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1 Focused Issue of This Month Drug Therapy for Breast Cancer Yeon Hee Park, MD Division of Hematology-Oncology/Department of Medicine, Sungkyunkwan University Scool of Medicine E - mail : yhparkhmo@skku.edu J Korean Med Assoc 2009; 52(10): Abstract Breast cancer is the second common cancer and the leading cause of cancer deaths in women in Korea. Contrary to public perception, it is a heterogeneous disease with varying morphology, prognosis, and response to therapy. Understanding of the tumor biology results in marked advance in drug therapy proceeding to individualized molecular targeted therapy using predictive biomarkers (hormonal receptor: HR and human epidermal growth factor receptor -2: HER2). This review considers various drug therapeutic options based on biologic background of breast cancer divided into metastatic, neoadjuvant, and adjuvant systemic drug therapies. These are conventional cytotoxic chemotherapy, hormonal therapy, and molecular targeted therapies including trastuzumab, an anti-her2 monoclonal antibody. In addition, bisphosphonate to improve outcomes of bone metastasis has seen an increased usage in adjuvant and metastatic setting. Microarray based genomic, transcription, and proteomic methods are transforming classification systems and identifying novel targets for the development of new therapeutics. It is important for us to appreciate and embrace the new developments as they will impact on daily clinical practice and require understanding of biomarkers as a tool for the determination of treatment options. Keywords: Breast cancer; Chemotherapy; Hormone receptor; HER2; Molecular targeted therapy 963

2 Park YH Figure 1. Integration of novel targeted therapies into the systemic treatment of breast cancer. 964

3 Drug Therapy for Breast Cancer Table 1. Therapeutic options of metastatic breast cancer according to risk factors Low risk High risk Hormone receptor Positive Negative HER2 expression Negative Endocrine Positive Chemotherapy Disease free interval > 2 years Therapy < 2 years Tumor growth Slow Fast Tumor burden Limited Extensive Metastatic sites Soft tissue, bone Viscera Table 2. Hormonal treatments in advanced breast cancer according to menopausal status Premenopausal Postmenopausal Antiestrogen Tamoxifen Antiestrogen Tamoxifen Toremifene Fulvestrant Exemestane Ovarian ablation LHRH agonist Aromatase Inhibitor Anastrozole Oophorectomy Letrozole High-dose estrogen High-dose estrogen 965

4 Park YH Table 3. Summary of trials comparing chemotherapy plus trastuzumab with chemotherapy alone in patients with metastatic breast cancer Reference Patient Therapy phase Outcomes population Slamon HER2-positive ORR 50% vs 32% 235 T + P/A or AC TTP 7 vs 5 months 234 P/A or AC OS 25 vs 20 months Marty HER2-positive Randomized ORR 61% vs 34% 92 T + D TTP 11 vs 6 months 94 D 31 vs 23 months Gasparini HER2-positive Randomized ORR 75% vs 57% 63 T + P TTP 12 vs 9 months 61 P IHC: immunohistochemistry, ORR: overall response rate, OS: overall survival, TTP: time to progression, T: trastuzumab, P: paclitaxel, A: doxorubicin, AC: doxorubicin+cyclophosphamide, D: docetaxel, ORR: overall response rate, TTP: time -to progression, OS: overall survival Table 4. Choice of treatment modalities in adjuvant systemic therapies Highly endocrine Incompletely endocrine Endocrine responsive* responsive non-responsive HER2- Endocrine therapy (consider Endocrine therapy (consider Chemotherapy negative adding chemotherapy adding chemotherapy according to risk) according to risk) HER2 - Endocrine therapy + Endocrine therapy + Trastuzumab + positive Trastuzumab + Chemotherapy Trastuzumab + Chemotherapy Chemotherapy * tumors express high levels of both steroid hormone receptors in a majority of cells some expression of steroid hormone receptors but at lower levels or lacking either ER or PgR tumors having no detectable expression of steroid hormone receptors 966

