Locally Advanced and Metastatic Disease 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

Locally Advanced 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.

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer Survival is related to axillary lymph node status after neoadjuvant chemotherapy. Positive nodes 5-year overall survival 0 75% 1-4 40-50% 5-10 30% >10 20%

Locally Advanced Breast Cancer 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 89% overall survival 64% overall survival Pathologic response Bonnadonna,1998 8 86% disease-free survival 56% disease-free survival

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer 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%

Locally Advanced Breast Cancer Impact of Taxanes in Neoadjuvant Chemotherapy, continued NSABP B-27 Preoperative AC X 4 vs preoperative AC X 4 plus Taxotere X 4 pathologic CR negative nodes AC X4 14% 51% AC X4,Tax X4 26% 58%

Locally Advanced Breast Cancer Consensus for chemotherapy Give 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.

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer 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

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer 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.

Locally Advanced Breast Cancer 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.

Metastatic Breast Cancer 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

Metastatic Breast Cancer Different options can be combined. Herceptin and chemotherapy. Hormonal agents and bisphosphonates. Herceptin, chemotherapy and bisphosphonates.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer Chemotherapy: Numerous agents have activity in metastatic breast cancer: Anthracyclines Taxanes Fluoropyrimidines Vinca alkaloids Other drugs: cyclophosphamide, methotrexate, gemcitabine

Metastatic Breast Cancer Anthracyclines doxorubicin (Adriamycin), epirubicin, mitoxantrone liposomal-PEGylated doxorubicin (Doxil-Caelyx) Are among the most active agents in breast cancer (response rate at least 50%)

Metastatic Breast Cancer Anthracyclines (cont’d) Used in combination with cyclophosphamide, and 5-fluorouracil Significant toxicities exist Nausea Alopecia Mucositis Myelosuppression Cumulative cardiomyopathy Radiation recall effect

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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

Metastatic Breast Cancer 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!

Metastatic Breast Cancer 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

Metastatic Breast Cancer 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

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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 (!)

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer 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.

Metastatic Breast Cancer Any questions about systemic treatment of metastatic breast cancer?

Locally Advanced and 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.

Locally Advanced and Metastatic Breast Cancer 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.

Locally Advanced and Metastatic Breast Cancer 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