1. Metastatic Breast Cancer
Jennifer Low, MD, PhD
November 17, 2003

2. BREAST CANCER Stage IV Examples of distant mestastatic disease
Any T any N M1
Examples of distant mestastatic disease

3. BREAST CANCER Sites of distant metastases
Brain
Pleura
Lung
Skin
Liver
Bone
Lymph nodes

4. BREAST CANCER Liver metastasis

5. Survival from Metastatic BC
From Greenberg P (MDAnderson), JCO 14: 2197, 1996

6. Modalities of treatment
Surgery may be considered for isolated local and regional recurrences, possibly for some isolated metastases
Radiation for “impending catastrophe” (spinal cord compression, superior vena cava syndrome, impending fracture, palliation, brain metastases) or inoperable local/regional disease
Systemic therapy for disseminated disease, disease not falling into above categories

7. Targeted Therapy in Breast Cancer
Hormone receptor status
Any Estrogen Receptor (ER) or Progesterone Receptor (PR) expression indicates possible response to hormonal therapy
1% or more cells positive or ER or PR by immunohistochemistry
Her2/neu (ErbB-2) overexpression
High overexpression of Her2/neu indicates possible responder to trastuzumab therapy
ER/PR/Her2 negative patients: chemotherapy

8. Metastatic Breast Cancer
Generally considered incurable
For most patients, primary goal should be palliation
First recurrences are always biopsied to confirm diagnosis
Confirm ER/PR status and Her2/neu status

9. Metastatic disease: Systemic therapy principles
Hormonal therapy for indolent disease
Single agent chemotherapy for aggressive/symptomatic disease or disease not responsive to hormonal therapy
Polyagent chemotherapy for visceral crisis or disease requiring rapid response

10. Systemic Treatment Approach for Metastatic Breast Cancer
Limited metastases (bone & soft tissue)
Positive hormone receptors
Hormone responsive
Disease-free interval 2 years
Extensive metastases or visceral crisis
Negative hormone receptors
No response to hormones
Hormonal Therapy
Chemotherapy
Response
No response
No progression
Progression of disease
If disease progresses, second-line hormonal therapy
Second-line chemotherapy

11. Rationale for Hormonal Treatment of Breast Cancer
Endocrine manipulation can:
Decrease levels of estrogen that stimulate tumor growth
Block estrogen interaction with estrogen receptors
Less toxicity
Response rates in metastatic disease:
30% of unselected patients
50% of ER-positive patients

12. Hormonal Therapies (FDA indications)
1st line therapy:
Tamoxifen, anastrozole (Arimidex), letrozole (Femara)
2nd line therapy:
Fulvestrant (Faslodex), toremifene (Fareston), exemestane (Aromasin)
“Palliative”
Goserelin (LHRH analog, Zoladex)

13. Hormonal Therapies for Post-menopausal Metastatic
Tamoxifen 20 mg po daily
Aromatase inhibitors:
anastrozole 1 mg po daily,
letrozole 2.5 mg po daily
exemestane 25 mg po daily
Fulvestrant 250 mg IM q month
Megace 40 mg po QID
Aminoglutethimide 250 mg po QID with hydrocortisone

14. Hormonal therapy for Premenopausal Metastatic
LHRH analog 7.5 mg depot every 28 days
Tamoxifen 20 mg po daily
May be considered with LHRH analog:
anastrozole 1 mg po daily,
letrozole 2.5 mg po daily
exemestane 25 mg po daily
Fulvestrant 250 mg IM q month ??
Premenopausal dose may be higher?
Megace 40 mg po QID

15. Treatment Sequence for Postmenopausal Women With Metastatic Breast Cancer
Antiestrogen or Nonsteroidal Aromatase Inhibitor (AI)
First line
Nonsteroidal AI or Antiestrogen
Second line
if response
Steroidal AI
Third line
No Response
Chemotherapy
if response
Fourth line
Progestin
if response
Fifth line
Androgen

16. Treatment of Metastatic Breast Cancer: Cytotoxic Agents
Anthracyclines (doxorubicin, liposomal doxorubicin)
Cyclophosphamide
Taxanes (paclitaxel, docetaxel)
Antimetabolites (5-FU, capecitabine)
Gemcitabine
Vinorelbine
Carboplatin/cisplatin

