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Current standards and practice changing studies in Early Breast Cancer in 2018
F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal
ESMO Board of Directors & Membership DirectorABC Global Alliance Chair
DISCLOSURES
Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics, Teva.
Institutional financial support for clinical trials from: Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi, Eisai, Fresenius GmbH, Genentech, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Tigris, Wilex, Wyeth.
Non-Financial disclosures: Chair ABC Global Alliance and ABC Consensus Conference and Guidelines. Member/Committee Member of ESMO, ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC
Bray et al, CA Cancer J Clin 2018;0:9–31; Globocan 2018
CANCER AS CAUSE OF DEATH
Bray et al, CA Cancer J Clin 2018;0:9–31Globcan 2018
CANCER IN WOMEN – Incidence and Mortality
GLOBOCAN 2018*
Incidence
Mortality
5-year Prevalence
BREAST CANCER WORLDWIDE
* Bray F et al. Global cancer statistics 2018: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018.
GLOBOCAN 2018*
5-year Prevalence
BREAST CANCER IN AFRICA
* Bray F et al. Global cancer statistics 2018: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018.
Incidence
Mortality
EBC OUTCOME EVOLUTION
Breast Cancer
Despite ↑ incidence - ↓ mortality
* Screening & early diagnosis
* Education & advocacy
but also
* Better treatment options
* Better treatment strategies
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
Is the difference between the curves clinically significant?
89.8%
89.4%
DFS Absolute difference 0.4%
96.1%
95.7%
Invasive DFS Absolute difference 2.3%
CLINICOPATHOLOGICAL PROGNOSTIC FACTORS IN EBC
• Tumor size
• Lymph node status
• Grade
• ER, PR and HER-2 receptor expression
• Presence of lymphovascular invasion
PROGNOSTIC VALUE OF BC MOLECULAR SUBTYPES
IHC TRANSLATION OF MOLECULAR CLASSIFICATION
ER/PR HER2 PCAD CK5 EGFR CK14
LUMINAL A
LUMINAL B
HER 2 OE
BASAL
Courtesy of MJ Brito
PROGNOSTIC VALUE OF SUBTYPES IHC SURROGATES
Dent et al, Clin Cancer Res, 2007
CRUCIAL ROLE OF HIGH QUALITY PATHOLOGY(and also cost-effective!)
8th Edition AJCC: ANATOMIC and PROGNOSTIC STAGGING
7th
Edition Stage
Tumor Size
Nodal Involvement
Metastasis
13
8th Edition Prognostic
Stage Group
Tumor Size
Nodal Involvement
Metastasis
ER/PR/HER2
Tumor Grade
Low risk GES
2010-2017 2018 and beyond
WHO NEEDS TREATMENT? WHICH TREATMENT IS BEST?
TREATMENT CHOICES
AVOID UNDER AND OVER TREATMENT INDIVIDUALIZE TREATMENT
2 MAIN QUESTIONS NEEDED TO BE ANSWERED
New/better PROGNOSTIC FACTORS New/better PREDICTIVE FACTORS
HER2
Negative predictive value
(<5% chance to respond to anti-estrogens or trastuzumab)
HIGH 95%
Positive predictive value
30-50%
Breast Cancer
ER/PGR
VALIDATED PREDICTIVE MARKERS
Cut off 1%
Courtesy F. Penault-Llorca
IHC Algorithm
When to question a Pathology report… according to Frédérique Penault-Llorca
• PgR+, ER-
• Lobular, tubular carcinoma HER2+
• Grade 1, ER+++, PgR+++, HER2+
• Grade 3, ER-, ki67 <5%
• Grade 3 ER+++, PgR+++
• Medullary carcinoma is extremely rare and has been removed from WHO classification
May redo HER2 (and ER) on surgical specimen if grade 3, ER- or ER+
If ER and/or PgR is negative on a biopsy redo on surgical specimen
MULTIDISCIPLINARY CARE IS CRUCIAL!
EARLY BREAST CANCER: WHO NEEDS ADJUVANT CT?
Bedard & Cardoso, Nat. Rev. Clin. Oncol. 8, 272–279 (2011)
• CLINICAL/PATHOLOGICAL/GENOMIC FACTORS ARE BEST USED IN COMBINATION.
• Responsiveness is a continuum.• PATIENT PREFERENCE!
