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): 963-974 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
Park YH Figure 1. Integration of novel targeted therapies into the systemic treatment of breast cancer. 964
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
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
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 FACx4 524 60 months 83% NR (2002) Tx4 FAC x 4 86% P = 0.09 CALGB 9344 AC x 4 3,121 69 months 65% 77% AC x 4 x 4 70% 80% P = 0.0011 P = 0.0098 BCIRG 001 FAC 1,491 55 months 68% 81% DAC 75% 87% P = 0.001 P = 0.008 ECOG E2197 AC x 4 2,952 66 months 80% 87% AT x 4 86% 90% P = 0.015 P = 0.05 GEICAM 9906 FEC x 6 1,248 46 months HR 0.63 HR 0.74 FEC x 4 weekly T P = 0.001 P = 0.14 HeCOG E x 3 T x 3CMF x 3 595 62 months HR 1.16 HR 2.42 E x 4 CMF x 4 P = 0.31 P = 0.02 NSABP B28 AC x 4 3,060 64 months 72% 85% AC x 4 T x 4 76% 85% P = 0.008 P = 0.46 PACS 01 FEC x 6 1,999 60 months 73.2% 86.7% FEC x 3 D x 3 78.3% 90.7% P = 0.041 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
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 0.87 5,216 HR+ vs (0.78~0.97) 5yr Anastrozole BIG I-98 8,010 total 26 5yr Tam DFS 0.81 5,055 HR+ vs (0.7~0.93) 5yr Letrozole vs Letrozole Tam vs Tam Letrozole IES 4,742 total 31 2-3yr Tam Tam DFS 0.68 3,853 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
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 2001~2005 2000~2005 2001~2004 2000~2003 2000~2004 Number of 3,387 3,351/3,969 3,222 232 528 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 (%) 51 51 52 50 49/48 Node+ (%) 68 94 71 84 100/100 HR positive (%) 50 52 54 54 61/58 Median F/U (months) 24 24/35 36 36 48 DFS; HR 0.64 0.48 0.61/0.67 0.42 0.86 0.49 3yr DFSR (%) 81 vs 74 87 vs 75 87 vs 86 vs 81 89 vs 78 Not reported 86 vs 73 OS; HR 0.66 0.67 0.59/0.66 0.41 1.27 0.63 3yr OSR 92 vs 90 94 vs 92 97 vs 95 vs 93 96 vs 90 Not reported Discontinuation 4.3 18 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
Park YH 970
Drug Therapy for Breast Cancer 11. Buzdar AU. Endocrine therapy in the treatment of metastatic breast cancer. Semin Oncol 2001; 28: 291-304. 12. National Comprehensive Cancer Network Web site. NCCN Practice Guidelines in Oncology-v.1.2009: Breast/PDF/ breast.pdf.accessed 13. Colozza M, de Azambuja E, Personeni N, Lebrun F, Piccart MJ, Cardoso F. Achievements in systemic therapies in the pregenomic era in metastatic breast cancer. Oncologist 2007; 12: 253-270. 14. Estevez LG, Tusquets, Munoz M, Adrover E, Rovira PS, Segui MA, Rodriquez CA, Lescure AR, Ruiz M, Alvarez, Mata JG. Advanced breast cancer: chemotherapy phase trials that change a standard. Anticancer Drugs 2007; 18: 843-859. 15. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). J Clin Oncol 2003; 21: 588-592. 16. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase trial. J Clin Oncol 2003; 21: 968-975. 17. Piccart MJ, Burzykowski T, Buyse M, Sledge G, Carmichael J, Luck HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, Jassem J, Bontenbal M, Bonneterre J, Chan S, Basaran GA, Therasse P. Taxanes alone or in combination with anthracyclines as first-line chemotherapy of patients with metastatic breast. J Clin Oncol 2008; 26: 1980-1986. 18. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O Shaughnessy J. Phase trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005 23: 7794-7803. 19. Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, von Euler M, Sahmoud T, Webster A, Steinberg M; Arimidex Writing Committee; Investigators Committee Members. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast cancer. Cancer 2001; 92: 2247-2258 10. Nabholtz JM, Budzar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter trial. J Clin Oncol 2000; 18: 3758-3767. 11. Paridaens R, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Boqaerts J, Therasse P. Phase study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the EORTC Breast Group. J Clin Oncol 2008; 26: 4883-4890. 12. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M. Superior efficacy of letrozole versus tamoxifen in postmenopausal women with advanced breast cancer: results of a phase study of the international Letrozole Breast Cancer Group. J Clin Oncol 2001; 19: 2596-2606. 13. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank A, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A. Phase study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the international Letrozole Breast Cancer Group. J Clin Oncol 2003; 21: 2101-2109. 14. Rugo HS. The breast cancer continuum in hormone-receptorpositive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors. Ann Oncol 2008; 19: 16-27. 15. Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer 2005; 104: 236-239. 16. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausalwomen previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 2004; 22: 1605-1613. 17. Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R. Combined tamoxifen and luteinizing hormonereleasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19: 343-353. 18. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 2001; 344: 783-792. 19. Von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer 971
