prospettive per l’adiuvante · triple negative breast cancer (tnbc) definition: –lack of...
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Prospettive per l’adiuvante
nel
Triple Negative
Grazia Arpino
Università Federico II,
Napoli
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Triple negative breast cancer (TNBC) definition:
– lack of expression of estrogen receptor and progesterone receptor
HER2 not overexpressed/amplified
10-20% of all breast cancers
TNBC includes rare histologies
Metaplastic, medullary, adenoid cystic carcinoma
High cell proliferation, poor cellular differentiation, many recurrent copy
number imbalances, and mutations in the TP53
TNBC- Epidemiology
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Associations between TNBC and gBRCA
Presented By Rebecca Dent at 2017 ASCO Annual Meeting
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Hazard rates of progression and death: TNBC
vs. Others
Liedtke C, et al., J Clin Oncol 2008;26;1275–81.
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British Columbia Cancer Agency stage I-III BC (7,178 patients)
1,132 (15.8%) patients with ER neg and HER2 neg BC
Cohort 1: 1986 - 1992 Cohort 2: 2004 - 2008
PROGRESS IN ADJUVANT CT: EFFECT FOR
TNBC
Cossetti RJD, et al., J Clin Oncol 2015;33:65–73.
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Adjuvant therapy in TNBC-Outline
• Small Tumor
• Addition of Taxanes
• High Dose Chemotherapy
• PARPi: narrowing target population to BRCA+
• Timing of chemotherapy
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Benefit from CTin TNBC
63%[43-76]
59%[34-74]
32%[-7-56]
ER neg
ER pos80%
60%
40%
20%
Recurrence
18%[-41-25]
Death
Adjusted for:
# pos nodes tumor size
menopausal status
Berry et al,
JAMA2005
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ADJUVANT CHEMOTHERAPY FOR PATIENTS WITH SMALL
TNBC
No chemotherapy Chemotherapy
5yrs DFS T1a: 96%
T1b: 93%
5yrs DFS T1a: 100%
T1b: 96%
Vaz-Luis I, et al., J Clin Oncol 2014;32:2142–50.
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Options for Stage I Disease
• Chemotherapy treatment options for lowrisk
disease:– 1) simple regimen (AC, TC,CMF)
– 2) sequential anthracycline/taxane
Enthusiasmfor
Chemotherapy
PossibleRegimens
Microinvasiononly Virtually none ---
T1a Low to moderate Simple
T1b Moderate to high Simple
T1c High Simple or selectively
sequentialapproach
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Adjuvant therapy in TNBC-Outline
• Small Tumor
• Addition of Taxanes
• High Dose Chemotherapy
• PARPi: narrowing target population to BRCA+
• Timing of chemotherapy
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CALGB 9344: AC x 4 ±Paclitaxel x 4 Outcomes
for Subtypes
Hayes D et al. N Engl J Med 2007;357:1496-1506
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BCIRG 001: TAC vsFAC
Outcome for Subtypes
Hugh J et al. JCO 2009;27:1168-1176
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GEICAM 9906: FEC vs FEC/P Outcomes by Subtypes
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Adjuvant therapy in TNBC-Outline
• Small Tumor
• Addition of Taxanes
• High Dose Chemotherapy
• PARPi: narrowing target population to BRCA+
• Timing of chemotherapy
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NSABPB-30. AC4-T4 vs TAC4 vs AT4
Overall Survival and Disease-free Survival.
Swain SM et al. N Engl J Med2010;362:2053-2065.
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Swain SM et al. N Engl J Med2010;362:2053-2065.
OS DFS
NSABPB-30. AC4-T4 vs TAC4 vs AT4
TNBC subgroup
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(F)EC Q2 vs. (F)EC Q3: Disease-free survival
N=335 HR-
(F)EC Q2
(F)EC Q3
GIM-2: ADJUVANT DOSE-DENSE CHEMOTHERAPY FOR
N+ BC PTS
Reprinted from Del Mastro L, et al., Lancet 2015;385:1863–72. Copyright 2015 with permission from Elsevier.
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Adjuvant therapy in TNBC-Outline
• Small Tumor
• Addition of Taxanes
• High Dose Chemotherapy
• PARPi: narrowing target population to BRCA+
• Timing of chemotherapy
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DRUG-SPECIFIC CHEMOTHERAPY FOR TNBC?
