Breast Cancer Locally Advanced and Metastatic Disease C. Legler MD FRCPC September 30, 2005

Breast Cancer

Locally Advanced and Metastatic Disease

C. Legler MD FRCPC

September 30, 2005

Locally Advanced and Metastatic Breast Cancer

Overview:– Principles of neoadjuvant chemotherapy for locally

advanced and inflammatory breast cancer– Systemic therapy of metastatic breast cancer

• Chemotherapy• Hormonal agents• Biologic agents• Bisphosphonates

– Rationale for selection of treatment in metastatic disease

• chemotherapy vs. hormonal agents• Ideal first line agents?

Locally Advanced Breast Cancer

Definition: breast cancer, without distant metastatic spread, which is unresectable due to

• Satellite skin nodules

• Extensive regional lymph node involvement

• Fixation to skin or chest wall

• Inflammatory breast cancer


Combined modality treatment is the standard of care for locally advanced breast cancer.– Neoadjuvant chemotherapy

• Goals are to improve resectability of the tumour and to increase rates of breast conserving treatment.

– Locoregional therapy• Surgery, or radiotherapy, or both.


• Response rates to neoadjuvant chemotherapy:– Major responders: 47-

100%– Clinical complete responders: 8-63%– Pathologic complete responders: 3-30%

• A major response to chemotherapy is associated with improved disease-free and overall survival.


Survival is related to axillary lymph node status after neoadjuvant chemotherapy.

Positive nodes 5-year overall survival0 75%

1-4 40-50%

5-10 30%

>10 20%


Survival is related to response of primary tumour to neoadjuvant chemotherapy.

Author Median follow-up, years

Survival, patients with complete response

Survival, patients with partial response

Method of response assessment

Eltahir, 1998 5 74% overall survival

36% overall survival

Clinical response

Kuerer, 1999 5 89% overall survival

64% overall survival

Pathologic response

Bonnadonna,1998

8 86% disease-free survival

56% disease-free survival

Clinical response


Duration of neoadjuvant chemotherapy– Optimal duration of treatment is not known.– Rule of thumb: “treat until maximal response.”– May require from 2-8 treatments, depending

on rapidity of response.– Patients should be assessed by

multidisciplinary team after every 2 cycles of chemotherapy to determine optimal timing of surgery.


• Ideal neoadjuvant chemotherapy regimen has not been identified.

• Anthracycline based (epirubicin or adriamycin) chemotherapy is often used at start (AC, CAF, FEC).

• Taxanes (taxol, taxotere) are also extremely effective and have been shown to increase the rate of pathologic complete responses.


Impact of Taxanes in Neoadjuvant Chemotherapy.

• TAX-301 trial– 162 patients, randomly assigned to pre-

operative CAVP X 8 cycles vs.

CAVP x 4 then Taxotere X4– 5 year overall survival:

• CAVP X 8: 78%• CAVP X 4 + Taxotere X 4: 97%


Impact of Taxanes in Neoadjuvant Chemotherapy, continued

• NSABP B-27Preoperative AC X 4 vs

preoperative AC X 4 plus Taxotere X 4pathologic CR negative

nodes

AC X4 14% 51%

AC X4,Tax X4 26% 58%


Consensus for chemotherapyGive 4 cycles of anthracycline based or taxane

chemotherapy.

Assess response:If CR or near CR: proceed to definitive local

therapy, then 4 cycles of non cross-resistant regimen.

If less than “near complete response”: proceed to 4 cycles of non cross-resistant chemotherapy, then definitive local therapy.


Consensus for chemotherapy, continued:A total of 8 chemotherapy cycles should be given

(anthracycline x 4, taxane x 4).

All 8 cycles may be given preoperatively, or they may be split between preoperative and postoperative chemotherapy.

e.g. Anthracycline x4 then surgery then Taxane x4.

Or Anthracycline x4 then Taxane x4 then surgery.

Or Taxane x4 then surgery then Anthracycline x4.

Or Taxane x4 then Anthracycline x4 then surgery.


• Role of Herceptin (trastuzumab):– Initial reports are encouraging, but use of

herceptin cannot be recommended outside of a clinical trial.

