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Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1
Endocrine and “Targeted”
Therapy in Metastatic
Breast Cancer
Endocrine Therapy of
Metastatic Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Version 2002:
Gerber / Friedrichs

Versions 2003–2015:
Albert / Bischoff / Dall / Fersis / Friedrich /
Gerber / Huober / Janni / Jonat / Kaufmann /
Liedtke / Loibl / Lück / von Minckwitz / Möbus /
Müller / Mundhenke / Nitz / Schneeweiß /
Schütz / Stickeler

Version 2016:
Hanf / Mundhenke
Guidelines Breast
Version 2016.1
www.ago-online.de
Endocrine Therapy in
Metastatic Breast Cancer
© AGO
Indication
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford LoE: 1a
Guidelines Breast
Version 2016.1
GR: A
AGO: ++
Endocrine therapy represents the first choice
for metastatic breast cancer with positive
(or unknown) hormone receptor (HR) status.
www.ago-online.de


Exception: acute life-threatening disease
Caveat: HR might change during the course of
disease. Histology of recurrent site should be
obtained whenever possible
Comparison ER/PR and HER2
Metastasis vs. Primary Tumor
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1
Meta-analysis based on 48 (mostly retrospective)
analyses:
Pooled discordance proportions were
 20% (95%CI 16-35%) for ER
 33% (95%CI 29-38%) for PR
 8% (95% CI 6-10%) for HER2
www.ago-online.de
Pooled proportions of tumors shifting from positive to
negative and negative to positive were
 4% and 14% for ER
 46% and 15% for PR
 13% and 5% for HER2
Endocrine Therapy
General considerations
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1
Within all lines of treatment, treatment options should
take previous endocrine therapies, age and
comorbidities into consideration as well as respective
approval status
www.ago-online.de
Endocrine Therapy
in Premenopausal Patients with
HER2-Negative Metastatic Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford / AGO
LoE / GR
Guidelines Breast
Version 2016.1
www.ago-online.de

GnRHa + tamoxifen (vs. OFS or Tam)
1a A
++

Ovarian function suppression (OFS)
2b B
+

Tamoxifen
2b B
+

GnRHa + AI (first or second line)
2b B
+

GnRHa + Fulvestrant
1b B
+

GnRHa + Fulvestrant +Palbociclib
1b B
+

Aromatase inhibitors without OFS
3
--
D
Endocrine Therapy
in Postmenopausal Patients with
HER2-Negative Metastatic Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1
*There is no evidence for superiority of a single aromatase inhibitor.
As everolimus plus exemestane is indicated after AI treatment, a
non-steroidal AI should be preferred in first line. MA§: Megestroleacetate, ** steroidal or non-steroidal resp. depending on previous AI
Oxford / AGO
LoE / GR
1b B ++
1a A ++
1a A ++
1b B +

Fulvestrant 500 mg
Aromatase inhibitors (3rd gen) **
Tamoxifen
Letrozole + Palbociclib

Fulvestrant 500 mg plus Palbociclib
1b
B
+

Exemestane + Everolimus
1b
A
+


Tamoxifen + Everolimus
MPA/MA§
Fulvestrant 250 mg + Anastrozol
Estradiol valerate 2-6 mg daily
2b
1a
1b
2b
B
A
B
C
+
+/+/+/-

Repeat prior treatments
5
D
+/-



www.ago-online.de


Therapy Algorithm After Adjuvant
Tamoxifen
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1
Fulvestrant 500 mg or
Non-steroidal AI 3rd generation or
Tamoxifen*
Exemestane +
everolimus
www.ago-online.de
Fulvestrant 500 mg +/Palbociclib
Fulvestrant 500 mg
+/- Palbociclib
Exemestane + everolimus
Tamoxifen
Tamoxifen
*(after long recurrence-free intervall)
Therapy Algorithm After Adjuvant AI
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Short treatment free
interval ≤12 months
Long treatment free
interval >12 months
Guidelines Breast
Version 2016.1
Exemestane
+ everolimus
Fulvestrant
500 mg +/Palbociclib
Fulvestrant 500 mg
Exemestane +
everolimus
Tamoxifen
www.ago-online.de
Tamoxifen
Tamoxifen
Fulvestrant 500 mg
+ Palbociclib
Endocrine Therapy in Postmenopausal
HER2-Negative Metastatic Breast Cancer Patients
in Combination with Bevacizumab
© AGO
e. V.
Oxford / AGO
LoE / GR
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1


www.ago-online.de
Maintenance bevacizumab plus endocrine
therapy after remission with chemotherapy
and bevacizumab
Bevacizumab plus endocrine treatment
as first line therapy for advanced disease
2b
B
+
1b
B
-
Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2016.1
HER2 Positive and
HR-Positive Metastatic
Breast Cancer
Endocrine Therapy in Postmenopausal HER2Positive Metastatic Breast Cancer Patients
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford / AGO
LoE / GR
Guidelines Breast
Version 2016.1




www.ago-online.de
Anastrozole plus trastuzumab
1b
Letrozole plus trastuzumab
2b
Letrozole plus lapatinib
1b
Fulvestrant plus lapatinib
1b
Poor efficacy of endocrine therapy alone.
B
B
B
B
Consider induction chemotherapy + anti-HER2-therapy!
+/+/+/+/-
Combination of Endocrine Treatment with
Anti-HER2-Treatment
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Treatment
(no. of pats)
PFS (months)
Response rate OS (months)
(CBR)
Trastuzumab +
anastrozole vs.
anastrozole
(n=207)
4.8 vs. 2.4
(5.6 vs. 3.8 with
centrally confirmed
receptor status)
42.7% vs. 27.9%
28.5 vs. 23.9 mo; n.s.
Trastuzumab +
letrozole vs.
letrozole
(n=57)
14,1 vs. 3.3
27% vs. 13%
not reported
Lapatinib +
letrozole vs.
letrozole
(n=219/1286)
8.2 vs. 3.0
48% v 29%
33.3 vs. 32.3 mo
Lapatinib +
fulvestrant vs.
fulvestrant
(n=146/145)
4.1 vs. 3.8 (HER2-) p:
0,25
5.9 vs. 3.3 (HER2+) p:
0,53
(CR +PR) 20 vs. 9%
p: 0,048
30 vs. 26.4 mo (all), n.s.
Guidelines Breast
Version 2016.1
www.ago-online.de
Concomitant or Sequential
Endocrine-Cytostatic Treatment
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford / AGO
LoE / GR
Guidelines Breast
Version 2016.1


Concomitant endocrine-cytotoxic
treatment

-
2b B
++
May increase response rate and progression
free interval but not overall survival

www.ago-online.de
1b A
May increase toxicity
Maintenance endocrine therapy after
chemotherapy induced response

Increases progression free interval
Endocrine and “Targeted” Therapy in Metastatic Breast Cancer (2/14)
No further information
No references
Endocrine and “Targeted” Therapy in Metastatic Breast Cancer (3/14)
No further information
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Endocrine Therapy General Considerations (5/14)
No further information
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Oncology 2003 14
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Mehta RS, Barlow WE et al. Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer. NEJM 367:43544, 2012
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Jyothirmayi R, Robinson A, Wardley AM, Wheatley D, Howell A, Coombes G, Sergenson N, Sin HJ, Folkerd E,
Dowsett M, Bliss JM; SoFEA investigators. Fulvestrant plus anastrozole or placebo versus exemestane alone after
progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally
advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013
Sep;14(10):989-98.
Letrozole and Palbociclib (vs. Letrozol)
1.
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