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

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

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

BREAST CANCER Liver metastasis

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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: 1785-1791, 1996

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: 1785-1791, 1996

Zoledronic Acid (Zometa) Bisphosphonic acid – inhibitor of osteoclastic bone resorption Indicated for solid tumor patients with bone metastases 4 mg IV over 15-30 minutes Check serum creatinine before each administration Comparable in efficacy to pamidronate Rosen LS, Cancer J 7:377, 2001

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

NCI Phase II Clinical Trials for Breast Cancer BMS-247550 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

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

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

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

Case Presentation, cont. After Herceptin + Taxol: NCI Clinical trial with docetaxel and flavopiridol (with progressive disease) NCI Clinical trial with BMS-247550 (epothilone analog) for 8 months with partial response Herceptin + Vinorelbine since July with stable disease