Neoadjuvante Therapie

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO
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Guidelines Breast
Version 2015.1
Neoadjuvant
(Primary) Systemic Therapy
Neoadjuvant Systemic Therapy
© AGO
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
Version 2002:
Costa

Versions 2003–2014:
Bauerfeind / Blohmer / Dall / Fersis /
Göhring / Harbeck / Heinrich / Huober /
Jackisch / Kaufmann / Loibl / Lux / von
Minckwitz / Müller / Nitz / Schneeweiss /
Schütz / Solomayer / Untch

Version 2015:
Friedrich / Schneeweiss
Guidelines Breast
Version 2015.1
www.ago-online.de
Neoadjuvant Systemic Chemotherapy
Indications
© AGO
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Guidelines Breast
Version 2015.1
www.ago-online.de

Inflammatory breast cancer
2b
B
++

Inoperable breast cancer
1c
A
++

Large operable breast cancer primarily
requiring mastectomy and adjuvant
chemotherapy with the goal of breast
conservation
1b
B
+
If similar postoperative adjuvant
chemotherapy is indicated
1b
A
+

Subtype-specific
General Systemic Strategies
© AGO
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Guidelines Breast
Version 2015.1


In case of indication for chemotherapy,
consider neoadjuvant approach


Conventionally dosed AT-based chemotherapy
Dose dense & escalated in case of high tumor
burden
Followed by endocrine therapy
Trastuzumab plus
•
Sequential A/T-based regimen with concurrent T + H
Anthracycline-free, carboplatin-cont. regimen
•
Dose dense & escalated in case of high tumor burden
•

++
++
+
++
HER2+

www.ago-online.de
Endocrine therapy without chemotherapy
HR+/HER2- and “high risk”


++
HR+/HER2- and “low risk”:


AGO
++
++
+
+
TNBC



Conventionally dosed AT-based chemotherapy
Dose dense & escalated
Plus Carboplatin in case of family history for BC/OC
or gBRCA alteration
++
+
+
Verbesserung der pCR-Raten durch Platin
beim TNBC
p=0,003
p=0,0029
60
p=0,005
61
P<0,0001
54
50
TNBC
53
48
40
41
37
ypT0 ypN0
ypT0 ypN0
ypT0 ypN0
ypT0 ypN0
ypT0/is ypN0
0
26
ypT0/is ypN0
10
32
ypT0/is ypN0
20
34
ypT0/is ypN0
30
ypT0/is ypN0
Anteil Patienten mit pCR (%)
70
(N=992)
1. Cortazar P, et al. Lancet 2014; 2. Ando M, et al. BCRT 2014; 3. Sikov WM, et al. J Clin Oncol 2015;
4. von Minckwitz G, et al. Lancet Oncol 2014; 5. Petrelli F, et al. BCRT 2014
HR 0.24
pCR als Surrogat für Überleben?
Überträgt sich die höhere pCR-Rate
in ein besseres Überleben?
Wenn ja, welches Δ pCR brauchen
wir für eine signifikante
Verbesserung des Überlebens?
Gibt es Subgruppen mit einem
größeren Δ pCR?
GeparSixto (Phase II): pCR abhängig von genetischer
Belastung nach PMB + Carbo vs. PMB beim TNBC (N=294)
Von Minckwitz G, et al. ASCO 2014 (abs 1005), oral abstract session
Neoadjuvant Systemic Chemotherapy
Recommended Regimens and Schedules
© AGO
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Guidelines Breast
Version 2015.1
Standard regimens used in the adjuvant setting
with a duration of at least 18 weeks
1a
A
++