• Role of High-dose chemotherapy with stem cell support:– No improvement in DFS or OS, with

significant increase in toxicity and worsening of quality of life, therefore not recommended.


Hormonal Management – Acceptable in Estrogen Receptor and/or

Progesterone Receptor positive cancers.– Best used in patients where chemotherapy is

relatively contraindicated• Elderly • Poor performance status• Comorbid illness• Patient reluctance to accept chemotherapy


Hormonal Management, continued:

• Rate of pathologic complete response is greatly diminished.

• Rate of breast-conserving treatment is greatly diminished.

• Response to treatment is much slower, e.g. 3-9 months.


Summary:• Standard of care is multimodality treatment.

– Chemotherapy: should contain anthracyclines and/or taxanes and should begin before surgery.

– Locoregional therapy: should be performed when a maximal tumour response has been obtained.

– Post-operative chemotherapy: should be performed if less than 8 cycles were given pre-operatively, until a total of 8 cycles of chemotherapy have been given.

– Hormonal management: is a slower option, and is restricted to ER and/or PR positive tumours.


Any questions on systemic treatment of locally advanced or inflammatory breast cancer?

Metastatic Breast Cancer

Goals of treatment of metastatic breast cancer:Cure: not a realistic goal

Few patients have complete responses, and disease free intervals are short.

Prolongation of survival:5-10% of patients will survive 5 years or more.2-5% of patients are long-term survivors (>10 years).

Improvement of Quality of Life:Most patients experience fewer disease symptoms, with

manageable treatment side effects.


Numerous treatment options exist:– Chemotherapy: anthracyclines, taxanes,

vinorelbine, capecitabine– Hormonal therapies: tamoxifen (Nolvadex),

anastrozole (Arimidex), letrozole (Femara), exemestane (Aromasin), megestrol acetate (Megace)

– Biologic agents: trastuzumab (herceptin)– Bisphosphonates: pamidronate,

zolendronate


Different options can be combined.– Herceptin and chemotherapy.

– Hormonal agents and bisphosphonates.

– Herceptin, chemotherapy and bisphosphonates.


How is initial therapy selected?– Patient factors: age, comorbid conditions,

willingness to accept side effects.– Tumour factors: ER, PR, her-2/neu status.– Course of illness: extent and location of

metastases, disease-free interval, pace of spread of metastases.

– Treatment factors: adjuvant chemotherapy, adjuvant hormonal agents, adjuvant radiotherapy.


The use of hormonal agents is favoured if:– Tumour is ER and/or PR positive.– Disease-free interval is long.– Few sites of metastases.– Metastases do not involve visceral organs. – Pace of disease progression is slow.– Patient has responded to previous hormonal

agents.


Use of hormonal agents, continued

Hormonal agents require 8-12 weeks to determine their efficacy, thus they are not recommended for patients with extensive visceral metastases.

Initial response to hormonal agents is 50-60% is ER/PR positive patients.


The use of chemotherapy is favoured if:– Tumour is negative for ER and PR.– Disease-free interval is short.– Extensive metastases are present, especially visceral

disease (liver, lung).– Disease is progressing rapidly.– Patient has not responded to previous hormonal

agents.

Initial response to chemotherapy is 50-75%.No clear advantage of combination regimens

over use of sequential single agents.


Hormonal agents:– Tamoxifen:

• Mixed estrogen receptor agonist-antagonist.• Can be used in premenopausal and

postmenopausal women.• Response rates are 50-60%.• Duration of response may be years.• Toxicities: hot flashes, increased risks of DVT/

pulmonary embolism, endometrial cancer• May be associated with tumour flare reaction in

up to 13% of patients.


Hormonal agents, continued:Aromatase inhibitors:

• Anastrozole (Arimidex), non-steroidal• Letrozole (Femara), non-steroidal• Exemestane (Aromasin), steroidal

Method of action: block conversion of adrenal androgens to estrogen in adipose tissue and in the breast.

Use is restricted to postmenopausal women.

Side effects: hot flashes, myalgias/arthralgias, increased risk of osteoporosis, altered lipid profiles.


