Chemotherapy With or Without Targeted Drugs* in Metastatic Breast

Chemotherapy With or Without Targeted Drugs* in Metastatic Breast

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
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Guidelines Breast
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Chemotherapy With or Without
Targeted Drugs* in Metastatic
Breast Cancer
*Substances are only discussed if there is at least published evidence
on one phase III / IIb study available
Chemotherapy Targeted Drugs in
Metastatic Breast Cancer
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Guidelines Breast
Version 2013.1
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www.ago-online.de
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Version 2002:
von Minckwitz / Schaller / Untch
Versions 2003–2012:
Dall / Fersis / Friedrichs / Harbeck /
Jackisch / Janni / Möbus / Rody / Scharl /
Schmutzler / Schneeweiss / Schütz /
Stickeler
Version 2013:
Bischoff / Thomssen
Disease-Free and Overall Survival
in Metastastic Breast Cancer
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General observation, not specific for
cytotoxic chemotherapy
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Guidelines Breast
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An increase in survival over time in MBC has
been shown in retrospective analyses
2a
A survival benefit has been shown in recent
single prospective randomized studies of
combination chemotherapy
1b
Multiple lines of sequential therapy are
beneficial (at least same efficacy, less toxicity)
1b
In some combinations of chemotherapy with
targeted drugs, a relevant survival benefit has
been observed
1b
Treatment of Metastatic Breast Cancer
Predictive Factors
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Therapy
Factor
Endocrine therapy
ER / PR
(primary tumor, metastasis)
1a
A
++
previous response
2b
B
++
Chemotherapy
previous response
1b
A
++
Anti-HER2-drugs
HER2
(primary tumor,
better metastasis)
1a
A
++
Bone modifying drugs bone metastasis
1a
A
++
Any therapy
1b
A
+*
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CTC monitoring
(other potentially biological factors see chapter „predictive factors“)
*within clinical trials
Cytotoxic Therapy
Goals
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GR: A
AGO: ++
Mono-Chemotherapy:
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Favourable therapeutic index
Indicated in case of
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Slow, not life-threatening progression
Insensitive to or progression during endocrine therapy
Poly-Chemotherapy:
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Unfavourable therapeutic index
Indicated to achieve rapid remission in the case of
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Extensive symptoms
Imminent life-threatening metastases
Survival benefit in comparison to sequential singleagent therapies with the same compounds not proven
Therapeutic index evaluates overall efficacy, toxicity and impact on quality of life
Cytotoxic and Targeted Therapy
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GR: A
AGO: ++
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Evaluate compliance before and during therapy (especially
in elderly patients, with reduced PS, or significant comorbidities)
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Assess subjective and objective toxicities, symptoms and
PS repeatedly
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Use dosages according to published protocols
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Assess tumor burden at baseline and approx. every 2
months, i.e. every 2-4 cycles. Assessment of a target
lesion might be sufficient. In slow growing disease, longer
intervals are acceptable.
ABC Statement #11
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Evaluation of response to therapy should generally occur
every 2-4 months for ET or after 2-4 cycles for CT,
depending on the dynamics of the disease, the location
and extent of metastatic involvement, and type of
treatment.
Imaging of a target lesion may be sufficient in many
patients. In certain patients, such as those with indolent
disease, less frequent monitoring is acceptable. Additional
testing should be performed in a timely manner,
irrespective of the planned intervals, if PD is suspected or
symptoms appear. Thorough history and physical
examination must always be performed.
Cytotoxic Therapy
Duration
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As long as therapeutic index remains positive
 Treatment until best response
2b B
 Treatment until progression
2b B
 Change to alternative regimen
before progression
2b B
+
+
-
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Stop therapy in case of
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
Progression
Non-manageable toxicity
1c A
++
Chemotherapy for MBC – General
Considerations: Drug Selection
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The choice of cytotoxic drugs to be used depends on:
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ER / PR, HER2; combination with biologicals
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Previous treatments (and their toxicities)
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Aggressiveness of disease and localization of metastases
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Biologic age
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Co-morbidities (including organ dysfunctions)
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Patients preference and expectations
ABC Statement #15
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Treatment choice should take into account at
least these factors:
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HR & HER-2 status;
previous therapies and their toxicities;
disease-free interval;
tumour burden (defined as number and site of metastases);
physiologic age;
performance status; co-morbidities (including organ
dysfunctions);
menopausal status (for ET);
need for a rapid disease/symptom control;
socio-economic and psychological factors;
available therapies in the patient’s country
patient preference.
MBC HER2 negative
Cytotoxic 1st-Line Therapy*
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Monotherapy:
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Doxorubicin, epirubicin, mitoxantrone (A),
Peg. liposomal doxorubicin (Alip)
Docetaxel (q3w), paclitaxel (q1w) (T)
Vinorelbine
Capecitabine
Nab-paclitaxel
Ixabepilone
1b
1b
3b
2b
2b
1B
A
A
B
B
B
B
++
++
+
+
+
-
1b
2ba
1b
2b
1b
2b
1b
1b
A
B
A
B
B
B
B
B
++
+
+
++
++
+/+/+/-
Polychemotherapy:
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www.ago-online.de
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