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 03-05 study: J Clin Oncol 2009; 27: 1999-2006. 20. 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 2006 355: 2733-2743. 21. Moy B, Goss PE. Lapatinib-associated toxicity and practical management recommendations. Oncologist 2007; 12: 756-765. 22. 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: 2666-2676. 23. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primarytherapy of early breast cancer 2007. Ann Oncol 2007; 18: 1133-1144. 24. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009. Ann Oncol 2009; 20: 1319-1329. 25. Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node negative breast cancers. J Clin Oncol 2008; 26: 5697-5704. 26. Curigliano G, Viale G, Bagnardi V. Clinical relevance of HER-2 overexpression/amplification in patients with small tumor size (pt1a-b) and node-negative breast cancer. J Clin Oncol 2009 in press 27. Smith IE. Targeting HER2 in the adjuvant setting: dealing with new standards and open questions. Breast 2009; 18 (Suppl 1): S17 (Abstr S41) 28. Buzdar AU, Singletary SE, Valero V, Booser DJ, Ibrahim NK, Rahman Z, Theriault RL, Walters R, Rivera E, Smith TL, Holmes FA, Hoy E, Frye DK, Manuel N, Kau SW, McNeese MD, Strom E, Thomas E, Hunt K, Ames F, Berry D, Hortobagyi GN. Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: Preliminary data of a prospective randomized trial. Clin Cancer Res 2002; 8: 1073-1079. 29. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicindose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003; 21: 976-983. 30. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweiqeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Binholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Voqul C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005; 352: 2302-2313. 31. Goldstein LJ, O'Neill A, Sparano J: E2197.Phase AT (doxorubicin/docetaxel) vac (doxorubicin/cyclophosphamide) in the adjuvant treatment of node-positive and high risk nodenegative breast cancer. J Clin Oncol 2005; 23: 16s (suppl: abstract 512) 32. Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz- Borrego M, Munarriz B, Rodriguez CA, Crespo C, de Alava E, Lopez Garcia-Asenjo JA, Guitian MD, Almenar S, Gonzalez- Palacio S JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Sequi MA, Mayordomo JI, Anton A, Baena JM, Palzaola A, Modolell A, Peleqri A, Mel JR, Aranda E, Adrover E, Alvarez JV, Garcia Puche JL, Sanchez-Rovira P, Gonzalez S, Lopez-Vega JM. Randomized phase III trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer: GEICAM9906 Trial. J Natl Cancer Inst 2008 100: 805-814. 33. Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM. Postoperative dose-dense sequential chemotherapy withepirubicin followed by CMF with or without paclitaxel in patients with high-risk operable breast cancer: A randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 2005; 16: 1762-1771. 34. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Ocnol 2005; 23: 3686-3696. 35. Roche H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulie P, Eichler F, Viens P, Monnier A, Vindevoqhel A, Campone M, Goudier MJ, Bonneterre J, Martin AL, Geneve J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients. The FNCLCCPACS01 Trial. J Clin Oncol 2006; 24: 5664-5671. 36. The ATAC Trialists' Group: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years adjuvant treatment of breast cancer. Lancet 2005; 365: 60-62 37. The Arimidex, Tamoxifen Alone or in Combination Trialists Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomized trial. Lancet 2002; 359: 2131-2139. 972
Drug Therapy for Breast Cancer 38. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early stage breast cancer. N Engl J Med 2003; 349: 1793-1802. 39. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081-1092. 40. Jonat W, Grant M, Boccardo F. Switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-responsive early breast cancer: A meta-analysis of the ARNO 95 trial, ABCSG trial 8, and the ITA trial. Breast Cancer Res Treat 2005; 94: 11. 41. Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kauffmann M, Wolfgang J; ABCSG and the GABG. Switching of postmenopausal women with endocrineresponsive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: Combined results of ABSCG trial 8 and ARNO 95 trial. Lancet 2005; 366: 455-462. 42. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14: 2738-2746. 43. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilchen N, Wist E, Sanchez Rovira P, Piccart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial. Lancet 2007; 369: 29-36. 44. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Maufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673-1684. 45. Perez EA, Romond EH, Bryant J. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. J Clin Oncol 2007; 24: 18S (abstract 512) 46. Slamon D, Eiermann W, Robert N. