terapia sistemica adiuvante: quando e quale? 15’...terapia sistemica adiuvante: quando e quale?...
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Terapia sistemica adiuvante: quando e quale?
Carmen Criscitiello, MD, PhD
Istituto Europeo di Oncologia
Milano
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Breast Cancer – Was One Disease, Now Several
Simply “breast cancer”
ER(+), ER (-)
ER(+) HER2(-) ER(-) HER2(+) ER(+) HER2(+) ER(-) HER2(-)
If ER(+) and HER2(-), either: High grade, Low ER level – or
Low grade, High ER level
Multigene Assays Molecular (intrinsic) Subtypes
Whole genome/next gen sequencing
Basal-like
HER2+
Luminal A Luminal B
Normal
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= The right treatment
for the right patient
at the right time “One size fits all”
“The right size for the individual
woman”
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Early
Curable disease
adjuvant therapy
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Triple Neg HER2+ Luminal B
Chemotherapy
Anti-HER2
agents
Subtype driven approach Luminal A
Endocrine therapy
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Triple Neg HER2+ Luminal B
Subtype driven approach Luminal A
Endocrine therapy
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ADJUVANT ENDOCRINE THERAPY IN PREMENOPAUSAL WOMEN
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Tamoxifen for premenopausal pts
• 1980 tamoxifen effective for premenopausal metastatic BC
• 1988 (1st) EBCTCG publication: adjuvant tamoxifen benefit in women > 50 years
• 1998 EBCTCG publication: adjuvant tamoxifen effective in women < 50 yrs with ER+ BC; 5 years better than 2
• 2011 EBCTCG publication: tamoxifen 5 yrs reduced 15-year BC mortality by ~ 1/3 in women < 45 yrs
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[TITLE]
ATLAS: 10 vs 5 years of Tamoxifen (6846 patients)
Davies et al. Lancet 2013
•Gain independent of age (<55 v >55) or nodes
•Reduced overall mortality (639 vs 722 deaths, p=0.01)
•Non-breast cancer deaths nsd (RR 0.99)
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SOFT/TEXT
• SOFT showed:
- DFS benefit with ovarian suppression only in higher risk patients receiving chemotherapy
- Ovarian suppression + AI better, especially in pts under 35
• TEXT confirmed ovarian suppression + AI better DFS than ovarian suppression + Tamoxifen
• But no OS benefit so far
• Adverse QoL issues for many patients, and this requires discussion and choice
Francis et al. NEJM 2015
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ADJUVANT ENDOCRINE THERAPY IN POSTMENOPAUSAL WOMEN
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0 5 2 3 10 Years After Diagnosis
Upfront ATAC, BIG 1-98, ABCSG 12, TEAM
Switch BIG 1-98, IES, ITA, NSAS BC-03, ARNO 95, ABCSG 8
TAM
AIs
AIs
TAM
AIs
Upfront vs switch
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Patient-level meta-analysis of RCTs with endocrine therapy
EBCTCG. Lancet 2015
TAM 5 vs AI 5 TAM 2-3 AI 3-2 vs AI 5
RR=0.90
9.6%
10.7%
Δ 1.1%
RR=0.80
9.0%
12.1%
Δ 3.1%
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ABCSG-6a (856pts)
Tamoxifen + AG Anastrozole
5 years
3 years
Placebo 0.64 0.05
Jakesz et al. J Clin Oncol. 2005
Tamoxifen Exemestane
placebo HR p
0.44 0.004
Mamounas et al. JCO 2008 26
5 years 5 years NSABP-B33 (1598pts)
Extended AIs after 5 yrs TAM significantly reduces recurrences, and likely improve OS
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Extended AIs after AIs: MA.17R Trial
RANDOMIZE
Placebo
4.5-6 yrs of AI
Letrozole
5 yrs
Any duration of prior Tamoxifen
•Any duration of prior TAM •54% N+ •58% Adjuvant chemotherapy
Goss et al, NEJM 2016
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Median FU 6.3 yrs Goss et al, NEJM 2016
Extended AIs after AIs significantly reduces recurrences, but not OS benefit
DFS OS
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Adjuvant Treatment Decision in ER+/HER2- Breast Cancer
Endocrine therapy only
• Low tumor burden • Low tumor grade and Ki67 • Degree of ER/PR expression
• Patient old age • Patient co-morbidities • Patient preference
• High tumor burden • High tumor grade and Ki67 • Degree of ER/PR expression
• Patient young age • Patient good health • Patient preference
Treatment Plan
Chemo + Endocrine therapy
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Multigene expression signatures to forego chemotherapy:
15 years of research efforts!
