Metastatic Breast Cancer 7

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 Extensive Visceral involvement Resistance to Chemo/ hormones Death within weeks

Long Indolent course Limited bone/ soft tissue disease Responsive to therapy 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

Toxicity

Tumor Control ◄

Survival

Quality of life

►

Compliance 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  Myelosupression  Fatigue

reactions

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 Median OS TTP (months) (months)

No. of patients

ORR (%)

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 Median OS TTP (months) (months)

No. of patients

ORR (%)

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 bFGF TGFβ-1

VEGF bFGF TGFβ-1 PlGF

VEGF bFGF TGFβ-1 PlGF PD-ECGF

VEGF bFGF TGFβ-1 PlGF 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

Posttherapy -

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 –  Clinical

status 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 8595%

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