breast cancer low

8/8/2019 Breast Cancer Low

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BREAST CANCER

Sites of distantmetastases

SkinSkin

Liver Liver

BoneBone

Pleur aPleur a

LungLung

Lymph nodesLymph nodes

Br ainBr ain



BREAST CANCER

Liver metastasis



Modalities of treatment Surgery may be considered for isolated local

and regional recurrences, possibly for some

isolated metastases Radiation for ³impending catastrophe´ (spinal

cord compression, superior vena cavasyndrome, impending fracture, palliation,

brain metastases) or inoperable local/regionaldisease

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 possibleresponse to hormonal therapy

± 1% or more cells positive or ER or PR byimmunohistochemistry

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 visceralcrisis or disease requiring rapid response



Rationale f or Hor monal Treatment

of Breast Cancer Endocrine manipulation can:

± Decrease levels of estrogen thatstimulate tumor growth

± Block estrogen inter action withestrogen receptors

Less toxicity

Response r ates in metastatic disease: ± 30% of unselected patients

± u50% 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)

³Palliative´

± 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



Treatment Sequence f or

Postmenopausal Women With

Metastatic Breast Cancer

First lineFirst line

Second lineSecond line

Third lineThird line

Fourth lineFourth line

Chemother apyChemother apy

Antiestrogen or Nonsteroidal Antiestrogen or Nonsteroidal Aromatase Inhibitor (AI)Aromatase Inhibitor (AI)

Nonsteroidal AI or AntiestrogenNonsteroidal AI or Antiestrogen

Steroidal AISteroidal AI

ProgestinProgestin

Fif th lineFif th line AndrogenAndrogen

if responseif response



NoNoResponseResponse



Treatment of Metastatic Breast Cancer :

Cytotoxic Agents

Anthr acyclines (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 diseaseand 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 determinestatus (amplified/not amplified)

± 3 = positive

Fluorescence In Situ Hybridization (FISH)correlates with response to Herceptin, butmore 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 Chemother apy with

Stem Cell Rescue Metastatic pts

with CR/PR

randomized to

HD/ABMT vsconventional

tx

33 vs 38% 3yr

survival

Stadtmauer EA, et al., NEJM 342:1069, 2000



Pamidronate in Metastatic Cancer Biphosphonates inhibit osteoclast-

induced bone resor ption

380 r andomized patients ± stage IV disease with at least 1 lytic bone

lesion

± 195 patients: chemother apy + placebo

± 185 patients: chemother apy 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

Hortobagyi GN et al, NEJM 335: 1785-1791, 1996

43% vs 56%

had anyskeletal

complication

after 12

months of

therapy



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 tomaximize the patient¶s needs and lifegoals



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

transferaseinhibitor, (inhibitsras oncogenepathway)

± May reversetamoxifen

resistance Phase II trial

± Measurabledisease

± Hormone receptor positive

T cell depleted

allogeneic stem

cell transplant

± Immunotherapyto induce a graftvs 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 rightbreast cancer ± ER/PR positive, her2/neu negative

± Treated with neoadjuvant chemotherapy, then

mastectomy with lymph node dissection andradiation and tamoxifen

1st recurrence at right chest wall duringradiation therapy

± Treated with radiation 2nd recurrence to spine a few months later

± Treated with radiation, removal of ovaries



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

breast cancer low

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