TAILORx Methods: Treatment Assignment & RandomizationAccrued between April 2006 – October 2010
Preregister – Oncotype DX RS (N=11,232)
Register (N=10,273)
ARM A: Low RS 0-10
(N=1629 evaluable)
ASSIGN
Endocrine Therapy (ET)
Mid-Range RS 11-25
(N=6711 evaluable)
RANDOMIZEStratification Factors: Menopausal
Status, Planned Chemotherapy, Planned Radiation, and RS 11-15, 16-20, 21-25
ARM B: Experimental Arm
(N=3399)
ET Alone
ARM C: Standard Arm
(N=3312)
Chemo and ET
ARM D: High RS 26-100
(N=1389 evaluable)
ASSIGN
Chemo and ET
Joseph A. Sparano, MD
2
0
TAILORx Results - ITT Population: All Arms (A,B,C & D)
IDFS
P<0.001
Joseph A. Sparano, MD
RS 0-10: Assigned to ET Alone
RS 11-25: Randomized to ET Alone
RS 11-25: Randomized to CHEMO + ET
RS 25-100: Assigned to CHEMO + ET
9-Year Event Rates
• RS 0-10 (Arm A)
• 3% distant recurrence with ET
alone
• RS 11-25 (Arms B & C)
• 5% distant recurrence rate overall
• < 1% difference for all endpoints
• IDFS (83.3 vs. 84.3%)
• DRFI (94.5 vs. 95.0%)
• RFI (92.2 vs. 92.9%)
• OS (93.9 vs. 93.8%)
• RS 26-100 (Arm D)
• 13% distant recurrence despite
chemo + ET
GENOMIC TESTS IN ALL OR ONLY SELECTED BREAST CANCER CASES?
TRIPLE NEGATIVE(ER-, PR-, HER-2 neg)
CT indispensible
HER-2 POSITIVE
CT + anti-HERindispensible
LUMINALER+ HER-2 neg
“Clear” indication from classical factors
All LOW risk: high levels ER, PR, grade 1, node
negative, low proliferation
HT alone
All HIGH risk: low levels ER, PR, grade 3, node
positive, high proliferation
CT HT
“No Clear” indication from classical factors; some high
& some low risk
GENOMIC TEST
CRUCIAL IMPORTANCE OF HIGH QUALITY PATHOLOGY
Practical use of Mammaprint® in the clinic based on evidence from the MINDACT trial
HR+ tumor:Define clinical risk
Clinical “low” risk* Clinical “high” risk
Treatment according to guidelines
Discuss with patient if she would value a 1.5% gain in DMFS with adjuvant chemotherapy
No
Order Mammaprint
Yes
Proceed with chemotherapy
Courtesy M. Piccart
PREOPERATIVE CHEMOTHERAPY IN BCHISTORICAL PERSPECTIVE
1970 1980 1990 2000
Locally advanced
Early Early Early
GOAL
DISEASE
Local control Rate of breastconservation
Survival Treatment tailoring
ACHIEVED NO DIFFERENCEACHIEVED ONGOING
Adapted from M. Piccart
EBCTCG Neoadjuvant vs Adjuvant CT. Lancet Oncology 2017
Substantially higher frequency of BCS with
neoadjuvant
Association between pCR and EFS by BC subtype
Cortazar P et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBCpooled analysis. Lancet. 2014
The magnitude of improvement in pCR ratedid not predict EFS and OS effect
Cortazar P et al. Pathological complete response and long-term clinical
benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014
Efficacy of adjuvant CT compared with no CT
Risk of recurrence Breast cancer mortality Overall mortality
Anthracycline based regimen vs no CT
RR:0.73, 95%CI
Absolute gain: 8%
RR:0.79, 95%CI
Absolute gain: 6.5%
RR:0.84, 95%CI
Absolute gain: 5%
CMF regimen vs no CT
RR:0.70, 95%CI
Absolute gain: 10.2%
RR:0.76, 95%CI
Absolute gain: 6.2%
RR:0.84, 95%CI
Absolute gain: 4.7%
Messages from the EBCTCG overview & individual trials
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
EBCTCG 2005-06 Overview Peto SABCS 2007
10
0 5 10 0 5 10 0 5 10
50
0
40
30
20
Anthra
31.0%
Taxane
25.9%
%
+ SE
15.3
12.8
YearsYearsYears
CMF
31.3%
Anthra
27.0%
Control
36.4%
CMF
32.2%
20.5
17.8
19.9
16.5
Taxanes > Anthra > CMF > No Chemo
4.2%
4.3% 5.1%
WHICH TYPE OF CHEMOTHERAPY?
