116/ 3125120 months
HR= 0·91 (95% CI 0·83-0·99)p = 0·04
0.97 (95% CI 0.88–1.08)
p = 0·6BIG 1.98 TAM 5y vs LET 5y
2459/ 246376 months
HR=0·88 (95% CI 0·78–0·99)p = 0.03
HR 0.87 (95% CI 0.75-1.02)p = 0.08
TEAM EXE 5y vs TAM 2-3y followed EXE 2-3y4868/4898
5.1 y HR=0·97 (0·88–1·08)p=0·60
HR=1.00 (0·89–1·14)p>0.9
Meta-analysis
Cohort 1
AIs initial monotherapy vs TAM
9,856
5.8 y 9.6% AI v 12.6% TAM
2.9% absolute decrease (SE 0.7%)
2P <.00001
4.8% AI v 5.9% TAM
1.1% (SE =0.5%) absolute decrease
2P =0 .1MA.27 EXE 5y vs ANA 5y
7,5764.1y HR=1.02 ( 95% CI, 0.87 to
1.18)
P =0 .85
HR=0.93 ( 95% CI,0.77 -1.13)
P= 0 .46
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
Efficacy of Tam & Aromatase Inhibitors in Sequence
Study Treatment arms/ Population (n)
MedianFU
Recurrence Mortality
AIs and Tamoxifen in switching strategiesBIG 1.98 LET 5 y
TAM 2 y followed by LET 3 y
LET 2 y followed by TAM 3 y
1546/ 1548/ 1540
71 months
HR=1·05 (95% CI 0·84–1·32)HR=0·96 (95% CI 0·76–1·21)
HR=1.13 (95% CI 0·83–1·53)HR=0.90 (95% CI 0·65–1·24)
ABCSG-8/ARNO 95
TAM 5y vs Tam f 2y followed by ANA
for 3 years
28 months
HR=0·60 (0·44–0·81)p=0·0009
p=0·16
ITA TAM 5y vs Tam f 2y followed by ANA
128 months
HR=0·64 (0·44–0·94)p = 0.023
HR=0.72 (0·44–1.17)p = 0.3
IES TAM 5y vs Tam f 2-3y followed by EXE 2-3y
55·7 months
HR=0·76 (95% CI 0.66–0·88)p=0·0001
HR 0.·85 (95% CI 0·71–1·02)p=0·08
Meta-analysis
Cohort 2AIs T after 2-3 y of TAM vsTAM9,015
3.9y 5.0% AI v 8.1% TAM
3.1% absolute decrease (SE 0.6%)
2P <.00001
1.7% AI v 2.4% TAM
0.7% (SE =0.3%) absolute decrease
2P =0 .2
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
Fulvestrant IM 500mg on day 0, 250mg day 14 and 28 and
250mg every 28 days thereafter for the first 3 years
+ Anastrozole PO 1mg/day for 5 years
Stratification factors:
• No. of lymph nodes (0 vs.
1-3 vs. >4)
• (Neo)Adjuvant
chemotherapy (yes vs. no)
• HR status (both positive vs.
only one positive)
• Site
HR+/HER2- postmenopausal patients with early breast cancer that have undergone
surgery with or without neo/adjuvant chemotherapy
RAnastrozole PO 1 mg daily for 5 years
1:1
GEICAM 2006-10 TRIAL
Courtesy of M. Ruiz-Borrego et al
Primary endpoint: DFSSecondary endpoints: BCSS, OS, Safety, Time to recurrence
872 pts
Disease Free Survival
Anastrozole
n = 437
Anastrozole + Fulvestrant
n = 433
Total
n = 870
Total number at risk 434 417 851
Events 62 49 111
Censored n (%) 372 (85.7) 368 (88.2) 740 (87.0)
HR: 0.839 (0.576-1.220)
Arm Event Total
Anastrozole 62 434
Anastrozole + Fulvestrant 49 417
Courtesy of M. Ruiz-Borrego et al
BC Specific Survival
Anastrozole
n = 437
Anastrozole + Fulvestrant
n = 433
Total
n = 870
Total number at risk 434 417 851
Events 47 39 86
Censored n (%) 387 (89.2) 378 (90.6) 765 (89.9)
HR: 0.884 (0.578-1.352)
Arm Event Total
Anastrozole 47 434
Anastrozole + Fulvestrant 39 417
Courtesy of M. Ruiz-Borrego et al
Overall Survival
Anastrozole
n = 437
Anastrozole + Fulvestrant
n = 433
Total
n = 870
Total number at risk 434 417 851
Events 34 28 62
Censored n (%) 400 (92.2) 389 (93.3) 789 (92.7)
HR: 0.863 (0.523-1.424)
Arm Event Total
Anastrozole 34 434
Anastrozole + Fulvestrant 28 417
Courtesy of M. Ruiz-Borrego et al
GEICAM 2006-10 TRIAL
WHICH DURATION OF ENDOCRINE THERAPY?