Hormonal agents, continued:

Aromatase inhibitors:Anastrozole and Letrozole:

are non-steroidal aromatase inhibitors.

are both superior to Megace in tamoxifen refractory patients.

have similar efficacy to tamoxifen, with fewer side effects.


Hormonal agents, continued:

Aromatase inhibitors:Exemestane:

is a steroidal aromatase inhibitor.

is superior to Megace, and at least as effective as Tamoxifen.

can be effective in patients who have failed non-steroidal aromatase inhibitors.


• Hormonal agents, continued:– Megace (megestrol acetate)

• Is a progestin• Before aromatase inhibitors, was considered

second-line therapy, after tamoxifen.• May still have activity in some patients who have

failed tamoxifen and/or aromatase inhibitors.• Side effects: increased appetite, weight gain,

increased risk of DVT/pulmonary embolism.


• Sequencing of Hormonal agents in metastatic breast cancer:– Postmenopausal patients:

• Anastrozole or Letrozole as first line• Exemestane as second line• Tamoxifen and Megace remain options for third line OR for

patients who do not tolerate aromatase inhibitors.

– Premenopausal patients:• Tamoxifen as first line• Megace OR aromatase inhibitor with ovarian ablation as

second line.


• Chemotherapy:– Numerous agents have activity in metastatic

breast cancer:• Anthracyclines• Taxanes• Fluoropyrimidines• Vinca alkaloids• Other drugs: cyclophosphamide, methotrexate,

gemcitabine


• Anthracyclines– doxorubicin (Adriamycin),

epirubicin,

mitoxantrone

liposomal-PEGylated doxorubicin (Doxil-Caelyx)

Are among the most active agents in breast cancer (response rate at least 50%)


• Anthracyclines (cont’d)– Used in combination with cyclophosphamide,

and 5-fluorouracil – Significant toxicities exist

• Nausea• Alopecia• Mucositis• Myelosuppression• Cumulative cardiomyopathy• Radiation recall effect


• Anthracyclines, cont’d– Cumulative cardiomyopathy is the limiting

toxicity in metastatic breast cancer, particularly in patients who received anthracyclines in the adjuvant setting.

– Liposomal PEGylated doxorubicin • has less cardiomyopathy, more cutaneous side

effects (palmar-plantar syndrome).• Much more expensive than doxorubicin.


• Taxanes– Paclitaxel (Taxol)– Docetaxel (Taxotere)– Nanoparticle albumin-bound paclitaxel (Abraxane)

• Are the single most active drugs in breast cancer and the most active in adriamycin-refractory patients. (RR = 60%)

• Common toxicities include peripheral neuropathy, myalgias, arthralgias and alopecia.


• Taxanes, cont’d:– Paclitaxel (taxol)

• can induce anaphylactoid reactions, requiring premedication with steroids and antihistamines.

• Efficacy and toxicity profile can be improved by weekly administration (as opposed to q3weeks).

– Docetaxel (taxotere)• Can induce responses in 25% of patients who are

resistant to paclitaxel. • Cumulative toxicities include fluid retention,

sclerosis of tear ducts, loss of fingernails/toenails.


• Taxanes, cont’d– Nanoparticle albumin-bound paclitaxel

(Abraxane)• Novel formulation, does not require Cremophor.• No risk of anaphylactoid reaction, thus no need for

steroids.• Better tissue penetration.• Less toxic and more effective than paclitaxel.• Approved in the USA, not yet approved in Canada.


• Fluoropyrimidines:– 5-fluorouracil:

• is commonly used in combinations, such as CMF, CAF, FEC.

• Has activity as a single agent, esp. in prolonged infusions, but these regimens are not convenient.

• Toxicities: mucositis (stomatitis, enteritis, colitis), hand-foot syndrome, some myelosuppression


• Fluoropyrimidines, cont’d– Capecitabine (Xeloda)

• Oral 5-FU derivative, given BID X14 days q21days.• Prodrug is activated to 5-FU in tumour cells,

mimics a prolonged 5-FU infusion.• Has activity even in patients who are refractory to

anthracyclines and taxanes!! (RR=25%)• Dose limiting toxicity is usually hand-foot

syndrome.• NOT HEPATICALLY METABOLIZED, thus ideal

agent in patients with severe liver dysfunction!