TAKE-HOME MESSAGES REGARDING (NEO)ADJUVANT CT
• For TNBC and HER-2+ Anthracyclines and Taxanes, in a sequentialregimen, are the standard.
• For Luminal A with high burden of disease justifying CT, probably it does not matter which regimen is chosen
• For Luminal B, depends on burden of disease: high burden: Anthracyclines and Taxanes: Low burden: probably ok to omit A
• Important to consider:• Long term toxicity of only 3 to 4 cycles of A is lower than the
“old” 6 cycles of FEC/FAC• No need to use 5-FU (LoE 1A)
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
AI vs. TAM
Switch AI after TAMvs. TAM
Adjuvant Aromatase Inhibitors: A meta-analysis
Dowsett M et al., J Clin Oncol 2010
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
N Engl J Med 2017;377:1836-46
Courtesy M. Gnant, SABCS 2016
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)
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
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 ?
5) WILL RESULTS CHANGE WITH LONGER FU (ER+ disease); NEED FOR OS RESULTS
TAKE HOME MESSAGES and OPEN QUESTIONS regarding ADJUVANT ET
• Ovarian suppression/ablation is indicated in pts with high risk of recurrence needing CT and recovering menses after CT. Reserve AI+OFS to very high risk only
(toxicity!)
• Decision for the individual patient still difficult; optimal duration unknown
• 5 years is the minimal duration for all patients. In pts with “sufficiently high risk” consider extended adjuvant
• Optimal duration for the individual patient is unknown; Best strategy for extended adjuvant (10 y Tam; 10 y AI, sequence, “sandwich”, …) is unknown
• TAMOXIFEN is essential. AIs provide a small additional benefit and different toxicity profile
•No predictive markers to discriminate between Tam & AI
HR
210
0.63
0.66
0.59
0.66
0.41
1.27
3.2%
2.7%*
6%
5%
6.6%*
Difference at
4y/3ya
–1.5%
3
Median
FU yrs
3
3
2
3
p
0.004
0.017
0.0115
0.07
n.s.
* Benefit at
3 y
4
Favours trastuzumab Favours chemotherapy only
Combined US (n=3969)b
HERA (n=3401)
BCIRG AC-DT (n=1074)
BCIRG DCarboT (n=1075)
FinHER (n=232)
PACS-04 (n=528)
Reference
Smith 2007
Slamon 2006
Joensuu 2006
Spielmann 2007
0.0004
aAbsolute difference in percentage of patients with OS at 4 or 3 yearsbCombined US: Joint analysis of NSABP B-31 and NCCTG N9831
Perez 2007
*Benefit at 3y
Adjuvant chemotherapy ± trastuzumab
trials: overall survival
Slamon 2006
REDUCTION IN MORTALITY RISK: 34%-59% IN EBC
COST TRASTUZUMAB: 2.300 €/cycle (s.c T)
MCBS: A
TRIALS EVALUATING ADJUVANT TRASTUZUMAB DURATION
1 vs. 2 years: HERA
9 weeks: FinHER (Finland)
1 year vs. 3 ms: E 2198 (US)
1 year vs. 9 weeks: ShortHER
1 year vs. 9 weeks: SOLD
1 year vs. 6 ms: PHARE (France)
1 year vs. 6 ms: HeCOG (Greece)
1 year vs. 6 ms: Persephone (UK)
Prof Helena Earl MD PhD
https://warwick.ac.uk/fac/med/research/ctu/trials/cancer/per
sephone
Persephone Study Design
4
4
1O : DFS [Diagnosis to 1st relapse (local or distant) or death]
2O :OS ; Cost effectiveness ; Cardiac function
4000 patients
DFS
Treatment delay due to cardiotoxicity: 6% (12m) vs 4% (6m), p=0.01 Treatment stopped due to cardiotoxicity: 8% (12m) vs 4% (6m), p<0.0001) Cardiac function recovers pós trastuzumab; 6m patients had a faster recovery
(p=0.02)
Persephone study
OS
TAKE HOME MESSAGES
Duration of adjuvant trastuzumab: 1 YEAR IS STILL THE STANDARD
In total about 15.000 pts enrolled to answer duration question!Really needed? Can we be smarter in trial design?