Recurrences Breast cancer deaths
EBCTCG, Lancet. 2005
Years
85.2
73.7
0
20
40
60
80
100
0 5 10 15
Tamoxifen
Control
15% 17%
0
20
40
60
80
100
0 5 10 15
87.8
Years
Tamoxifen
Control
9% 18%
91.4
% o
f p
ati
en
ts
% o
f p
ati
en
ts
54.9
68.2 73.0
64.0
More than Half of all Breast Cancer Recurrences
and Deaths Occur Post- 5y Tamoxifen
Annual Risk of Recurrence by ER Status
Saphner T et al., J Clin Oncol 1996
Hormone receptor positivity is a strong predictor for late recurrence !
• Over half of breast cancer recurrences occur >5 years post-surgery!
• The annual risk of late recurrence is particularly high in ER+ tumors (5.2%
between years 5 and 8, 4.6% between years 8 and 12).
Years
0
0.1
0.2
0.3
0 1 2 3 4 5 6 7 8 9 10 11 12
Recu
rren
ce
hazard
rate
ER– (n = 1305)
ER+ (n = 2257)
N Engl J Med 2017;377:1836-46
Data from about 70,000 women with ER+ T1/T2, with 5 years of adjuvant ET
N Engl J Med 2017;377:1836-46
Meta-analysis on Five or More Years of
Adjuvant Tamoxifen: Safety Profile
Al-Mubarak M et al.,PLOS One 2014
Extended adjuvant Tamoxifen:
• Higher incidence of hot flushes, vaginal discharge and fluid retention.
• Higher incidence of thromboembolic events.
• Significant increase in endometrial carcinoma (OR 2.06, p< 0.001) ,
absolute risk increase from 1.1 to 2.2%; without significant influence on
death from endometrial cancer.
• Non- significant reduction in death from cardiovascular diseases (OR
0.89, p=0.25), absolute reduction from 3.2 to 2.8%;
• No association between extended Tamoxifen and other (non-
endometrial) second cancers.
EBCTCG “summary” 10 years Tam vs 5 years(at the current FU):
Relative benefit: 15%Absolute benefit: 3%
Increase in mortality: 0.4%
All patientsPremenopausal
(n=889)
Postmenopausal
(n=4,277)
HR= 0.57;
p ≤ 0.001
Absolute benefit 10.1%
HR = 0.25
p<0.0001
Absolute benefit 3.3%
HR = 0.69
p = 0.0008
Goss PE et al. SABCS 2009; Goss PE et al., Ann Oncol 2013
• Premenopausal (n=889)
< 50 years of age with menses, but underwent subsequent bilateral oophorectomy
or became amenorrhoic during adjuvant Cht or Tam.
• Postmenopausal (n=4,277)
MA.17: DFS by Menopausal Status
Women who had been premenopausal at diagnosis experienced significantly
greater benefit of extended letrozole in terms of DFS; significant interaction
between treatment and menopausal status (p = 0.03).
NSABP B-42: Schema
Letrozole X 5 yrs Placebo X 5 yrs
• 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
Stratification:
Pathological nodal status (Negative, Positive)
Prior adjuvant TAM (Yes, No)
Lowest BMD T score: spine, hip, femur (>-2.0, ≤ -2.0 SD)
AI X 5 yrs or
R
San Antonio Breast Cancer Symposium - December 6-10, 2016
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to reprint and/or distribute.