• Vinca alkaloids:– Vinorelbine (Navelbine)

• Semi-synthetic vinca alkaloid, related to VCR/VBL• Less neurotoxicity, due to diminished binding to

axonal microtubules.• Active even in heavily pretreated patients

(response rates = 25-50%).• Excellent toxicity profile: no nausea, no alopecia,

no mucositis• Well tolerated by elderly, frail patients


• Other drugs:– Cyclophosphamide– Methotrexate– Gemcitabine

• All have limited activity as single agents, but are useful in combinations with other active drugs

• e.g. CMF, CAF, Gemcitabine-Taxol


Biologic agents

• Herceptin (trastuzumab)– Humanized mouse monoclonal antibody

directed against the her-2/neu protein.– Has activity against breast cancers that

strongly overexpress her-2/neu (score= 3+/3).– Has activity as a single agent, even in heavily

pre-treated patients.


• Herceptin, cont’d– Can be safely administered with taxanes and

vinorelbine, with increased response rates (compared to chemotherapy alone).

– Cannot be given with adriamycin; response rates increase BUT rate of cardiomyopathy rises to 27%!!!

– Patients on herceptin who have received anthracyclines in the past need monitoring for cardiac toxicity.


• Bisphosphonates:– Pamidronate (Aredia)– Zolendronate (Zometa)

• Given monthly to patients with bone metastases.• Leads to decreased risk of skeletal complications

(pain, fractures, need for radiotherapy)• Few toxicities: fever and chills post-infusion,

muscle spasms (transient hypocalcemia)• Rare cumulative toxicity: osteonecrosis of the

mandible (!)


• A rational approach to selecting therapy for patients with metastatic breast cancer:– For patients with bone metastases:

• monthly administration of Pamidronate or Zolendronate (regardless of ER/PR/her-2 status)

– For patients with ER and/or PR positive breast cancer, with low burden of metastases and slow pace of disease:

• start with hormonal agents.• If patient was on a hormonal agent at time of relapse, try to

select a non cross-resistant agent.


• A rational approach to selecting therapy for patients with metastatic breast cancer:– For patients with ER-negative/PR-negative

disease OR for patients with high tumour burden OR with rapid disease progression:

• Start with chemotherapy– In anthracycline-naïve patients, use anthracyclines.– In patients who had adjuvant anthracyclines, use

taxanes.


• A rational approach to selecting therapy for patients with metastatic breast cancer:– For patients with ER-negative/PR-negative

disease OR for patients with high tumour burden OR with rapid disease progression:

2nd, 3rd, 4th lines of treatment depend on patient’s previous side effects and current symptoms.

e.g. navelbine contraindicated in patient with abnormal liver function tests; capecitabine would be a safer choice.


• A rational approach to selecting therapy for patients with metastatic breast cancer:– For patients with her-2/neu 3+ disease:

• Herceptin should be given with taxane or vinorelbine chemotherapy.

• Herceptin can be given as a single agent even in heavily pre-treated patients.

• Herceptin as a single agent can be given as “maintenance” therapy after “inducing” a major reduction in tumour burden with herceptin-chemo combination.


Any questions about systemic treatment of metastatic breast cancer?


• Summary:– For locally advanced breast cancer:

• Assessment by a multidisciplinary team (surgical, radiation and medical oncologists) is essential.

• Neoadjuvant chemotherapy is used to improve resectability.

• Anthracyclines and taxanes are key components of neoadjuvant chemotherapy.


• Summary, cont’d– For metastatic breast cancer, numerous

active agents exist• Hormonal agents• Chemotherapy agents• Biologic agents • Bisphosphonates

– These agents can be combined to optimize treatment.


Summary, continued:Choice of initial therapy depends on– Patient factors: age, comorbidities – Tumour factors: receptor status, Her-2 status– Course of illness: tumour burden, pace of

progression– Treatment factors: adjuvant treatment

received; response to and tolerance of prior treatment

Documents

Breast Cancer Locally Advanced and Metastatic Disease C. Legler MD FRCPC September 30, 2005