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2neu positive early breast cancer. Breast Cancer Res Treat 2006; 100: abstract 52 47. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, Alanko T, Kataja V, Asola R. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 354: 809-820. 48. Spielmann M, Roche H, Machiels JP. Trastuzumab following adjuvant chemotherapy in node-positive, HER2-positive breast cancer patients: 4-year follow-up results of the PACS- 04 trial. 2007; 31th San Antonio Breast Cancer Symposium, San Antonio, Texas 49. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. Natl Cancer Inst Monogr 2001; 30: 96-102. 50. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkely SM, Sneige N, Buchholz TA, Ross MI, McNeese MD, Buzdar AU, Hortobagyi GN, Singletary SE. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999; 17: 460-469. 51. Swain SM, Jeong JH, Geyer CE, Costantino JP, Pajon ER, Fehrenbacher L. NSABP B-30: definitive analysis of patient outcome from a randomized trial evaluating different schedules and combinationsof adjuvant therapy containing doxorubicin, docetaxel and cyclophophamide in women with operable, node-positive breast cancer. 2008; abstract 75. 32th San Antonio Breast Cancer Symposium, San Antonio, Texas 52. Eiermann W, Paepke S, Appfelstaeldt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Chaudri-Ross HA, Dugan M, Borgs M; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized doubleblind multicenter study. Ann Oncol 2001; 12: 1527-1532. 53. Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe- Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1-and/or ErbB-2- positive, estrogen receptor-positive primary breast cancer: evidence from a phase randomized trial. J Clin Oncol 2001; 19: 3808-3816. 54. Dowsett M. on behalf of the ATAC Trialists Group. Analysis of time to recurrence in the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial according to estrogen receptor and progesterone receptor status. Breast Cancer Res Treat 2003; 83: abstract 143 55. Smith I, Dowett M. on behalf of the IMPACT Trialists. Comparison of anastrozole vs tamoxifen vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptorpositive (ER+) operable breast cancer inpostmeno-pausal women: the IMPACT trial. Breast Cancer Res Treat 2003; 83: abstract 1 56. Buzar AU, Ibrahim NK, Francis D, Booser D, Thomas ES, Theriault RL, Pusztai L, Arun BK, Giordano SH, Cristofanilli M, 973
Park YH Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathological complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal group factor receptor 2-positive disease. J Clin Oncol 2005; 23: 3676-3685. 57. Buzar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-flourouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factorreceptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 2007; 13: 228-233. 58. Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: A systemic review. Cancer Treat Rev 2008; 34: 539-557. 59. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U. The molecular mechanism of nitrogen-containing bisphophonates as antiosteoporosis drugs. Proc Natl Acad Sci USA 2006; 103: 7829-7834. 60. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000; 88: 2961-2978. 61. Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS, Vessella RL. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostatic cancer. Clin Cancer Res 2003; 9: 295-306. 62. Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, Coleman RE, Holen I. Sequence and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxoru-bicin in breast and prostate cancer cells. Int J Cancer 2005; 113: 364-371. 63. Ottewell PD, Jones M, Lefley DV, Coleman RE, Holen I. Combined effects of cytotoxic drugs and anti-resorptive agents in vivo. Breast Cancer Res Treat 2006; abstract 6102 64. Van Valckenborgh E, De Raeve H, Devy L, Blacher S, Munaut C, Noël A, Van Marck E, Van Riet I, Van Camp B, Vanderkerken K. Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo. Br J Cancer 2002; 86: 796-802 65. Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S; American Society of Clinical Oncology. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042-4057. 66. Theriault RL, Biermann JS, Brown E, Brufsky A, Demers L, Grewal RK, Guise T, Jackson R, McEnery K, Podoloff D, Ravdin P, Shapiro CL, Smith M, Van Poznak CH. NCCN Task Force Report: Bone Health and Cancer Care. J Natl Compr Canc Netw 2006; 4: 1-20. 67. Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, Wheeler H, Simeone JF, Seaman JJ, Knight RD, Heffernan M, Mellars K, Reitsma DJ. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998; 16: 2038-2044. 68. Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, Costello S, Kennedy I, Simeone J, Seaman JJ, Knight RD, Mellars K, Heffernan M, Reitsma DJ. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebocontrolled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999; 17: 846-854. Peer Reviewers Commentary 974