If we had done 1 trial but sufficiently powered?
BUT: PHERSEPHONE results demand discussion of shorter duration in “low risk” patients
Open questions: De-escalate anti-HER2 therapy or CT or both?How to define “low risk HER2+ BC”?Can we find a biomarker to help with the decision?
TRIALS EVALUATING DUAL HER2 BLOCKADE
Advanced DiseaseEGF104900
Cleopatra PERUSE
PHEREXA
NeoSPHERE TRYPHAENAWSG-ADAPT
KRISTINE
NeoALTTOCherlob
LPT 109096 NSABP B-41
CALGB 40601
Neoadjuvant setting
ALTTO APHINITY Adjuvant setting
STRATEGY A STRATEGY B
Alvaro Moreno-Aspitia et al, ASCO 2017
Presented by:
DISEASE-FREE SURVIVAL (DFS) ANALYSIS
*Bracketed data in all KM curves represent results of the Primary Analysis – ASCO 2014
*
Alvaro Moreno-Aspitia et al, ASCO 2017
Absolute difference: 2 to 3%
Presented by:
OVERALL SURVIVAL (OS) ANALYSIS
Alvaro Moreno-Aspitia et al, ASCO 2017
DUAL BLOCKADE COST: 5.800 €/cycle
MCBS: No Evaluable Benefit
COST LAPATINIB: 3.500 €/cycle
ALTTO trial
49The slides are the property of BIG. Permission required for reuse
63The slides are the property of BIG. Permission required for reuse
APHINITY: Trial Design
Chemotherapy* + trastuzumab+ placebo
Chemotherapy* + trastuzumab+ pertuzumab
Randomisation and treatmentwithin 8 weeks of surgery
Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)
Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy
Central confirmation
of HER2 status(N = 4805)
FOLLOW-UP
10
YEARS
R
S
U
R
G
E
R
Y
*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed
G. von Minckwitz et al, ASCO 2017, NEJM 2017
75The slides are the property of BIG. Permission required for reuse
A HINIT Intent to Treat rimary Endpoint Analysis Invasive isease free urvival
Number needed to treat: 112
expected: 89.2%
G. von Minckwitz et al, ASCO 2017, NEJM 2017
Absolute difference: 2 %
APHINITY trial
DUAL BLOCKADE COST: 6.400 €/cycle
MCBS: Afor Node+ or ER neg
COST PERTUZUMAB: 4.100 €/cycle
53The slides are the property of BIG. Permission required for reuse
APHINITY: Node-positive Subgroup
Number needed to treat: 56
G. von Minckwitz et al, ASCO 2017
G. von Minckwitz et al, ASCO 2017, NEJM 2017
Absolute difference: 3 %
56The slides are the property of BIG. Permission required for reuse
APHINITY: Hormone Receptor-negative Subgroup
Number needed to treat: 63
G. von Minckwitz et al, ASCO 2017
Absolute difference: 3 %
De-Escalation
Tolaney S, NEJM 2015
Timing of Distant Recurrences in relation to Adjuvant Trastuzumab
Romond EH, N Engl J Med 2005; 353:1673-1684. NSABP B-31 and NCCTG N9831
< 2% of patients relapse on adjuvant trastuzumab
and < 5% in the year following
Courtesy G. Curigliano
HR (95% CI) = 0.73 (0.57–0.92)Two-sided P = 0.008
Intention-to-treat population. Cut-off date: March 1, 2017
NeratinibPlacebo
50
60
70
80
90
0 6 12 18 24 30 36 42 48 54 60
No. at risk Neratinib Placebo
1420 1420
1316 1354
1272 1298
1225 1248
1106 1142
978 1029
965 1011
949 991
938 978
920 958
885 927
Months after randomization
Inva
sive
dis
ease
-fre
e s
urv
ival
(%
)100
95.5%∆ 2.4%
97.9%
91.7%∆ 2.6%
94.3%
90.2%∆ 2.0%
92.2%
89.1%
∆ 2.1%
91.2%
87.7%∆ 2.5%
90.2%
0
Treatment
ExteNET: 5-year analysis: iDFS
M. Martin et al, ESMO 2017
Absolute difference: 3.5 %
ExteNET: Side Effects
Chan i wsp. Abst.508
N % Neratinib (n=14080) Placebo (n=1408)
All grades G3-4 All grades G3-4