AI to Complete 5 yrsTAM X < 3 yrs
San Antonio Breast Cancer Symposium,
December 6-10, 2016
NSABP B-42: Overall Survival
San Antonio Breast Cancer Symposium - December 6-10, 2016
This presentation is the intellectual property of the author/presenter. Contact them at
[email protected] for permission to reprint and/or distribute
Letrozole
Placebo
100
80
60
40
20
0
0 2 4 6 8 Years After Randomization
Dis
ease
-Fre
e S
urv
iva
l
Letrozole
Placebo
100
80
60
40
20
0
0 2 4 6 7 8 Years After Randomization
Letrozole 1959 1902 1781 1499 287
Placebo 1964 1902 1791 1528 291
Overa
ll S
urv
ival
92.3%
91.8%
HR=1.15 (0.92-1.44) P=0.22
# Deaths
164
146
San Antonio Breast Cancer Symposium,
December 6-10, 2016
NSABP B-42:Cum. Inc. of Arterial Thrombotic Events
Cu
m.
Inc.
of
Art
eri
al
Th
rom
bo
tic E
ven
ts12
10
8
6
4
2
00 2 4 6 7 8
4.0%
HR=1.21 (0.85-1.70) P=0.29
3.4 %
Letrozole
Placebo
Years After Randomization
San Antonio Breast Cancer Symposium - December 6-10, 2016
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[email protected] for permission to reprint and/or distribute
# Events
71
59
Non-proportionality of
Hazards for AT: p=0.007
HR=0.55
p=0.054
HR=1.85
P=0.007
NSABP B-42:Cumulative Incidence of Osteoporotic Fx
San Antonio Breast Cancer Symposium - December 6-10, 2016
This presentation is the intellectual property of the author/presenter. Contact them at
[email protected] for permission to reprint and/or distribute
Letrozole
Placebo
Cu
mu
lati
ve I
ncid
en
ce o
f
Oste
op
oro
tic F
x
12
10
8
6
4
2
0
0 2 4 6 7 8
5.4% HR=1.19 (0.88-1.60) P=0.27
Years After Randomization
4.8 %
# Events
91
78
MA.17R Trial Schema and Design <br />AI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen
Presented By Paul Goss at 2016 ASCO Annual Meeting
Slide 11
Presented By Paul Goss at 2016 ASCO Annual Meeting
Courtesy M. Gnant, SABCS 2016
EARLY BREAST CANCER: WHO NEEDS EXTENDED ADJUVANT ET?
All ER+ EARLY BREAST CANCER patients with sufficient high risk??!
•No proven biomarker•Role of some genomic signatures for determination
of late relapses risk?!PAM 50 (Prosigna Breast Cancer Assay)
Breast Cancer Index (BCI)
Endopredict /Endopredict Clin
Estimated bone loss with AI’s
Comparing different strategies
Arthralgia Endometrial polyp
Co-Morbidity & Side effects
MBC UZ Leuven Abstr. 4056, Neuven et al
Surprisingly: Tam was worse than AI
Also seen in the TEAM study
ADJUVANT ENDOCRINE THERAPY WITH AN A.I. :COMPLIANCE AND COST ISSUES
Treatment with an AI will often necessitate:
Earlier initiation of lipid-lowering drugs, antihypertensivesand aspirin to reduce cardiac and cerebrovascular events
Earlier initiation of medication for osteopenia/osteoporosis
The use of pain medication, such as anti-inflammatory for myalgia / arthralgia
Courtesy of M. Trudeau
Routine follow-up of lipids
Monitoring of blood pressure
Routine assessment of bone mineral density & frequently preventive therapy
R
A
N
D
O
M
I
Z
E
Intermittent letrozole over 5 yrs
0 6 12 18 24 3630 42 48 54 60
Continuous letrozole x 5 yrs
9 mos.9 mos.9 mos.9 mos. 12 mos.
4884 Patients Randomized in ITT, Nov 2007 - July 2012
Stratify
Institution
Prior ET:
SERM
AI
Both
SOLE TRIAL: Study of letrozole extension after 4 to 6 years of prior adjuvant endocrine therapy postmenopausal, HR+, N+
De-escalating
Presented ASCO, 2017Courtesy M. Colleoni
SOLE PRIMARY ENDPOINT: DFS
60 mos. median follow-up
Presented ASCO, 2017Courtesy M. Colleoni
SOLE QUALITY OF LIFE: CHANGE FROM BASELINE TO 12 AND 24 MONTHS
Presented ASCO, 2017Courtesy M. Colleoni
ROLE OF OFS & AI IN PREMENOPAUSAL WOMENTEXT & SOFT Trials
Francis et al, N Engl J Med, 2015
TEXT and SOFT Trials: Comparison of Tamoxifen or Exemestane With OFS
Tamoxifen 20 mg/day+ OFS* (n = 1328)
PremenopausalPatients 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
Premenopausalpatients 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.