17. Her2/neu status
Membrane-associated tyrosine kinase receptor (aka erbB2) related to EGF
Expressed in breast cancers, DCIS, and some other tissues such as heart
Overexpressed in 25-30% of breast cancers
Associated with more aggressive disease and worse prognosis

18. Measurement of Her2/neu
Measured by immunohistochemistry (IHC)
Graded 0, 1+, 2+, or 3+
Based on characteristics of staining
0-1 = negative
2 = indeterminant, should be followed with FISH (fluorescent in situ hybridization) to determine status (amplified/not amplified)
3 = positive
Fluorescence In Situ Hybridization (FISH) correlates with response to Herceptin, but more expensive than IHC

19. Trastuzumab (Herceptin)
Humanized monoclonal antibody against her2/neu
FDA approved for metastatic breast cancer in 1998
Responses in patients with her2/neu positive breast cancer
IHC 3+
FISH positive
Single agent therapy has 26% response rate as 1st line therapy
May be given as an IV infusion weekly or every 3 weeks

20. Herceptin + Chemotherapy
Response rate approx 25% as single agent, as high as 75% in combination therapy
Taxol
Taxotere
Vinorelbine
Gemcitabine
Capecitabine
Taxane/platinum

21. High Dose Chemotherapy with Stem Cell Rescue
Metastatic pts with CR/PR randomized to HD/ABMT vs conventional tx
33 vs 38% 3yr survival
Stadtmauer EA, et al., NEJM 342:1069, 2000

22. Pamidronate in Metastatic Cancer
Biphosphonates inhibit osteoclast-induced bone resorption
380 randomized patients
stage IV disease with at least 1 lytic bone lesion
195 patients: chemotherapy + placebo
185 patients: chemotherapy plus pamidronate (90 mg IV q month x 12)
Hortobagyi GN et al, NEJM 335: , 1996

23. Pamidronate decreases skeletal complications in breast cancer
43% vs 56% had any skeletal complication after 12 months of therapy
Hortobagyi GN et al, NEJM 335: , 1996

24. Zoledronic Acid (Zometa)
Bisphosphonic acid – inhibitor of osteoclastic bone resorption
Indicated for solid tumor patients with bone metastases
4 mg IV over minutes
Check serum creatinine before each administration
Comparable in efficacy to pamidronate
Rosen LS, Cancer J 7:377, 2001

25. Metastatic disease: More thoughts on palliation
Because metastatic breast cancer is not considered curable, there are very few imperatives of treatment regimens
Clinical trials at any point of metastatic diagnosis is appropriate
Treatment should be individualized to maximize the patient’s needs and life goals

26. NCI Phase II Clinical Trials for Breast Cancer
BMS
Epothilone B analog
Microtubule stabilizer
Active in taxane resistant tumors
Phase II trial
Measurable disease
Metastatic or locally advanced patients for whom you would consider taxane therapy
Tamoxifen/ Zarnestra
Oral farnesyl transferase inhibitor, (inhibits ras oncogene pathway)
May reverse tamoxifen resistance
Phase II trial
Measurable disease
Hormone receptor positive
T cell depleted allogeneic stem cell transplant
Immunotherapy to induce a graft vs tumor effect
Phase II trial
Measurable disease
HLA matched sibling donor
Prior chemotherapy

27. Metastatic Breast Cancer Case Presentation
Patient CC
Jennifer Low, MD, PhD

28. Case Presentation
At age 30, found to have stage IIIA right breast cancer
ER/PR positive, her2/neu negative
Treated with neoadjuvant chemotherapy, then mastectomy with lymph node dissection and radiation and tamoxifen
1st recurrence at right chest wall during radiation therapy
Treated with radiation
2nd recurrence to spine a few months later
Treated with radiation, removal of ovaries

29. Case Presentation, cont.
2 years after original diagnosis, she found
Left (contralateral) breast mass (ER/PR positive, Her2/neu 3+)
Lung metastasis
Liver metastasis
Treated with mastectomy, anastrazole (hormonal therapy)
Several months later, developed pleural effusion
Treated with Herceptin and Taxol

30. Case Presentation, cont.
After Herceptin + Taxol:
NCI Clinical trial with docetaxel and flavopiridol (with progressive disease)
NCI Clinical trial with BMS (epothilone analog) for 8 months with partial response
Herceptin + Vinorelbine since July with stable disease