Metastatic Breast Cancer

Jennifer Low, MD, PhD

November 17, 2003
 BREAST CANCER
Stage IV
Any T any N M1

Examples of distant mestastatic disease

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

Liver

Bone
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
Metastatic
Metastatic Breast
Breast Cancer
Cancer

•• Limited
Limited metastases
metastases (bone
(bone && soft
soft tissue)
tissue)
•• Positive
Positive hormone
hormone receptors
receptors •• Extensive
Extensive metastases
metastases or
or visceral
visceral crisis
crisis
•• Hormone
Hormone responsive
responsive •• Negative
Negative hormone
hormone receptors
receptors
•• Disease-free interval 22 years
Disease-free interval years •• No
No response
response to
to hormones
hormones

Hormonal
Hormonal Therapy
Therapy Chemotherapy
Chemotherapy

Response
Response No
No response
response No progression Progression
No progression Progression of
of disease
disease

IfIf disease
disease progresses,
progresses, second-line
second-line hormonal
hormonal therapy
therapy Second-line
Second-line chemotherapy
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
First line Aromatase Inhibitor (AI)

Second line Nonsteroidal AI or Antiestrogen

if response

Third line Steroidal AI No

if response Response Chemotherapy

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 • Tamoxifen/ • T cell depleted
– Epothilone B analog Zarnestra allogeneic stem
– Microtubule – Oral farnesyl cell transplant
transferase
stabilizer – Immunotherapy
inhibitor, (inhibits
– Active in taxane ras oncogene to induce a graft
resistant tumors pathway) vs tumor effect

• Phase II trial – May reverse • Phase II trial

tamoxifen – Measurable
– Measurable disease resistance disease
– Metastatic or locally • Phase II trial – HLA matched
advanced patients sibling donor
– Measurable
for whom you would disease – Prior
consider taxane chemotherapy
– Hormone
therapy receptor positive
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