AC or EC  D q3w or P q1w
2b
A
++

DAC
2b
B
++

AP  CMF
1b
A
+

Taxane followed by anthracycline sequence
1a
A
+

Dose-dense regimen (e.g. E -P-CMF, E-P-C)
1b
B
+*

Platinum in TNBC
1a
A
+/-
2b
B
+

www.ago-online.de

in case of family history of BC/OC or
BRCA alteration
*Study participation recommended
Superior Carboplatin Containing
Regimens in the Neoadjuvant Setting
© AGO
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Guidelines Breast
Version 2014.1
www.ago-online.de
Author
Study
Regimen
pCR rate
Sikov WM,
et al. (JCO
2015)
CALGB
40603
Phase II
Paclitaxel 80mg/m² qw x12 +
Carboplatin AUC 6 q3w x4 –
dd AC q2w x4
TNBC ± Cb:
54% vs 41%
(ypT0/is ypN0)
von
Gepar
Minckwitz G, Sixto
et al. (Lancet Phase II
Oncol 2014)
NPLD 20mg/m² qw x18 +
TNBC ± Cb:
Paclitaxel 80mg/m² qw x18
53% vs. 37%
+ Carboplatin AUC 1.5 qw x18 (ypT0 ypN0)
+ Bev 15mg/kg q3w x6
Ando M, et
al. (BCRT
2014)
Paclitaxel 80mg/m² qw x12 +
Carboplatin AUC 5 q3w x4 –
FEC q3w x4
Phase II
TNBC ± Cb:
61% vs. 26%
Neoadjuvant Systemic Chemotherapy
Recommended Regimens and Schedules
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
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in der DKG e.V.
Guidelines Breast
Version 2015.1
Standard regimens used in the adjuvant setting
with a duration of at least 18 weeks
1a
A
++

AC or EC  D q3w or P q1w
2b
A
++

DAC
2b
B
++

AP  CMF
1b
A
+

Taxane followed by anthracycline sequence
1a
A
+

Dose-dense regimen (e.g. E -P-CMF, E-P-C)
1b
B
+*

Platinum in TNBC
1a
A
+/-
2b
B
+

www.ago-online.de

in case of family history of BC/OC or
BRCA alteration
*Study participation recommended
Neo-tAnGo (Phase III): Neoadj. Pac ± Gem  EC vs.
EC  Pac ± Gem beim HER2- EBC > 2cm (N=831) – pCR, Überleben
pCR (ypT0/is ypN0): 20% vs. 15%, p=0.03
Disease-free Survival
Earl HM, et al. Lancet Oncol 15: 201–12, 2014
Overall Survival
Review: (Neo)adj. Taxan  Anthrazyklin vs.
Anthrazyklin  Taxan beim EBC
• Seven studies in the adjuvant setting and eight in the neoadjuvant setting
(10 randomized trials)
• Nearly 5000 patients
• None of the clinical trials has shown disadvantages in terms of efficacy or
toxicity for…taxane…first.
• Similar or increased pathological complete response rates for sequences
in which the taxane…first.
Conclusion: There seems to be sufficient evidence to
suggest that a taxane followed by an anthracycline is a
sequence option that can be incorporated into daily
clinical practice.
Bines J, et al. Ann Oncol 25: 1079-85, 2014
Neoadjuvant Systemic
Therapy Response Prediction II
© AGO
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Guidelines Breast
Version 2015.1
Factor
Multigene signature
III
C
B
+/-
Ki-67
I
B
A
+
Tumour infiltrating lymphocytes
I
B
B
+/-
PIK3CA mutation
II
B
B
+/-



www.ago-online.de
LoE2009 CTS GR AGO

Standards für die Evaluation von
Tumor-infiltrierenden Lymphozyten (TILs)
•
Nur stromale TILs
•
Als % des Tumorstroma-Areals
•
Innerhalb der Tumorgrenzen
•
Semiquantitativ
•
Bei heterogener Verteilung gilt
der Durchschnitt
Salgado R, Denkert C, Demaria S, et al. Ann Oncol 2014 [Epub ahead of print]
Stromale TILs scheinen prädiktiv für das Erreichen einer
pCR nach neoadjuvanter CT + Trastuzumab
Retrospektive Analyse der GeparQuattro-Studie (N=156)
Loi S, et al. SABCS 2013 (S1-05), oral presentation
Stromale TILs scheinen prädiktiv für eine Sensitivität gegenüber der
adjuvanten CT aber nicht gegenüber Trastuzumab
Retrospektive Analyse der N9831-Studie (N=945; 9,9% ≥ 60% sTILs = LPBC):
TILs scheinen nicht prädiktiv für eine adjuvante
Trastuzumabwirkung
Perez EA, et al. SABCS 2014 (S1-06), oral pesentation
Neoadjuvant Systemic
Therapy Response Prediction II
© AGO
e. V.
in der DGGG e.V.
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in der DKG e.V.
Guidelines Breast
Version 2015.1
Factor
Multigene signature
III
C
B
+/-
Ki-67
I
B
A
+
Tumour infiltrating lymphocytes
I
B
B
+/-
PIK3CA mutation
II
B
B
+/-