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A+T
Paclitaxel + capecitabine
Docetaxel + capecitabine after adj. A
T + gemcitabine after adj. A
(F) + A + C or Alip + C
CMF(1+8)
BMF (bendamustine)
Ixabepilone + capecitabine
*In ER pos. disease only if endocrine therapy is not or not anymore indicated
MBC HER2 negative: Cytotoxic Therapy
after Anthracycline Treatment*
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Docetaxel q3w
1a
A
++

Paclitaxel q1w
1a
A
++

Capecitabine
2b
B
++

Nab-paclitaxel
2b
B
++

Peg-liposomal doxorubicin
2b
B
+

Vinorelbine
2b
B
+

Docetaxel + Peg-liposomal Doxo
1b
B
+/-

Etoposid / cisplatinum
2b
B
+/-
*independent whether anthracyclines were used in adjuvant
or 1st line metastatic situation
MBC HER2 negative: Cytotoxic Therapy After
Taxane and Anthracycline Treatment
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www.ago-online.de
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Experimental therapies within studies
Capecitabine
Eribulin
Vinorelbine
(Peg)-liposomal Doxorubicin
Gemcitabine + Cisplatin / Carboplatin
Gemcitabine + Capecitabine
Gemcitabine + Vinorelbine*
Ixabepilone + Capecitabine*
*Cave neutropenia / therapeutic index!
2b
1b
2b
2b
2b
2b
1b
1b
B
B
B
B
B
B
B
B
++
++
++
++
+
+/+/-
Triple Negative Metastatic
Breast Cancer (TNBC: ER-, PR-, HER2-)
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Cytotoxic therapy as for
ER pos. HER2 neg. patients
Experimental therapies within studies
Platinum-based regimen
4 C
Bevacizumab added to cytotoxic
therapy
2b B
++
++
+/+
First Line Therapy of HER2 Overexpressing
Metastatic Breast Cancer
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Docetaxel + trastuzumab + pertuzumab
Paclitaxel + trastuzumab + pertuzumab
1st-Line chemotherapy* + trastuzumab
Trastuzumab mono
Taxanes + lapatinib
1b
5
1b
2b
1ba
A
D
B
B
B
Trastuzumab + aromatase inhibitors (if ER+)
Lapatinib + aromatase inhibitors (if ER+)
2b B
2b B
++
+/+
+/+/+/-**
+/-**
*Taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel
**see Chapter Endocrine +/- targeted
Second Line Therapy of HER2
Overexpressing Metastatic Breast Cancer
(If Pretreatment with Trastuzumab)
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www.ago-online.de
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Capecitabine + lapatinib
Trastuzumab + lapatinib (if CT not possible)
TBP: 2nd-Line chemotherapy + trastuzumab
Taxane + trastuzumab + pertuzumab
Any other 2nd-Line chemotherapy* +
trastuzumab + pertuzumab
Trastuzumab mono
1b
1b
2b
5
B
B
D
D
+
+
+
+
5
D
2b B
+/+/-
Trastuzumab + aromatase inhibitors (if ER+)
Lapatinib + aromatase inhibitors (if ER+)
3b B
3b B
+
+
*e.g. vinorelbine; taxane/carboplatin; capecitabine/docetaxel (toxicity!)
Second and Further Lines of Therapy of HER2
Overexpressing Metastatic Breast Cancer
(If Pretreatment with Trastuzumab and Pertuzumab)
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TBP: 2nd-line chemotherapy* + trastuzumab +
pertuzumab („treatment beyond progression“)
5