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Neoadjuvant talazoparib for BRCA mut
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Neoadjuvant talazoparib for BRCA mut
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N=1,320
• Study to start recruiting patients with TNBC; plan to add ER/PR+ patients once data available from PK/PD interactions (expected Mid 2014)
• Primary endpoint: IDFS (invasive disease-free survival; STEEP approach)• HR=0.7 (CV=0.81), 90% power, 5% significance level, approx 330 events required
• Assumes consistent treatment effect (HR=0.7) across patient groups• N=1320 (25% maturity), assuming 4 years recruitment, IDFS analysis estimated approx. 5.5–
6 years from FSI
Post-neoadjuvant gBRCATNBCNon pCR patientsAssumptions: - Control arm 3-year EFS ~ 60%C
Post-adjuvant gBRCA TNBCNode positive or N0 with T>2 cmAssumptions: - Control arm 3-year EFS ~ 77%C
12 mos Olaparib300mg bd
DDFS, OS
12 mos Placebo
IDFS1:1 R
OlympiA
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Adjuvant therapy in TNBC-Outline
• Small Tumor
• Addition of Taxanes
• High Dose Chemotherapy
• PARPi: narrowing target population to BRCA+
• Timing of chemotherapy
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Morante Z, et al. SABCS 2018
Impact of the delayed initiation of adjuvant CT in TNBC
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Morante Z, et al. SABCS 2018
Impact of the delayed initiation of adjuvant CT in TNBC
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Impact of the delayed initiation of adjuvant CT in TNBC
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Morante Z, et al. SABCS 2018
Impact of the delayed initiation of adjuvant CT in TNBC
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Morante Z, et al. SABCS 2018
Impact of the delayed initiation of adjuvant CT in TNBC
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Adjuvant therapy in TN
• Lowthresholds for adjuvant chemotherapy treatment for TNBC ( ~ 0.5 cm, node- negative)
• Standard chemotherapy agents areeffective adjuvant therapy
• Enhancements to adjuvant chemotherapy (addition of taxanes, sequential therapy, dose
dense schedule) should be considered
• Alternative regimens
– Preferred regimen without anthracyclines:TC
– Preferred regimen without taxanes: AC or CMF
• PARP inhibitors hold great promises for BRCA-mut patients
• Timing of adjuvant treatment matters!
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(Neo)Adjuvant therapy in TNBC-Outline
• Addition of carboplatin
• Addition of Bevacizumab
• Addition of Nab-paclitaxel
• Post-neoadjuvant setting
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0
10
20
30
40
50
60
TACGepar31
EC-D EC-D+BevGepar53
PM PM+carbo(+ Bev)
Gepar64
P-AC P+carbo-AC(+/- Bev)
CALGB406035
P+carbo+bevCa.Pa.Be6
nabP-ECGepar78
EC-P (+/-gem)
NeoTango2
nabP-carboADAPT7
1. Huober J, BCRT 2010; 2. Earl HM, Lancet Oncol 2014; 3. von Minckwitz, NEJM 2012; 4. von Minckwitz, Lancet Oncol 2014; 5. Sikov, J Clin Oncol 2015; 6. Guarneri V, Ann Surg Oncol 2015; 7. Gluz O, SABCS 2015; 8. Untch M, SABCS 2014
pCR rates (breast/axilla) in TNBC
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Poggio F. et al. Ann Oncol 2018
Adding platinum to neoadj CT increases pCR
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Hazard-ratios for overall survival
Safety profile
Poggio F. et al. Ann Oncol 2018
Survival benefit is uncertain and adding
platinum is more toxic
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pCR RATES BY TREATMENT AND ACCORDING TO HR DEFICIENCY
STATUS (ypT0 ypN0)
Presented By Von Minckwitz G, at 2015 ASCO Annual Meeting.
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QUESITO GRADE n.5: Platino nella terapia neoadiuvante per TNBC
• Framework Evidence to
Decision (EtD) utilizzato per
supportare lo sviluppo della
raccomandazione
(allegato).
• Importanza degli effetti di
beneficio: «MODERATE»
• Importanza degli effetti di
danno: «SMALL»
• Qualità delle evidenze:
«MODERATE»
• Valutazione rapporto
beneficio/danno: «Incerto:
favorevole» (10/11)
Roma2018
MV Dieci, AIOM 2018
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(Neo)Adjuvant therapy in TNBC-Outline
• Addition of carboplatin
• Addition of Bevacizumab
• Addition of Nab-paclitaxel
• Post-neoadjuvant setting
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Hypoxia-related features and basal like tumours
VEGF 13-gene VEGF-signatureE
xpre
ssio
n
Perou CM, The Oncologist 2010; 15(5):39-48.
Antiangiogenic approaches work in TNBC at least as well as other subtype,
possibly more
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CALGB 40603: RESULTS BEV/NO BEV
Sikov WM, et al., J Clin Oncol 2014;33:13–21
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GEPARQUINTO: NEOADJUVANT BEVACIZUMAB AND
SURVIVAL
von Minckwitz G, et al., Ann Oncol 2014;25:2363-72.