www.ago-online.de
LoE2009 CTS GR AGO

PIK3CA-Mutation und PTEN-Verlust scheinen prädiktiv für eine Resistenz
auf CT + Anti-HER2-Therapie neoadjuvant
Loibl S, et al. J Clin Oncol 2014; Baselga J, et al. ECC 2013; Guarneri V, et al. ESMO 2014
PIK3CA-Mutation scheinen nicht prädiktiv für eine Resistenz auf
Trastuzumab adjuvant
(retrospektive Analyse der FinHER-Studie, N=157)
Loi S, et al. J Natl Cancer Inst 105:960–967, 2013
Neoadjuvant Targeted Therapy in
HER2 Positive Tumors
© AGO
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Guidelines Breast
Version 2015.1




www.ago-online.de


Trastuzumab in combination with
chemotherapy
Lapatinib in combination with
chemotherapy
1b
A
++
1a
B
-
Lapatinib + Trastuzumab in combination
with chemotherapy
1a
B
+/-
Pertuzumab + Trastuzumab in combination
with chemotherapy
1a
B
+*
Two anti-HER2 agents without
chemotherapy
2b
B
+/-
Anti-HER2 agent in combination with
endocrine treatment
2b
C
+/-
* Study participation recommended
Verbesserung der pCR-Raten (ypT0/is ypN0) durch
duale Anti-HER2 Therapie beim HER2+ EBC
Anteil Patienten mit pCR (%)
80
70
60
50
40
30
pCR
pCR HR+
pCR HR-
20
10
0
1Cortazar.
5Von
Lancet 2014; 2Carey. ASCO 2013; 3Baselga. Lancet 2012; 4Robidoux. Lancet Oncol 2013;
Minckwitz. Lancet Oncol 2014; 6Gianni. Lancet Oncol 2012; 7Schneeweiss. Ann Oncol 2013
pCR-Raten (ypT0/is ypN0) beim HER2+ EBC
Getrennt nach HR-Status
Anteil Patienten mit pCR (%)
80
70
60
50
40
30
+ 40%
pCR
pCR HR+
pCR HR-
20
10
0
HER2+ HRHR 0.25
1Cortazar.
5Von
Lancet 2014; 2Carey. ASCO 2013; 3Baselga. Lancet 2012; 4Robidoux. Lancet Oncol 2013;
Minckwitz. Lancet Oncol 2014; 6Gianni. Lancet Oncol 2012; 7Schneeweiss. Ann Oncol 2013
Neoadjuvant Targeted Therapy in
HER2 Positive Tumors
© AGO
Oxford / AGO
LoE / GR
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in der DGGG e.V.
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Guidelines Breast
Version 2015.1




www.ago-online.de


Trastuzumab in combination with
chemotherapy
Lapatinib in combination with
chemotherapy
1b
A
++
1a
B
-
Lapatinib + Trastuzumab in combination
with chemotherapy
1a
B
+/-
Pertuzumab + Trastuzumab in combination
with chemotherapy
1a
B
+*
Two anti-HER2 agents without
chemotherapy
2b
B
+/-
Anti-HER2 agent in combination with
endocrine treatment
2b
C
+/-
* Study participation recommended
Neoadjuvant Targeted Therapy in
HER2 Negative Tumors
© AGO
Oxford / AGO
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Guidelines Breast
Version 2015.1
Bevacizumab in combination with chemotherapy
In hormone receptor positive BC
1b
B
-
In TNBC
1b
B
+/-


