METASTATIC

BREAST CANCER

Dr A. K. Rathi
Associate Professor
Department of Radiotherapy
Maulana Azad Medical College, New Delhi
GREETINGS FROM MAMC
 Overview

• INTRODUCTION TO MBC
• WORK-UP
• THERAPEUTIC OPTIONS
• COMMON METASTASES
Metastatic Breast cancer (MBC)

• Stage IV
any T, any N, M1

• Presence of disease
at distant sites such
as bone, brain, liver
or lung
 MBC :
A Heterogeneous Disease

Two ends of spectrum

Rapid disease progression Long Indolent course

Extensive Visceral involvement Limited bone/ soft tissue disease
Resistance to Chemo/ hormones Responsive to therapy
Death within weeks Extended survival
 Goals Of Therapy

Definitive cure not possible

Palliation is the mainstay

 Prolong survival
 Improve quality of life
Cost at which goals are achieved

Tumor Control Toxicity

◄ Quality of life ► Compliance

Survival
Cost Burden
 Managing MBC

Variables in choosing options for therapy

 Menopausal status
 Hormone receptor status
 Her-2/ neu status
 Interval from prior adjuvant therapy
 Previous regimen for therapy
 Patients age
 Co-morbid conditions
 Tumor burden or sites of disease
 Evaluation

Histopathological confirmation with receptor

status

Tumor markers like CEA/ CA 15-3 or BRCA

Radio-nuclide Bone Scan

CXR, USG, CT & MRI for metastatic survey

 Treatment Options

*Surgery

*Chemotherapy

*Biologic Therapy

*Radiotherapy

*Hormonal management
 Hormonal Therapy

Advantages :
1. Well tolerated
2. Oral Medication

Disadvantages:
• Slow onset (3-4 months)
• Lack of activity in certain subgroups
 Hormonal Therapy

Indications:

 Hormone receptor positive cases

 Not immediate life threatening disease
 Non-visceral disease (bone, nodes,
skin)
 Long disease free survival
 Prior response to hormonal therapy
 Hormonal Agents

1. Ovarian Ablation
2. Selective Estrogen Receptor
Modulators
• Tamoxifen

3. Non-Steroidal Aromatase Inhibitors

• Anastrozole, Letrozole

4. Steroidal Aromatase Inhibitors

• Exemestane
 Ovarian Ablation

 Surgical Oophorectomy
 Radiation induced ablation
 Medical (LHRH agonist)

Option only in pre-menopausal cases

 Tamoxifen

 SERM
 Competitive inhibitor at ER
 Blocks Estrogen induced cancer cell stimulation
 Estrogenic effects in bone, vessels, endometrium

Toxicity
• Hot flushes
• Venous thrombo-embolism
• Endometrial Hyperplasia
 Non- Steroidal AI

Reversible inhibition of Aromatase

enzyme
Anastrazole, Letrozole.
Toxicity
• Hot flushes
• G.I. upset
• Myalgia/ Arthralgia
• Skeletal related events
 Steroidal AI

Irreversible inhibition of Aromatase

Enzyme
Exemestane.

Toxicity
• Similar to non-steroidal AIs
• Lesser osteoporosis
• Rare androgenic side effects
 Chemotherapy

Advantages:
2. Rapid onset of effectiveness
3. Generally effective in all sub
groups

Disadvantages:
6. Higher toxicity
 Chemotherapy

Indications:

3. Hormone receptor negative

disease
4. Rapid growth/ life threatening
disease
5. Visceral disease (liver, lung)
6. Short disease free interval
7. Hormone refractory disease
 Chemotherapy regimens

• Many potential regimens

 Single vs combinations
 combinations have increased RR with toxicity

• Initial trials of 2-3 cycles to assess

response

• Continued if:
 Patient tolerating treatment
 Ongoing benefit ( no tumor growth,
progression)
 What is the most effective
chemotherapy for MBC?

• No standard regimen

• Selection based on:

 Prior Rx ( dose, tolerance, timing, response)
 Symptoms
 Performance status
 Co-morbidities
 Patient’s choice, goals
 Toxicity Vs Effectiveness

HIGHLY EFFECTIVE LESSER TOXICITY

 Taxanes  Capecitabine

 Anthracyclines  Mitoxantrone

 Capecitabine  CMF
 Vinorelbine
 Taxanes

• Like Docetaxel or Paclitaxel

• Response rates – 18-55%

• Toxicity:
 Alopecia
 Neuropathy
 Hypersensitivity reactions
 Myelosupression
 Fatigue
 Anthracyclines

• Like Doxorubicin, Epirubicin

• Response rates – 35 – 50%

• Toxicity:
 Alopecia(100%)
 Dose dependant cardiotoxicity
 Myelosupression
 Capecitabine

• Oral 5-FU prodrug

• Effective in Anthracycline and Taxane
refractory cases
• Response rate – 20-28%
• Toxicity
 No alopecia
 Diarrhea
 Mucositis
 Hand foot syndrome
 CAPECITABINE & DOCETAXEL
COMBINATION

Median
No. of ORR Median OS
TTP
patients (%) (months)
(months)

O’Shaughnessy et al. 20021 255 42 6.1 14.5

Chan et al. 20052 152 32 8.0† NR

Mavroudis et al. 20053 98 49 9.8 35

Soto et al. 20064 91 74 8.1† 24+

Beslija et al. 20065 50 68 9.3 22.0

 CAPECITABINE & PACLITAXEL
COMBINATION

Median
No. of ORR Median OS
TTP
patients (%) (months)
(months)