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TAILORx Methods: Treatment Assignment & Randomization<br />Accrued between April 2006 – October 2010
Sparano et al, NEJM 2018
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Sparano et al, NEJM 2018
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TAILORx Results: Association between Continuous RS 11-25 and 9-Year Distant Recurrence Rate by Treatment Arms Stratified by Age (</=50 vs.>50 Years)<br />
Sparano et al, NEJM 2018
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Triple Neg HER2+ Luminal B
Chemotherapy
Subtype driven approach Luminal A
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Looking for the optimal adjuvant chemotherapy
Blum et al JCO 2017
Joint Analysis of 3 ABC Trials TC vs TaxAC 4242 high risk pts
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ABC trials: IDFS
Blum et al JCO 2017
Δ 2,5%
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Forest plots of IDFS by stratification variables
Blum et al JCO 2017
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St Gallen 2017
28
The role of 5-FU in the adjuvant setting
– 5FU has been a component of adjuvant chemo since the development of CMF
– 2x2 design:
– Primary endpoint: DFS
N=2091 Operable N+
EBC R
dd FEC-Paclitaxel
dd EC-Paclitaxel
3-weekly EC-Paclitaxel
3-weekly FEC-Paclitaxel
Del Mastro et al, Lancet 2015
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St Gallen 2017
29
5-FU: NO improved outcome Toxicity increased
5-year DFS 5-year OS Toxicity
5FU vs no 5FU (HR, 95% CI, p-value)
78% vs 79% (1.06, 0.89-1.25; p=0.561)
91% vs 92% (1.16, 0.91-1.46; p=0.234)
More G3-4 neutropenia, fever, nausea and vomiting with 5FU
So why are we still using it?
Del Mastro et al, Lancet 2015
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• In patients who can tolerate it, use of a regimen containing anthracycline-taxane is considered the optimal strategy for adjuvant chemotherapy, particularly for patients deemed to be at high risk.
Denduluri N JCO 2016
Selection of optimal adjuvant chemotherapy
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910 HER2- pts with RD and N+ after neoadjuvant chemotherapy
Masuda, et al. NEJM 2017
Adding capecitabine in TNBC?
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Triple Neg HER2+ Luminal B
Chemotherapy
Anti-HER2
agents
Subtype driven approach Luminal A
Endocrine therapy
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34
34
Overall benefit by «add-on» strategy with:
Anthracyclines Taxanes
Trastuzumab +/- Endocrine Therapy
Clinical need for improvement
Trastuzumab + chemotherapy
Perez EA JCO 2014
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Esclation attempts
35
35
Pertuzumab? Lapatinib? Neratinib?
Perez EA JCO 2014
Clinical need for improvement
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APHINITY trial
von Minckwitz G et al, NEJM 2017
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APHINITY: Intent-to-Treat Primary Endpoint Analysis <br /> Invasive Disease-free Survival
APHINITY trial: ITT IDFS
von Minckwitz G et al, NEJM 2017
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Pertuzumab-trastuzumab
(n = 1503)
Placebo– trastuzumab
(n = 1502)
Events, n (%) 139 (9.2) 181 (12.1)
Unstratified HR (95% CI) 0.77 (0.62, 0.96)
Descriptive p value 0.02
Pertuzumab-trastuzumab
(n = 864)
Placebo– trastuzumab
(n = 858)
Events, n (%) 71 (8.2) 91 (10.6)
Unstratified HR (95% CI) 0.76 (0.56, 1.04)
Descriptive p value 0.085
N+ subgroup (n = 3005)
HR- subgroup (n = 1722)
Time (months)
IDFS
(
pro
po
rtio
n e
ven
t-fr
ee)
0 6 12 18 24 30 36 42 48
0.2
0.0
1.0
0.6
0.8
0.4
Time (months) ID
FS
(p
rop
ort
ion
eve
nt-
fre
e)
0 6 12 18 24 30 36 42 48
0.2
0.0
1.0
0.6
0.8
0.4
90.2% 92.0%
3 years 4 years
86.7% 89.9% 93.7%
94.9% 98.2% 98.1%
1 year 2 years
91.2% 92.8%
3 years 4 years
88.7% 91.0% 93.7%
96.2% 97.9% 98.1%
1 year 2 years
Who may derive more benefit from adjuvant pertuzumab?
von Minckwitz G et al, NEJM 2017
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Neratinib in high risk early BC?
39
Chan A SABCS 2015
Δ 2.1%
5 years
Δ 2.5%
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Who may derive more benefit from neratinib?
40
Δ 4.3% Δ -0.7%
Chan A SABCS 2015
5 years
Δ 4.4%
5 years
Δ 0%
Martin M ESMO 2017
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AVOID UNDUE OVERTREATMENT
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De-escalation attempts: APT trial
Tolaney SM et al. N Engl J Med 2015
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
H
Pac
Paclitaxel (80 mg/m2) + Herceptin (2 mg/kg) x 12 weeks (q1w)
N = 406
• HER2-positive
• ER+ or ER–
• Node-negative tumour ≤3 cm
Primary endpoint:
IDFS
H H H H H H H H H H H H H
q3w doses of Herceptin (6 mg/kg) x 13
Total 18 cycles of Herceptin
Overall IDFS at 3 years: 98.7%
(95% CI = 97.6, 99.8)
7 years: 93.3%
(95% CI = 90.4, 96.2)
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Is medicine art or science?
“If it were not for the great variability among individuals,
medicine might have well been a science and not an art”
Sir William Osler (1849 –1919)
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Thank you