Pagani et al, N Engl J Med, 2014
This presentation is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium, December 9-13, 2014
Hazard Ratio of Relapse
0.5 1 1.5 2
ER+, 35+
ER-, 35+
ER+, <35
ER-, <35
Hazard Ratio of Relapse
0.5 1 1.5 2
ER+, 35+
ER-, 35+
ER+, <35
ER-, <35
Outcomes from Premenopausal Adjuvant Chemotherapy Trials with no Hormonal Rx
Goldhirsch A et al. JNCI Monogr 2001;30:44-51
Hazard Ratio of Relapse
0.5 1 1.5 2
ER+, 35+
ER-, 35+
ER+, <35
ER-, <35
Hazard Ratio of Relapse
0.5 1 1.5 2
ER+, 35+
ER-, 35+
ER+, <35
ER-, <35
• About 12% LESS RECURRENCES in PTS NOT TREATED WITH CT
• Not selected for ER!
EBCTCG Ovarian Suppression/AblationOFS/OFA Meta-analysis EBCTCG 2006
CT DECISION WITH PHYSICIAN
Francis et al, N Engl J Med, 2015
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
SOFT DFS8 years median follow-up
T+OFS significantly improves DFS vs T-alone in the overall population
Francis et al, N Engl J Med, 2015Updated at SABCS 2017. Fleming et al
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
SOFT Secondary EndpointsDistant Recurrence-Free Interval Overall Survival
A small overall survival benefit is seen with T+OFS vs T, at 8 yrs median follow-up
Francis et al, N Engl J Med, 2015Updated at SABCS 2017. Fleming et al
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
SOFT Secondary Endpoints: No Chemo
No Chemo cohort remains at low risk of distant recurrence with T alone;
12 of 24 deaths were in setting of no distant recurrence
Distant Recurrence-Free Interval Overall Survival
Francis et al, N Engl J Med, 2015Updated at SABCS 2017. Fleming et al
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
Prior Chemo cohort has small absolute OS improvements in OFS arms at 8 yrs
SOFT Secondary Endpoints: Prior Chemo
Distant Recurrence-Free Interval Overall Survival
Francis et al, N Engl J Med, 2015Updated at SABCS 2017. Fleming et al
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
Protocol and Non-protocol Therapy
T T + OFS E + OFS
Stopped assigned oral endocrine
therapy early22.5% 18.5% 27.8%
Stopped triptorelin early* 21.4% 19.6%
Received OFS (in first 5 yrs) 15.5%
Used oral endocrine therapy at ≥6 yr** 24.7% 24.3% 12.6%
*and did not undergo oophorectomy or ovarian irradiation
**as adjuvant therapy; denominator is patients alive and in follow-up at 6 yrs
Francis et al, N Engl J Med, 2015Updated at SABCS 2017. Fleming et al
Absolute improvement at 5 years – HR (95% CI)
T+OFS vs T E + OFS vs T
BCFI 11,2% 15,7%
94% received CT
N=350
Francis et al, N Engl J Med, 2015
SOFT Trial: CONCLUSIONSSTRENGTHS:
1) LARGE, PROSPECTIVE, RANDOMIZED TRIAL
2) PRAGMATIC APPROACH TO USE OF CT
3) PROVIDES EVIDENCE THAT IN SOME PATIENTS WITH BETTER PROGNOSIS TAMOXIFEN ALONE IS A VERY GOOD TREATMENT
4) GIVES SUPPORT TO USE OF OFS IF NO AMENORRHEA IS OBTAINED WITH CT
5) HELPS DEFINING THE ROLE OF AIs IN PREMENOPAUSAL PATIENS, TOGETHER WITH THE TEXT TRIAL
OPEN QUESTIONS:
1) PATIENTS RECEIVING CT (higher risk) WITH AMENORRHEA
2) PATIENTS RECOVERING MENSES AFTER 8 MONTHS
3) <35 years AND no need for CT
4) OPTIMAL DURATION OF OFS: are 5 years really necessary ?