www.ago-online.de
GeparQuinto (Phase III): Neoadj. ECDoc vs. ECB DocBev
beim HER2- EBC ≥ 2cm (N=1.925) – Überleben
Disease-free Survival
Gerber B et al. SABCS 2014 (P3-11-01), poster discussion
Overall Survival
Keine Verbesserung des invasiven DFS durch
Bevacizumab adjuvant beim TNBC
Studie
N
(TNBC)
Therapie
Primärer
Endpunkt
HR
p
BEATRICE
2591
≥ 4 x CT± B
 B (1y)
IDFS
0,87
0,18
E5103
1079
AC-P ± B
 B (1y)
IDFS
0,77
0,08
AC, Doxorubicin/Cyclophosphamid; B, Bevacizumab; CT, Chemotherapie; HR, hazard ratio; IDFS, invasive
disease-free survival; P, Paclitaxel
38% TNBC
Cameron D, et al. Lancet Oncol 2013; Miller K, et al. ASCO 2014 (abs 500), oral abstract session
Neoadjuvant Systemic Chemotherapy
Clinical Benefit
© AGO
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Guidelines Breast
Version 2015.1
Oxford / AGO
LoE / GR
Survival is similar after neoadjuvant
(preoperative, primary) and adjuvant
systemic therapy
1a
A
Pathological complete response
is associated with improved survival in
particular subgroups
1b
A
Can achieve operability in primary inoperable
tumors
1b
A
++

Improved options for breast conserving surgery
1b
A
++

Allows individualization of therapy
according to mid-course treatment effect
1b
B
+*
Allows individualization of post-neoadjuvant management
according to refined risk assessment after
neoadjuvant treatment and surgery
2b
B
+/-*



www.ago-online.de

* Study participation recommended
Adjuvant Systemic Therapy
after Neoadjuvant Systemic Treatment
© AGO
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Guidelines Breast
Version 2015.1



www.ago-online.de
Endocrine treatment in
endocrine responsive disease
Complete trastuzumab treatment
for 1 year in HER2-positive
disease
In case of insufficient response
1a A
2b B ++
3
 Experimental therapies in clinical trials
5

Further chemotherapy
++
C
D
+
KATHERINE (Phase III): Studiendesign und
Endpunkte
Operation
cT1-4, cN0-3,
M0 HER2+
Neoadjuvante
Therapie:
Anti-HER2/
Taxan ±
Anthrazyklin
14 x Trastuzumab 6mg/kg i.v. q3w
Residualer
invasiver
Tumor
14 x T-DM1 3,6mg/kg i.v. q3w
Bestrahlung gemäß Leitlinien;
endokrine Therapie falls ER/PgR
pos
Primärer Endpunkt: Invasives Disease-free Survival (IDFS);
3y-IDFS 70%76,5% (HR 0,75)
Sekundäre Endpunkte: IDFS, inklusive Zweitkarzinome; DFS; OS;
distantes Rezidiv-freies Interval (DRFI)
PI: G. von Minckwitz
PENELOPEB (Phase III): Studiendesign und
primärer Endpunkt
Operation
Residualer
cT1-4, cN0-3,
M0 HR+ HER2- invasiver
Tumor mit
Neoadjuvante
CPS-EG
Chemotherapie
inklusive Taxan
Score
≥3
13 x Placebo p.o. d1-21 q4w
13 x Palbociclib 125mg p.o.
d1-21 q4w
Bestrahlung und endokrine
Therapie gemäß Leitlinien
Primärer Endpunkt: Invasives Disease-free Survival (IDFS)
PI: G. von Minckwitz
Neoadjuvant Systemic Therapy
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Guidelines Breast
Version 2015.1
Vielen Dank für Ihre
Aufmerksamkeit
www.ago-online.de
Neoadjuvant Systemic Chemotherapy
Response Prediction I
© AGO
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Factor
CTS
LoEOx2001 GR AGO
Guidelines Breast
Version 2015.1

Young age
B
1a
A
+

cT1 / cT2 tumors o. N0 o. G3
B
1a
A
++

Negative ER and PgR status
B
1a
A
++
Triple negative breast cancer
(TNBC)
B
1a
A
++


Positive HER2 status
B
1a
A
++

Non-lobular tumor type
B
1a
A
+

Early clinical response
B
1b
A
+
www.ago-online.de
Neoadjuvant Systemic Chemotherapy
Recommended Methods of Monitoring of
Response
© AGO
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Guidelines Breast
Version 2014.1
www.ago-online.de