Diarrhea 1343 (95.4) 562 (39,9) 499 (35,4) 23 (1,6)
Dose reduction: 26%
Tx termination: 17%
What does G 3 diarrhea mean ?- > 7 stools daily- incontinence;
-hospitalization indicated- limiting self care ADL
Courtesy of Dr Aleksandra Łacko
NEWER NEOADJUVANT TRIALS IN HER-2+ EBC
Trying to differentiate HER2+/ER+ from HER2+/ER neg
The biological complexity of HER2+ breast cancer
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
HER2+ tumor cells features
TCGA Nature 2012
HER2+ disease today
HER2 +3 HER2 ISH+
ER-positive ER-negative
Courtesy of Dr. Pedro Fernández
HER2+ tumor microenviroment
Tumor Infiltrating
Lymphocytes(TILs)
Courtesy Aleix Prat, EBCC 11
pCR by Central ER/PR Receptor Status
Presented by:
pC
R(%
)a
ER and PR negative ER and/or PR positive
60/82 45/83 56/128 46/131
TCH+P T-DM1+P TCH+P T-DM1+P
aypT0/is, ypN0; patients with missing or unevaluable pCR status were considered nonresponders. Twenty patients had “unknown” ER/PR status by
central analysis.
Difference (95% CI):
−19.0 (−33.3, −4.6)
Difference (95% CI):
−8.6 (−20.5, 3.2)
73%
54%
44%35%
KRISTINE
ADAPT HER2+/HR+ Trial
ar eck et al. A C 2015. A stract 5 0 .
Outcome, n/N (%) T-DM1 T-DM1 + ETTrastuzumab +
ET
pCR (ypT0 or ypT0/is, ypN0) All pts* Premenopausal
women Postmenopausal
women
48/117 (41.0)22/58 (37.9)26/59 (44.1)
51/123 (41.5)24/63 (38.1)27/60 (45.0)
18/119 (15.1)8/59 (13.6)
10/60 (16.7)
Near pCR (ypT1a) 14/117 (12.0) 14/123 (11.4) 5/119 (4.2)
Early response†
Nonresponders Responders
9/36 (25.0)24/61 (39.3)
6/25 (24.0)36/76 (47.4)
5/40 (12.5)11/62 (17.7)
*P < .001 for comparison between each T-DM1 arm vs trastuzumab + ET.†Low cellularity (< 500 tumor cells) or Ki67 decline ≥ 0%in -wk biopsy.
THE ROLE OF T-DM1 IN EBC(neoadjuvant)
• Similar pCR rates with T-DM1 alone or with T-DM1 + Pertuzumab
• In line with Marianne in ABC HER2+• Why dual blockade with T-DM1 + P
does not seem to work??!
• Good pCR in Triple + EBC
San Antonio Breast Cancer Symposium December 4–8, 2018
KATHERINE Study Design
This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at [email protected] for permission to reprint and/or distribute.
cT1-4/N0-3/M0 at presentation (cT1a-b/N0 excluded)
Centrally confirmed HER2-positive breast cancer
Neoadjuvant therapy must have consisted of
– Minimum of 6 cycles of chemotherapy
• Minimum of 9 weeks of taxane
• Anthracyclines and alkylating agents allowed
• All chemotherapy prior to surgery
– Minimum of 9 weeks of trastuzumab
• Second HER2-targeted agent allowed
Residual invasive tumor in breast or axillary nodes
Randomization within 12 weeks of surgery
Stratification factors:
Clinical presentation: Inoperable (stage cT4 or cN2–3) vs operable (stages cT1-3N0-1)
Hormone receptor: ER or PR positive vs ER negative and PR negative/unknown
Preoperative therapy: Trastuzumab vs trastuzumab plus other HER2-targeted therapy
Pathological nodal status after neoadjuvant therapy: Positive vs negative/not done
T-DM1
3.6 mg/kg IV Q3W
14 cycles
Trastuzumab
6 mg/kg IV Q3W
14 cycles
Radiation and endocrine therapy per protocol and local guidelines
R
1:1
N=1486
THE ROLE OF T-DM1 IN EBC(post-neoadjuvant)
San Antonio Breast Cancer Symposium December 4–8, 2018
Invasive Disease-Free Survival
This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at [email protected] for permission to reprint and/or distribute.