Combined analysis TEXT and SOFT Trials:Comparison of Tamoxifen or Exemestane With OFS
Tamoxifen 20 mg/day+ OFS* (n = 1328)
PremenopausalPatients 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
Premenopausalpatients 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 et al, N Engl J Med, 2014
December 5-9, 2017
This presentation is the intellectual property of the IBCSG. Contact [email protected] for permission to reprint and/or distribute.
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
4.0% absolute improvement in 8-yr DFS for E+OFS after 9 years median follow-up
Exemestane With Ovarian Function
Suppression Improves DFS
Pagani et al, N Engl J Med, 2014
Updated analysis: P. Francis and O. Pagani, SABCS 2017
December 5-9, 2017
This presentation is the intellectual property of the IBCSG. Contact [email protected] for permission to reprint and/or distribute.
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
Overall Survival
E+OFS did not improve Overall Survival vs T+OFS, after 9 years median follow-up
Pagani et al, N Engl J Med, 2014
Updated analysis: P. Francis and O. Pagani, SABCS 2017
December 5-9, 2017
This presentation is the intellectual property of the IBCSG. Contact [email protected] for permission to reprint and/or distribute.
2017 SAN ANTONIO BREAST CANCER SYMPOSIUM
INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.
Adverse Events and Treatment Adherence
• Incidence of grade 3-4 targeted AEs was similar in the two groups
(32% and 31%)
• Overall, 15% of patients stopped all protocol-assigned treatment early
More patients on E+OFS stopped assigned oral ET early
• 14% vs 6% by 1 year
• 25% vs 19% by 4 years
No difference in the rate of triptorelin cessation
• 18% vs 19% by 4 years
Pagani et al, N Engl J Med, 2014
Updated analysis: P. Francis and O. Pagani, SABCS 2017
NEOADJUVANT ENDOCRINE THERAPY
Endocrine Therapy Neoadjuvant Clinical Trials (AI vs. Tam)
Drug NClinical
Response
US
Response Increase BCS
P0241
4 months
Letrozole
Tamoxifen
154
170
55%
36%
35%
25%
45%
35%
IMPACT2
3 months
Anastrozole
Tamoxifen
Both
113
108
109
37%
36%
39%
24%
20%
28%
46%
22%
26%
PROACT3
3 months
Anastrozole
Tamoxifen
228
223
50%
46%
40%
35%
38%
30%
P = .022
P = .03
ns
1. Ellis M, et al. Breast Cancer Res Treat. 2007;105(Suppl 1):33-43. 2. Smith IE, et al. J Clin Oncol. 2005;23(22):5108-
5116. 3. Cataliotti L, et al. Cancer. 2006;106(10):2095-2103.
Neoadjuvant Endocrine Therapy (AI vs. AI): ACOSOG Z1031 Trial
ML, marginal for lumpectomy; MO, mastectomy only at baseline
Ellis M, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-2.
CR
CR CR
PR
PR PR ML
ML ML
MO MO MO
Clinical Response, % Breast Conservation, %
Sorlie et al PNAS 2001
Rouzier et al. Clin Cancer Res 2005
pCR% with CT depends on cellular type and on molecular type
N=22
10 pCR (45%)
61 genes signature
N=20
9 pCR (45%)
no signature
identified
N=28
2 pCR
³Exemestane
“Conclusion: Over half of patients become BCS-eligible within 4 months of preoperative letrozole
treatment. While prolonged treatment for up to 8 months can result in further tumor volume
reduction in some patients, there is no clear optimum for treatment duration”1
Duration of Neoadjuvant Endocrine Therapy
²Duration letrozole % CR
3 months 9.5
6 months 29
12 months 36
1. Paepke S, et al. BMC Cancer. 2008;8:62. 2. Renshaw L, et al. Breast Cancer Res Treat. 2004;88(Suppl 1): Abstract
204. 3. Barnadas A, et al. Br J Cancer. 2009;100(3):442-449
¹
Response to treatment as evaluated by mammography.OR, objective response; PD, progressive disease; SD, stable disease.
NEO-ADJUVANT ENDOCRINE THERAPY
Is neoadjuvant endocrine therapy without cytotoxics a reasonable option for postmenopausal patients with endocrine responsive disease? YES 87.9%
If yes, for which duration?