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BEATRICE PHASE III ADJUVANT TRIAL
Reprinted from Cameron D, Lancet 2013;14:933–42.
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(Neo)Adjuvant therapy in TNBC-Outline
• Addition of carboplatin
• Addition of Bevacizumab
• Addition of Nab-paclitaxel
• Post-neoadjuvant setting
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Neoadjuvant nabpaclitaxel for triple-negative breast
cancer Geparsepto
Surg
ery
12 weeks 12weeks
N=1200
*Centrally confirmed:- Subtypes HER 2/ HR- Ki67- SPARC
Paclitaxel80 mg/ m2
weekly
nab-Paclitaxel
125 mg/ m2
weekly
Epirubicin 90 mg/m2
Cyclophosphamide 600 mg/m2
If HER2 positive:
Trastuzumab 8 mg/kg (loading dose) followed by 6 mg/kg
Pertuzumab (absolute dose per application) 840 mg (loading dose) followed by 420 mg
If H
ER2
posi
tive:
trastu
zum
ab
acc.
to
AG
OG
uid
elin
es
Corebiopsy
Core
bio
psy*
(aft
er
anti-
HE
R2 tre
atm
en
t /
befo
re s
tudy
en
try)
ArmA
R*
Arm B
Corebiopsy
optional
Corebiopsy
optional
R*
Core
bio
psy*
(befo
re s
tudy
en
try)
N=60(HER2 positive)
6weeks
* Randomizations carried outsimultaneously
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GEPAR7: SUBGROUP ANALYSIS
Reprinted from Untch M, Lancet 2016;17(3):345-56. Copyright 2015, with permission from Elsevier.
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Neoadjuvant nabpaclitaxel for triple-negative breast
cancer Geparsepto
Untch M, et al. Lancet Oncol. 2016. Epub ahead ofprint.
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PHASE III RANDOMISED ETNA TRIAL
Gianni L, at 2016 ASCO Annual Meeting.
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(Neo)Adjuvant therapy in TNBC-Outline
• Addition of carboplatin
• Addition of Bevacizumab
• Addition of Nab-paclitaxel
• Post-neoadjuvant setting
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Post-Neoadjuvant setting
C. Liedtke JCO, 26, 8, 2008: pp. 1275-1281
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CMM MAINTENANCE AFTER ADJUVANT
CHEMOTHERAPY
75%TNBC
Colleoni M, at 2015 ASCO Annual Meeting.
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All patients TN patients
Colleoni M, at 2015 ASCO Annual Meeting
CMM MAINTENANCE AFTER ADJUVANT
CHEMOTHERAPY
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GEICAM/CIBOMA randomized phase III trial
M. Martin, SABCS 2018
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GEICAM/CIBOMA randomized phase III trial: patient characteristics
M. Martin, SABCS 2018
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M. Martin, SABCS 2018
GEICAM/CIBOMA randomized phase III trial: DFS and
OS in ITT population
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M. Martin, SABCS 2018
GEICAM/CIBOMA randomized phase III trial: DFS
and OS basal vs non basal
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Study Patients RFS/DFS in TN OS in TN
FinXX 1500 (202 TN) HR 0.53(95%CI 0.31-0.92)
HR 0.55 (95%CI 0.31-0.96)
GEICAM/2003-10 1384 N+(166 TN) HR 1.19(95%CI 0.70-2.04)
NR
GAIN 2994 N+ (421 TN) HR 0.971(95%CI 0.682-1.38)
NR
NCT00089479 2611 (780 TN) HR 0.81(95%CI 0.57-1.15)
HR 0.62(95%CI 0.41-0.94)
Create-X 910 (286 TN)(post-neoadj)
HR 0.58(95%CI 0.39-0.87)
HR 0.52(95%CI 0.30-0.90)
Joensuu H et al, J Clin Oncol 2012 & JAMA Oncol 2018; Martin M et al, J Clin Oncol 2015; Mobus V et al, Ann Oncol 2017;O’Shaughnessy CCR 2015; NEJM 2017
RCTs of Capecitabine in EBC
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Chemotherapy is the mainstay of treatment:
Anthracycline+taxanes: first choice in the (neo)adjuvant setting
BRCA-mut (or BRCAwt with BRCAness features?): chance for
tailored- chemotherapy with platinum salts
No role for bevacizumab-encouraging data for nab-paclitaxel
If no pCR post neoadjuvant therapy may be a feasible and
effective option
(Neo)Adjuvant therapy in TNBC