Lück et al. 20061 170 52 12.0† 25.6

Soto et al. 20062 95 65 6.7† 24+

Batista et al. 20043 73 52 8.1 16.5

Blum et al. 20064 55 55 10.1 17.0

Gradishar et al. 20045 47 51 10.6 29.9

 Mitoxantrone

• Anthracenedione
• Improved toxicity vs
anthracyclines
• RR – under 30%

• Toxicity
 No alopecia
 Less cardiotoxicity
 Myelosupression
 Vinorelbine

• Vinca alkaloid
• Modest activity (25-50%)

• Toxicity:
 No aloplecia
 Myelosupression
 Neuropathy
 Infusion related myalgias
Focused approach is the call of the hour
 Biologic Therapy

Advantages:
2. Minimal toxicity
3. Targeted therapy

Disadvantages:
6. Effective in only small sub groups
7. costly
Her-2-neu gene

• Codes for growth

factors

• 25-30% cases
overexpress

• Over-expression
reduces median
survival

• Transtuzumab or
Herceptin targets HER-2
 Trastuzumab

• Single agent RR 10-30% in HER 2+

• In combination with chemotherapy
RR >50% with improved survival

• Toxicity:
 Hypersensitivity reactions
 Cardiotoxicity (more with anthracyclines)
 Efficacy of Trastuzumab plus Paclitaxel vs
Paclitaxel alone in MBC

Trastuzumab Plus
Paclitaxel Paclitaxel Alone

All IHC 3+ All IHC 3+

(n=92) (n=68) (n=96) (n=77)

ORR (%) 41 49 17 17

Median TTP (months) 6.9 7.1 3 3

Median DR (months) 10.5 10.9 4.5 4.6

Median TTF (months) 5.8 6.7 2.9 2.8

Median OS (months) 22.1 25 18.4 18

 Progression of angiogenic
activity in human tumours
Breast cancer

Tumour growth

VEGF VEGF VEGF VEGF VEGF

bFGF bFGF bFGF bFGF
TGFβ-1 TGFβ-1 TGFβ-1 TGFβ-1
PlGF PlGF PlGF
PD-ECGF PD-ECGF
Pleiotrophin
Adapted from Relf, et al. Cancer Res
1997
Bevacizumab (Avastin) in MBC

• Avastin plus paclitaxel

significantly prolongs
progression-free survival, and
significantly improves response
rate

• Ongoing trials are evaluating

Avastin with other
chemotherapy agents and in
other settings, including the
adjuvant and neoadjuvant
settings
 Reduction of lesions following
Herceptin and Tarceva

Baseline
-

Post-
therapy -
 Surgery

• Surgery is treatment of choice for single

visceral metastatic disease

• Surgical resection occasionally in

extensive local disease unresponsive to
treatment

• Spinal cord compression

• Surgical fixation of fractured bone

 Radiotherapy

• Painful Bony
metastases

• CNS metastases
Sanctuary sites for
systemic therapy

• Spinal cord
compression
 COMMON SITES
IN
METASTATIC
BREAST CARCINOMA
 Brain Metastases

SURGERY
Factors to be considered –
 Clinicalstatus of the patient
 Solitary vs multiple lesions
 Surgical accessibility
 Brain Metastases

RADIOTHERAPY
 Relieve symptoms in 60 – 80% cases
 20 Gy/ 4 #, 30 Gy/10 # or 40 Gy/20#
used

Favourable prognostic factors:

 KPS 70 to 100
 Absent or a controlled primary
 Age < 60 years
 Metastases limited to brain
 Brain Metastases

STEREOTACTIC RADIOSURGERY

Optimal for lesions–

 Less than 30 mm size
 Nearly spherical
 Minimally invasive
 Displacing normal
brain parenchyma

Local control rates 85-

95%
 Brain Metastases

CHEMOTHERAPY
• Limited use
• Response rates 15 to 60 %
• Best response in combination with
corticosteroids and supportive
management
 Bone
Metastases

• In 30 – 70% cases

• Spine  pelvis 
femur  skull 
upper extremity

• Pain is M/C
presentation
 Bone metastases

SURGERY

• Stabilization of weight bearing

bone

• Fragment removal, debulking

helps in pain relief
Bone Metastases

RADIOTHERAPY

Local
• Pain relief and
improving
function

Systemic
• Phosphorus-32
• Strontium-89
• Samarium-153
 Bone Metastases

SYSTEMIC THERAPY

• Hormonal management Rx of choice

in receptor +ve cases

• Receptor negative or with liver mets

 systemic chemotherapy

• Bisphosphonates have shown

significant reduction in skeletal
morbidity with no increase in survival
Lung Metastases

• Surgery:
Solitary lung mets
Primary controlled
No other mets
Complete resection
possible

• Radiotherapy:
Relieve pain, bleeding,
obstruction
 Liver metastases

• Prognosis usually
poor

• Surgery for Solitary

lesions
Survival depends
on:
number of mets,
disease free
interval, pre-op CEA
levels
 The greatest mistake in the treatment of diseases is that
there are physicians for the body and there are physicians for
the soul, although the two cannot be separated
-Plato
THANK YOU