1. 1 – 2 weeks “window” prior to surgery 71%
2. 3 – 4 months 3.6%
3. 4 – 8 months 42.9%
4. Until maximal response 42.9%
9. Abstain 3.6%
Ki67 Changes With Endocrine Neoadjuvant Can Surrogate for Results in Adjuvant?
Drug
Comparison
Neoadjuvant
Trial
Ki67 Results Adjuvant
Trial
Efficacy
Results
Let vs Tam P024
(n = 185)
Mean Ki67 @ 4 mos
RFS L > T
BIG 1-98
(n = 8010)
L > T
Ana vs Tam vs
Tam+Ana
IMPACT
(n = 259)
Mean Ki67 @ 2/12
weeks: RFS A>T or AT
ATAC
(n = 9366)
A > T or
A+T
Ana vs Let vs
Exe
ACOSOG
Z1031
(n = 266)
Mean Ki67 @12-16
weeks. No Diff
MA 27 (n =
7576)
A = E
POTENTIAL PREDICTIVE ROLE OF CHANGE IN Ki67 AFTER NEOADJUVANT ET
PREOPERATIVE ENDOCRINE PROGNOSTIC INDEX (PEPI)
Ellis et al, JNCI 2008
May help decision of adjuvant therapy:
PEPI Group 1 (0): No adjuvant CT needed
PEPI Group 3 (≥4): Adjuvant CT needed
PEPI Group 2 (1-3): unknown
Model built on only 158 pts P024 study
Validated in 203 pts IMPACT study
SOME LUMINAL A TUMORS BECAME LUMINAL B
AFTER NEOADJUVANT AI
Arm IS
U
R
G
E
R
Y
F
O
L
L
O
W
SURGERY
Arm II
Cycle 1 day 2 optional biopsy
(if receiving paclitaxel)
Neoadjuvant Chemotherapy GroupChemotherapy of physician choice
or weekly paclitaxel x 12
R
A
N
D
O
M
I
Z
E
Arm IA x 4.5 yrs
Arm IIF x 1.5 yrs then A x 3 yrs
FOLLOW
AFTER SURGERYTherapy of Physician Choice
Arm III
B
I
O
P
S
YArm III
(A+F) x 1.5 yrs then Ax3 yrs
Modified
PEPI 0Chemo NOT
recommended
Modified
PEPI > 0Chemo
recommended
Endocrine therapy of
Physician’s Choice
F
O
L
L
O
W
Arm I
Arm II
Arm III
Ki67
<10%
Ki67>10%
4w
12 w
B
I
O
P
S
Y
6 cycles (each cycle is 4 weeks)
BEFORE SURGERY AFTER SURGERY
Arm I: Anastrozole (A)
Arm II: Fulvestrant (F)
Arm III: Anastrozole + Fulvestrant
Red: required tissue collection
Blue: optional tissue collection
ALTERNATE Schema (A011106)
R
E
G
I
S
T
R
A
T
I
O
N
Eligibility
Post-menopausal
Clinical Stage II or III
ER+ (Allred 6-8) HER2-
Primary Endpoints:
1st Phase: Modified PEPI 0 rate
2nd Phase: RFS in Modified PEPI 0
Prognosis
Core-
biopsy
(RS,
Ki-67)
Endocrine
therapy3 weeks
Intermediate
RS risk
endocrine
therapy
Response
Surgery /
Core-
biopsy
(RS,
Ki-67)
good proliferation
response (Ki67 ≤10%)
low proliferation
response (Ki67 >10%)
chemotherapy
endocrine therapy
Principal investigators: N. Harbeck (LKP), Munich; U. Nitz, Mönchengladbach
WSG-ADAPT Trial:
HR+ Subprotocol
Hofmann et al, Trials 2013(courtesy Nadia Harbeck)
Neoadjuvant (Ph 2): Adding Everolimus to
Letrozole Improved Response Rates
Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; Ph, phase; RR , response rate; vs, versus.
Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.