Breast ultrasound
2b
B
++

Palpation
2b
B
++

Mammography
2b
B
++

MRI
2b
B
+

PET(-CT)
2b
B
+/-

Clip tumour region
5
D
++
Neoadjuvant Systemic Therapy
Procedures in Case of Early Response
© AGO
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Guidelines Breast
Version 2014.1
In case of early response following
6 to 12 weeks of neoadjuvant
chemotherapy:
Complete all chemotherapy before
surgery i.e. ≥ 18 weeks of treatment
1b A ++
In case of response after 2 cycles of
DAC in HR positive breast cancer
consider 8 instead of 6 cycles of DAC
2b C

www.ago-online.de

+
Neoadjuvant Systemic Therapy
Procedures in Case of No Early Response
© AGO
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Guidelines Breast
Version 2014.1
www.ago-online.de
In case of no change:
 Completion of NST, followed by surgery
 Continuation of NST with non cross-resistant
regimen

AC or EC x 4  D x 4 or Pw x 12

DAC x 2  NX x 4
In case of progressive disease:
 Stop of NST and immediate surgery or
radiotherapy
 Additional adjuvant chemotherapy with non
cross-resistant regimen
2b C ++
2b B +
2b B +
1b B +
4
D ++*
4
D +/-*
* Study participation recommended
Local/Regional Procedure after
Neoadjuvant Therapy
© AGO
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Guidelines Breast
Version 2014.1
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
Mark previous tumor region
5

Surgery
2b C ++

Microscopically clear margins
5

Tumor resection in the new
margins

Sentinel node biopsy
(see chapter “Surgery”)
D ++
D ++
3b C +
Surgical Procedure of the Axilla Before or
After NACT
© AGO
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Guidelines Breast
Version 2014.1
SLNB before or after NACT in cN0
SLNB before NACT
SLNB after NACT
2b
2a
B
B
+
+/-
Further surgical procedures depending on SLNB
www.ago-online.de
cN-Status
(before NST)
pN-Status
(before NST)
cN-Status
(after NST)
Surgical
procedure
cN0
pN0(sn)
-
nihil
1a
A
+
cN0
pN+(sn)
analogue
ACOZOG
ycN0
ALND
3
B
+/-
cN0
pN+(sn) not
analogue
ACOZOG
ycN0
ALND
2b
B
+
ycN0
SNB
ALND
2a
2b
B
B
+/+
ycN+ (CNB/FNA)
ALND
2b
B
++
cN+
cN+ (CNB/FNA)
Neoadjuvant Systemic Therapy
Indications for Mastectomy
© AGO
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Guidelines Breast
Version 2014.1

Positive margins after repeated excisions
3b C
++

Radiotherapy not feasible
5
++

In case of clinical complete response

Inflammatory breast cancer

www.ago-online.de
D
2b C
+
+/-
In case of pCR

Multicentric lesions
2b C
+/-

cT4a-c breast cancer
2b B
+/-
Neoadjuvant Systemic Therapy
Timing of Surgery and Radiotherapy
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Guidelines Breast
Version 2014.1

Surgery

4
C
++
2b B
++
After the nadir of the leucocyte count
(2 to 4 weeks after last course of
chemotherapy)
www.ago-online.de

Radiotherapy after surgery
2–3 weeks after surgery BCS
Neoadjuvant Endocrine Therapy
in patients with endocrine-responsive breast cancer
© AGO
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Guidelines Breast
Version 2014.1
Postmenopausal patients:
who are inoperable
and can / will not receive chemotherapy
2a
B
+

Optimizes the option for breast conserving therapy
1b
A
+

Aromatase inhibitors (for > 3 months)
1aa
B
+

Aromatase inhibitor + lapatinib (HER2+ BC)
2b
B
+/-
who are inoperable
and can / will not receive chemotherapy
5
C
+

Tamoxifen
2b
C
+

Aromatase inhibitors + LHRH
1b
C
+/-

Concurrent chemo-endocrine therapy
1b
A
-

Prognostic factors during/after NST: quantitative ERexpression, level of Ki-67, N status, T status
1b
B
+


Premenopausal patients

www.ago-online.de
Optimal duration of neoadjuvant endocrine therapy is unknown
No long term results for neoadjuvant endocrine therapy (vs. adjuvant endocrine therapy)