Metastatic Breast Cancer

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Metastatic Breast Cancer

• Jennifer Low, MD, PhD
• November 17, 2003

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BREAST CANCERStage IV
Any T any N M1
Examples of distant mestastatic disease
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BREAST CANCERSites of distant metastases
Pleura Lung
Brain
Skin Liver Bone
Lymph nodes
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BREAST CANCERLiver metastasis
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Survival from Metastatic BC
From Greenberg P (MDAnderson), JCO 14 2197, 1996
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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

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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

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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

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Metastatic disease Systemic therapy principles

• Hormonal therapy for indolent disease
• Single agent chemotherapy for aggressive/symptomat
  ic disease or disease not responsive to hormonal
  therapy
• Polyagent chemotherapy for visceral crisis or
  disease requiring rapid response

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Systemic Treatment Approach for Metastatic
Breast Cancer
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
Progression of disease
No progression
If disease progresses, second-line hormonal
therapy
Second-line chemotherapy
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Rationale for Hormonal Treatmentof Breast Cancer

• Endocrine manipulation can
• Decrease levels of estrogen thatstimulate tumor
  growth
• Block estrogen interaction with estrogen
  receptors
• Less toxicity
• Response rates in metastatic disease
• 30 of unselected patients
• ?50 of ER-positive patients

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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)

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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

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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

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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
NoResponse
Chemotherapy
if response
Fourth line
Progestin
if response
Fifth line
Androgen
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Treatment of Metastatic Breast Cancer Cytotoxic
Agents

• Anthracyclines (doxorubicin, liposomal
  doxorubicin)
• Cyclophosphamide
• Taxanes (paclitaxel, docetaxel)
• Antimetabolites (5-FU, capecitabine)
• Gemcitabine
• Vinorelbine
• Carboplatin/cisplatin

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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

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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

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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

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Herceptin Chemotherapy

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

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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 3421069, 2000
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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
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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
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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 7377, 2001

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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 patients needs and life goals

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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

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Metastatic Breast CancerCase Presentation

• Patient CC
• Jennifer Low, MD, PhD

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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

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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

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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