2 nd Consensus on Medical Treatment of Metastatic Breast Cancer Central European Cooperative Oncology Group Annals of Oncology 18: 215–225, 2007 Review

Introduction : Metastatic breast cancer [MBC] Primary goals of treatment - maximazing of QOL - prevention and palliation of symptom - Prolongation of survival Guidance of treatment choice - hormone receptor status : ER, PR - HER-2/neu status - duration of relapse-free interval since primary diagnosis of disease ( 2yr) - previous treatment - location of metastasis (visceral vs non-visceral) - symptom - pt. preference - side effect profile - availability of treatment

Treatment choices 1 Endocrine treatment 2 Cytotoxic chemotherapy 3 Non-endocrine ‘target therapy’ 4 Bisphosphonate 5 Supportive measure

Diagnosis of Metastatic Breast Cancer and Assessment of Biologic Variables Assessment of steroid receptor expression - estrogen receptor - progesterone receptor : decision making for endocrine treatment Assessment of Her-2/neu status - IHC : definition of Her-2/neu protein overexpression - FISH : measurement of gene amplification - CISH : chromogenic in situ hybridization : indication for treatment with trastuzumab ; recombinant DNA-derived humanized monoclonal antibody against the HER2 protein

Prognostic Factors Prognostic factorFavorableUnfavorable Performance statusGoodPoor Site of diseaseBone, soft tissueViscera No. of sites of diseaseOligoMultiple Hormone receptor status PositiveNegative Her-2/neu statusNegative Positive (significance less clear in trastuzumab era) Disease-free interval> 2 years< 2 years Prior adjuvant therapyNoYes Prior therapy for MBCNoYes

I. Endocrine Treatment First option to patients with hormone sensitive MBC Characteristics - long disease-free interval (>2 year) - no (or limited) visceral involvement - limited metastatic sites and disease-related symptoms - slow disease progression

Treatment options for postmenopausal patients 1. Tamoxifen 2. Nonspecific aromatase inhibitor ; aminoglutethimide, progestins medroxyprogesterone acetate ; not superior to tamoxifen, no benefit with combination 3. Non-steroidal third generation aromatase inhibitor ; anastrozole ; letrozole 4. Steroidal third generation aromatase inhibitor ; exemestane 5. Fulvestrant : selective estrogen receptor downregulator

▶ First line endocrine treatment Aromatase inhibitor vs. tamoxifen - anastrozole vs. tamoxifen : longer time to progression for anastrozole - letrozole vs. tamoxifen : significantly longer time to progression [TTP] and overall response rate [ORR] for letrozole - exemetrane vs. tamoxifen : superior to tamoxifen with TTP and ORR - fulvestrant vs. tamoxifen : no difference  Third generation aromatase inhibitor : first-line treatment for postmenopausal women with hormone receptor-positive MBC

▶ Second line endocrine treatment Failure of tamoxifen treatment - third generation AI vs. progestins or aminoglutethimide : superiority to third generation AI - anastrozole vs. letrozole : no difference - anastrozole vs. fulvestrant : no difference  Following tamoxifen treatment failure : third generation AI or fluvestrant for second-line endocrine therapy Failure of third generation AI treatment - exemestane, tamoxifen, fluvestrant - no definite available recommendation

Endocrine treatment for premenopausal patients - ovarian ablation(LHRH agonist) + tamoxifen/AI

II. Cytotoxic Chemotherapy Efficacy of polychemotherapy rather than monotherapy  anthracycline-based with taxanes - higher response rate and longer progression-free survival - improvement in overall survival - increased toxicity  Decision of treatment plan ; According to prognosis, performance status, symptom control, toxicity profile, quality of life

Definition of optimal first-line chemotherapy - no definitive recommendation - patients without preceding anthracycline : anthracycline-based treatment  doxorubicin, epirubicin, liposomal doxorubicin formulation - relapsed patients more than 12 months after anthracycline-based Tx : possible reinduction - cardiotoxicity : increasing incidence with combination of doxorubicin and paclitaxel  Anthracycline and/or taxane based- regimen : preferrable choice of first line chemotherapy : improvement of ORR and TTP, overall survival rate