100
80
60
40
20
0
743
743
No. at Risk
Trastuzumab
T-DM1676
707
635
681
594
658
555
633
501
561
342
409
220
255
119
142
38
44
4
4
0 6 12 18 24 30
Time (months)
Invasiv
e D
isease
-Fre
e S
urv
ival R
ate
(%
)
36 42 48 54 60
Trastuzumab
T-DM1
3-year IDFS 77.0% 88.3%
Trastuzumab T-DM1
(n=743) (n=743)
IDFS Events, no. (%) 165 (22.2) 91 (12.2)
P<0.0001
Unstratified HR=0.50 (95% CI, 0.39–0.64)
San Antonio Breast Cancer Symposium December 4–8, 2018
Distant Recurrence
This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at [email protected] for permission to reprint and/or distribute.
743
743
No. at Risk
Trastuzumab
T-DM1679
707
643
682
609
661
577
636
520
564
359
412
233
254
126
143
41
45
4
4
Dis
tant
Re
curr
ence-F
ree R
ate
(%
)
Trastuzumab
T-DM1
Trastuzumab T-DM1
(n=743) (n=743)
Events, no. (%) 121 (16.3) 78 (10.5)
Unstratified HR=0.60 (95% CI, 0.45–0.79)
3-year event-free rate 83.0% 89.7%
100
80
60
40
20
0
0 6 12 18 24 30
Time (months)
36 42 48 54 60
THE ROLE OF T-DM1 IN EBC(post-neoadjuvant)
MAIN PROBLEM:COST!!
Absolute difference: 11% in iDFS
Biosimilar trastuzumab in Phase 3 clinical trials: setting and primary endpoint
*Non-inferiority margin. NA, not available
1. Amgen press release. June 2016. Available at: http://www.amgen.com/media/news-releases; 2. NCT01901146. Available at:
https://clinicaltrials.gov/ct2/show/NCT01901146; 3. Shustova M, et al. Ann Oncol 2016;27(Suppl 6):vi68–vi99; 4. Im Y-H, et al. ASCO 2013; Abstract and poster
presentation 629; 5. NCT02162667. Available at: https://clinicaltrials.gov/ct2/show/NCT02162667; 6. Rugo HS, et al. JAMA 2017;317:37–47;
7. NCT02149524. Available at: https://clinicaltrials.gov/ct2/show/NCT02149524; 8. NCT01989676. Available at: https://clinicaltrials.gov/ct2/show/NCT01989676;
9. NCT02187744. Available at: https://clinicaltrials.gov/ct2/show/NCT02187744. All websites accessed March 2017.
Trastuzumab
biosimilarPatients Setting Primary endpoint Equivalence margins
ABP 9801,2 827Neoadjuvant + adjuvant in
EBC (includes switch)pCR (breast + lymph)
EMA: -13%, 13% with 90% CI for pCR
difference
FDA: 0.758 to 1.318 with a 90% CI for pCR
ratio
BCD-0223 126 MBC ORR -20%* with 95% CI for ORR difference
CT-P64 475 MBC ORR-15%, +15% with 95% CI for
ORR difference
CT-P65 562Neoadjuvant + adjuvant in
EBCpCR (breast + lymph) NA
MYL-1401O6 500 MBC ORR at Week 24
EMA: -15%, 15% with 95% CI for
ORR difference
FDA: 0.81 to 1.24 with a 90% CI for ORR ratio
SB37 806 Neoadjuvant in EBC pCR (breast only) NA
PF-052800148 690 MBC ORR NA
PF-052800149 226 Neoadjuvant in EBC Powered for PK endpoints NA
Courtesy M. Thill
TAKE HOME MESSAGES regarding HER2+ EBC
• Trastuzumab is life-saving and has changed the natural history of HER2+ EBC! (should be the focus of lobbying/pressure for access)
• Dual blockage with Pertuzumab adds only a small benefit in Node + or ER negative disease.
• Lapatinib not useful. Neratinib too toxic and small benefit.
• T-DM1 role is post-neoadjuvant is interesting (but expensive!)