5 Drug Therapy for Breast Cancer Table 5. Summary of adjuvant trials containing taxanes Study Regimen Number of Median DFS (Disease OS (Overall patients follow-up Free Survival) Survival) M.D. Anderson FAC x 4 FACx months 83% NR (2002) Tx4 FAC x 4 86% P = 0.09 CALGB 9344 AC x 4 3, months 65% 77% AC x 4 x 4 70% 80% P = P = BCIRG 001 FAC 1, months 68% 81% DAC 75% 87% P = P = ECOG E2197 AC x 4 2, months 80% 87% AT x 4 86% 90% P = P = 0.05 GEICAM 9906 FEC x 6 1, months HR 0.63 HR 0.74 FEC x 4 weekly T P = P = 0.14 HeCOG E x 3 T x 3CMF x months HR 1.16 HR 2.42 E x 4 CMF x 4 P = 0.31 P = 0.02 NSABP B28 AC x 4 3, months 72% 85% AC x 4 T x 4 76% 85% P = P = 0.46 PACS 01 FEC x 6 1, months 73.2% 86.7% FEC x 3 D x % 90.7% P = P = 0.05 HR: hazard ratio, AC: doxorubicin, cyclophosphamide, T: paclitaxel, FAC: fluorouracil, doxorubicin, cyclophosphamide, DAC: docetaxel doxorubicin cyclophosphamide, E: epirubicin, FEC: fluorouracil epirubicin cyclophosphamide 967

6 Park YH Table 6. Summary of randomized trials of adjuvant aromatase inhibitors Trial Sample Size Follow-up Study Design Primary HR (95% CI) for (months) End Point primary end point ATAC 9,366 total 68 5yr Tam DFS ,216 HR+ vs (0.78~0.97) 5yr Anastrozole BIG I-98 8,010 total 26 5yr Tam DFS ,055 HR+ vs (0.7~0.93) 5yr Letrozole vs Letrozole Tam vs Tam Letrozole IES 4,742 total yr Tam Tam DFS ,853 HR+ vs (0.56~0.82) 2~3yr Tam Exemestane ABCSG trial 8 3,700 total 30 2yr Tam Tam EFS 0.68 All HR+ vs (0.49~0.91) 2yr Tam Anastrozole ITA 448 total 52 2~3yr Tam Tam PFS 0.43 All HR+ vs (0.25~0.73) 2~3 Tam Anastrozole MA-17 5,170 total 30 5yr Tam 5yr Letrozole EFS 0.58 All HR+ vs (0.45~0.76) All LN+ 5yr Tam Placebo HR+: hormone receptor-positive, LN+: lymph node-positive, Tam: tamoxifen, DFS: disease -free survival, EFS: event-free survival, PFS: progression-free survival 968

7 Drug Therapy for Breast Cancer Table 7. Summary of randomized, phase III trials evaluating adjuvant Trastuzumab in patients with HER2-positive early-stage breast cancer HERA NSABP B-31/ BCIRG 006 FinHer PASC 04 NCCTG N9831 Randomization 2001~ ~ ~ ~ ~2004 Number of 3,387 3,351/3,969 3, patients Design CTx T AC P vs AC P vs V/D CEF vs FE100C T/No vs CTx AC P+T AC P+T vs V/D+T CEF E75, D75 T/No DCT Age < 50 years (%) /48 Node+ (%) /100 HR positive (%) /58 Median F/U (months) 24 24/ DFS; HR / yr DFSR (%) 81 vs vs vs 86 vs vs 78 Not reported 86 vs 73 OS; HR / yr OSR 92 vs vs vs 95 vs vs 90 Not reported Discontinuation Not reported Not reported 16 of T d/t cardiac toxicity (%) T: trastuzumab, CTx: chemotherapy, AC: doxorubicin+cyclophosphamide, P: paclitaxel, DCT: docetaxel+carboplatin+ trastuzumab, V/D: vinorelbine or docetaxel, CEF: cyclophosphamide+epirubicin+fluorouracil, FECHR: hazard ratio, DFS: diseasefree survival, DFSR: disease-free survival rate, OS: overall survival, OSR: overall survival rate 969

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10 Park YH W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Liobl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2- positive advanced breast cancer: a German breast group 26/breast international group study: J Clin Oncol 2009; 27: Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jaqiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berqer M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med : Moy B, Goss PE. Lapatinib-associated toxicity and practical management recommendations. Oncologist 2007; 12: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. 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