Anthracycline resistance or failure 1. Monotherapy - Paclitaxel : weekly administration rather than q 21 days  better outcomes and limited haematologic toxicity increased cost and neurotoxicity - Docetaxel : significant increased TTP and OS over paclitaxel - nanoparticle albumin paclitaxel(ABI-007, Abraxane) : significant higher ORR, TTP with lower hypersensitivity and toxicity

2. Polychemotherapy - improved OS with polychemotherapy - docetaxel + capecitabine > single docetaxel : ↑↑ RR, TTP, OS / ↑↑toxicity - paclitaxel + gemcitabine > single paclitaxel : ↑↑ pain relief, quality of life  Anthracycline-resistance or treatment failure : Taxane-based treatment - taxane monotherapy - taxane + gemzar / xeloda

Chemotherapy after taxane / anthracycline - no definitive recommendation - capecitabine, gemcitabine, liposomal doxorubicin, vinorelbine - quality of life : major consideration - high dose chemotherapy with autologous PBSC support : no longer recommended Treatment duration - no information about optimal duration - higher number of cycles : longer survival and better QOL - controversial study result  Decision of treatment plan according to individual case by case : Sx, sign, side effect, QOL - continuation of chemotherapy in the absence of PD or severe side effect - possible treatment break with SD or optimal treatment response

Choice of Chemotherapy or Endocrine Therapy Treatment cascade - endocrine therapy as first-line treatment with slowly progressive hormone receptor-positive MBC - lower toxicity, longer response than chemotherapy - no overall survival benefit Concurrent use of endocrine and cytotoxic chemotherapy - no recommended

Trastuzumab-based Treatment Trastuzumab - effective single agent in HER-2/neu overexpressing MBC (3 + by IHC or FISH-positive) Trastuzumab + chemotherapy - ↑↑ ORR, OS than chemotherapy alone [with taxane, anthracycline] - increased cardiotoxiciy with anthracycline combination - combination with capecitabine, gemcitabine - triple combination with platinum salt + taxane Dosage - 4mg/kg initial loading  2mg/kg weekly - 8mg/kg initial loading  6mg/kg q 21 days : more safe and effective

Treatment schedule - maintenance without chemotherapy after optimal clinical response with trastuzumab-based treatment - no available information after PD despite of trastzumab treatment  In patients with Her-2/neu IHC or FISH-positive ; first-line trastuzumab monotherapy or non-anthracycline combination therapy  In patient with newly diagnosed with hormone receptor(+) and Her-2/neu(+), both ; initially endocrine treatment recommended

Bisphosphonate Indication - bone metastasis from MBC : reduction of incidence of skeletal events Dosage - pamidronate 90mg iv - zolendronate 4mg iv - ibandronate 6mg iv - ibandronate 50mg PO/day - clodronate 1600mg PO/day - better effect of zolendronate than pamidronate - no optimal duration q 3~4 wks

Supportive Care Symptomatic anemia - caused by cytotoxic drug - need of correction with symptomatic anemia [Hb < 11g/dL] - erythropoiesis-stimulating protein - RBC transfusion Leukopenia - myeloid colony-stimulating factor Psychological support Hormone replacement therapy and topical estrogen : discouraged - tolerable with receptor-negative women?

Emerging Treatment and Future Direction Emerging treatment with promising results - bevacizumab [Avastin] : humanized monoclonal Ab directed against the VEGF : disruption of angiogenesis - lapatinib : tyrosine kinase inhibitor directed both against the erbB1 and erbB2 receptor Future direction - proper definition of target, mechanism of drug sensitivity and resistance - investigation of target expression by biopsy specimen - investigation of biomarker [functional imaging] - combination with conventional treatment for most successful approach