Capecitabine + lapatinib
Trastuzumab + lapatinib (if CT not possible)
2b B
3b B
+
+

Experimental anti-HER2-regimen
5
+**


www.ago-online.de
D
D
+/-
*Taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel
**Study participation recommended
Antibody Drug Conjugates in Trastuzumab
pretreated Breast Cancer
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Trastuzumab-Emtansine (T-DM1)
(superior to Capecitabine & Lapatinib)
1b
A +*
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* Not yet approved, study participation recommended
Trastuzumab in HER2-positive
Metastatic Breast Cancer
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Guidelines Breast
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
As Monotherapy
 After cytotoxic pretreatment
 As 1st line therapy
As combination therapy
 With taxanes (1st line)
 With paclitaxel / carboplatin
 Vinorelbine (first line)
 Capecitabine / docetaxel
 Other cytotoxic agents
 In combination with aromatase inhibitors
As treatment beyond progression
 With capecitabine
 With lapatinib for heavily pre-treated pts.
Duration and dosing of treatment:
 Start of treatment as early as possible
 Treatment until progression of disease
 Weekly or 3weekly
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1b
2b
A
B
++
+
1b
1b
1b
1b
2b
2b
A
A
B
B
A
B
++
++
++
+
+
+/-
1b
2b
B
B
+
+
2b
1b
2b
B
A
C
++
++
++
Lapatinib in HER2-positive
Metastatic Breast Cancer
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In combination with
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
Paclitaxel in 1st line
2b
B
+/-

Capecitabine in ≥ 2nd line
1b
B
+

AI in ER positive disease
2b
B
+/-

Trastuzumab for heavily
pre-treated pts
2b
B
+
2b
B
In patients with brain metastases
(radioresistance) in combination
with capecitabine
+/-
Bevacizumab Treatment in
HER2-neg. Metastatic Breast Cancer
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1st line in combination with:





www.ago-online.de

Paclitaxel (q1w)
Capecitabine
Anthracyclines
Nab-Pac
Docetaxel (q3w)
1b
2b
2b
2b
1b
B
B
B
B
B
+
+
+/+/+/-
1b
1b
1b
B
B
B
+/-*
+/- *
-
2nd line in combination with:



Taxanes
Capecitabine
Gemcitabine or vinorelbine
*Study participation recommended
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„For Avastin in combination with paclitaxel, the Committee concluded
that the benefits continue to outweigh the risks, because the available
data have convincingly shown to prolong progression-free survival
of breast cancer patients without a negative effect on the
overall survival.“
Targeted Agents Registered in Other Indications –
Potentially Effective in HER2 negative BC
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
Sorafenib
2ba B -*

Sunitinib
1b B -

Vandetanib
1b B -* Study participation recommended
Palliative High Dose Chemotherapy
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High dose-therapy
1a A
--
1a A
--
(No treatment outside studies)
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
Dose dense therapy
(No treatment outside studies)