Primary endpoint: RR at 16 weeks (palpation)
270 Postmenopausal women with ER+ early BC
Everolimus 10 mg/day +Letrozole 2.5 mg/day
Placebo +Letrozole 2.5 mg/day
Surgery
RANDOMIZE
• Higher RR: 68% vs 59% (P = 0.062)
• Greater antiproliferative response: Ki67 by 57% vs 30% (P < 0.01)
70
neoMONARCH: Phase II study design
Abbreviations: HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; Q12H = every 12 hours; QD = once dailyaParticipants receive loperamide with each dose of abemaciclibbParticipants who experience benefit following 14 weeks may remain on neoadjuvant therapy for up to 8 additional weeks
♦ Abemaciclib 150 mg BID is tolerable
when dosed on a continuous
schedule with endocrine therapy1
♦ The most common adverse event
has been diarrhea
♦ Typically occurred within the
first 7 days of treatment
♦ Manageable with use of
loperamide or dose reduction
♦ Loperamide was administered
prophylactically for the first 28 days
then at discretion of investigator
Post-menopausal women (N=220) HR+, HER2-
breast cancer stage: I (T ≥1 cm), II, IIIA or IIIB
suitable for neoadjuvant endocrine therapy
Primary endpoint:
Compare the change from baseline in Ki67
expression after 2 weeks of therapy
Randomization
Core biopsy at baseline
Core biopsy after 2 weeks of treatment
Abemacicliba 150 mg
Q12HAnastrozole 1 mg QD
Abemacicliba 150 mg Q12H
+ anastrozole 1 mg QD
Core biopsy after 14 weeks of treatmentb
Abemacicliba 150 mg Q12H
+ anastrozole 1 mg QD
Surgery (optional)1Patnaik A et al. Cancer Discovery 2016;6:740-5
*Key inclusion criteria : post menopausal women; ER Allred ≥ 4; not candidate for breast conservation**FNA or biopsy; no SLN allowed***Stratification factors (block permutation): T2 vs T3; Luminal A vs luminal B****Surgery was performed 24h after the last palbociclib dosing
Newly
diagnosed
stage II-III
BC*
Biopsy
ER+, HER2-
Nodal status available**
SU
RG
ER
Y**
**
R***
1 : 1Prosigna
Exclude non luminal
tumors
Luminal A N+
or Luminal B
3 FEC 100 fwd by
3 Docetaxel 100
(q3w)
Letrozole 2.5 mg/day
+ Palbociclib 125
mg/day, 3w/4
19 weeks
Cottu et al, ESMO 2017
LETROZOLE AND PALBOCICLIB VERSUS 3RD GENERATION CHEMOTHERAPY AS NEOADJUVANT TREATMENT OF LUMINAL BREAST CANCER.
RESULTS OF THE UNICANCER - NEOPAL STUDY LORELEI STUDY DESIGN
1:1
Letrozole 2.5 mg QD + taselisib 4 mg (2 x 2 mg tablets)
5 days on/2 days off
Letrozole 2.5 mg QD + placebo
5 days on/2 days off
S
U
R
G
E
R
Y
30-day safety
follow-up,
then investigator’s
choice of:
adjuvant endocrine
therapy and/or
chemotherapy
and/or
radiotherapy
Pre
treatment
Week 3 Week 9 Week 16 Surgery
(Week 17–18)
Tumor tissue
MRI *
Breast U/S
Mammogram
• Untreated
• Postmenopausal
• Estrogen receptor (ER)-
positive/HER2-negative
• Stage I–III operable BC
• ≥ 2 cm tumors by MRI
16 weeks
* MRI @ Week 9: only required if suspicion of progression or if unevaluable by U/S at baseline
KEY INCLUSION CRITERIA:
• Multifocal disease allowed
• Sample for centralized PIK3CA genotyping
• Fasting glucose ≤125 mg/dL
KEY EXCLUSION CRITERIA:
• cT4 or cN3 stage BC
• Bilateral invasive or multicentric BC
• Excisional biopsy of primary tumor and/or sentinel
lymph node biopsy prior to study treatment
• Stage IV BC
STRATIFICATION FACTORS:
• Tumor size (T1–2 vs T3)
• Nodal status
Saura et al, ESMO 2017
OPEN QUESTIONS
• Role of ovarian suppression/ablation for the individual patient: STILL OPEN QUESTION until OS data; Optimal duration of OFS?
• Optimal duration for the individual patient (> 5 years…)
• No predictive markers to discriminate between Tam & AI
• Best strategy for extended adjuvant (10 y Tam; 10 y AI, sequence, “sandwich”, …)
• Resistance!