• Open questions:•Role of 2 anti-HER-2 agents alone (with no CT)?•Resistance•Biomarkers to decide for dual-blockade
• Expensive medicines are not the priority! Except TRASTUZUMAB, which is now an WHO essential medicine
• FOCUS ON:
• EARLY DETECTION / EDUCATION / AWARENESS
• MULTIDISCIPLINARY CARE
• QUALITY PATHOLOGY
• ACCESS TO RADIOTHERAPY (no RT – BCS very, very difficult)
• BIOSIMILARS and GENERICS (if approved and high-quality)
• FIGHT FOR TRASTUZUMAB
• FOCUS ON TAMOXIFEN, ANTHRACYCLINES, TAXANES
• ON’T WA TE RE OURCE on “fashionable things”
TAKE-HOME MESSAGES
Is the difference between the curves clinically significant?
89.8%
89.4%
DFS Absolute difference 0.4%
96.1%
95.7%
Invasive DFS Absolute difference 2.3%
PERSEPHONE
APHINITY
THANK YOU! OBRIGADA!
Breast Unit
BACK-UP
Superiority of (some) A-based regimens over CMF
WHICH TYPE OF CHEMOTHERAPY?
Messages from the EBCTCG overview & individual trials
EBCTCG Overview – Anthracyclines versus CMFStandard strenght anthracycline–based regimen vs standard or near-standard CMF
Recurrence RR: 0.89 (P=0.003)
BC Mortalitiy RR: 0.80 (P=0.00001)
Overall mortality RR: 0.84
(P=0.0002)
Low strenght anthracycline–based regimen vs standard or near-standard CMF
Recurrence RR: 0.99 (P=0.76)
BC Mortalitiy RR: 0.98 (P=0.67)
Overall mortality RR: 0.97
(P=0.55)
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
Superiority of A & T-containing regimens over those A-based
WHICH TYPE OF CHEMOTHERAPY?Messages from the EBCTCG overview & individual trials
EBCTCG Overview – Taxane-plus-anthracycline versus anthracycline based regimenResults for all trials that test taxane effect (n = 44,000)
Distant Recurrence RR: 0.87Any recurrence RR:0,86, (P=0.00001)
BC Mortality RR: 0.87 (P=0.00001)Other mortality RR:0.99
Overall mortality RR: 0.89 (P=0.0001)
Unconfounded trials*(taxane vs control group)
8-y Recurrence: 30.2% vs 34.8% (absolute gain 4.6%)
8-y BC Mortality: 21.1% vs 23.9% (absolute gain 2.8%)
8-y Overall mortality 23.5% vs 26.7% (absolute gain 3.2%)
Counfounded trials*(taxane vs control group)
8-y Recurrence: 19.2% vs 22% (absolute gain 2.9%)
8-y BC Mortality: 10.1% vs 11.5% (absolute gain 1.4%)
8-y Overall mortality 11.2% vs 12.4% (absolute gain 1.2%)
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
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
Efficacy of Extended Adjuvant Strategies
Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book
Study Treatment arms/Population (n)
MedianFU
Recurrence Mortality
ATLAS TAM 5y vs TAM 10y3428/ 3418
NR RR=0·90 (95% CI 0.79–1·02) 5-9yRR=0·75 (95% CI 0·62–0·90) laterRR 0·84, 95% CI 0·76–0·94;p=0·002in ER+
RR=0.97 (95% CI 0·79–1·18) 5–9 yRR= 0·71 (95% CI 0·58–0·88) later639 deaths vs 722 deaths, p=0·01 in ER+
NSABP-B14
TAM 5y vs TAM >5y579/ 593
7 y DFS = 82% TAM 5y vs 78% TAM >5y
p= .03
OS7Y = 94% TAM 5y vs 91% TAM >5y; p= .07
aTTOM TAM 5y vs TAM 10y6,934
4.2 y 415 vs 442 recurrencesRR=0.94 (95% CI 0.81–1.09); p=0.4
NA
MA.17 TAM 5y followed LET 5y vs TAM 5y2594/ 2593
30 ms HR= 0·58 (95% CI 0·45–0·76)p <.001
HR=0·82(95% CI 0·57–1.19)p =0.03
NSABP-
B33
TAM 5y followed EXE 5y vs TAM 5y
779/ 786
30 ms DFS 4y 91% v 89%RR=0·68 (p=0·07)
16 deaths vs 13 p =0.1
ABCSG-6a TAM 5y followed ANA 3y vs TAM 5y
469/ 387
62 ms HR= 0·62 (95% CI 0·40–0·96)p=0.031
HR= 0·89 (95% CI 0·59–1·34)p=0.57