Thursday, March 7, 2019

Breast Cancer Treatment (PDQ®) 3/3 —Health Professional Version - National Cancer Institute

Breast Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Fisher B, Fisher ER, Redmond C, et al.: Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer. Breast Cancer Res Treat 7 (3): 147-60, 1986. [PUBMED Abstract]
  2. Thor AD, Berry DA, Budman DR, et al.: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90 (18): 1346-60, 1998. [PUBMED Abstract]
  3. Paik S, Bryant J, Park C, et al.: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90 (18): 1361-70, 1998. [PUBMED Abstract]
  4. Simpson JF, Gray R, Dressler LG, et al.: Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 18 (10): 2059-69, 2000. [PUBMED Abstract]
  5. Hutchins LF, Green SJ, Ravdin PM, et al.: Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23 (33): 8313-21, 2005. [PUBMED Abstract]
  6. Abrams JS, Phillips PH, Friedman MA: Meeting highlights: a reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst 87 (24): 1837-45, 1995. [PUBMED Abstract]
  7. Weiss MC, Fowble BL, Solin LJ, et al.: Outcome of conservative therapy for invasive breast cancer by histologic subtype. Int J Radiat Oncol Biol Phys 23 (5): 941-7, 1992. [PUBMED Abstract]
  8. van Dongen JA, Voogd AC, Fentiman IS, et al.: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92 (14): 1143-50, 2000. [PUBMED Abstract]
  9. Fisher B, Anderson S, Bryant J, et al.: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347 (16): 1233-41, 2002. [PUBMED Abstract]
  10. Blichert-Toft M, Rose C, Andersen JA, et al.: Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr (11): 19-25, 1992. [PUBMED Abstract]
  11. van Dongen JA, Bartelink H, Fentiman IS, et al.: Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr (11): 15-8, 1992. [PUBMED Abstract]
  12. Sarrazin D, Lê MG, Arriagada R, et al.: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14 (3): 177-84, 1989. [PUBMED Abstract]
  13. Jacobson JA, Danforth DN, Cowan KH, et al.: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332 (14): 907-11, 1995. [PUBMED Abstract]
  14. Veronesi U, Cascinelli N, Mariani L, et al.: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347 (16): 1227-32, 2002. [PUBMED Abstract]
  15. Veronesi U, Salvadori B, Luini A, et al.: Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 31A (10): 1574-9, 1995. [PUBMED Abstract]
  16. Freedman GM, Anderson PR, Li T, et al.: Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 115 (5): 946-51, 2009. [PUBMED Abstract]
  17. Schmidt-Ullrich R, Wazer DE, Tercilla O, et al.: Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int J Radiat Oncol Biol Phys 17 (4): 733-8, 1989. [PUBMED Abstract]
  18. Solin LJ, Fowble BL, Schultz DJ, et al.: The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 279-87, 1991. [PUBMED Abstract]
  19. Wazer DE, Schmidt-Ullrich RK, Schmid CH, et al.: The value of breast lumpectomy margin assessment as a predictor of residual tumor burden. Int J Radiat Oncol Biol Phys 38 (2): 291-9, 1997. [PUBMED Abstract]
  20. Moran MS, Schnitt SJ, Giuliano AE, et al.: Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 32 (14): 1507-15, 2014. [PUBMED Abstract]
  21. Chagpar AB, Killelea BK, Tsangaris TN, et al.: A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer. N Engl J Med 373 (6): 503-10, 2015. [PUBMED Abstract]
  22. Barth RJ Jr, Danforth DN Jr, Venzon DJ, et al.: Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival. Arch Surg 126 (5): 574-7, 1991. [PUBMED Abstract]
  23. Rivadeneira DE, Simmons RM, Christos PJ, et al.: Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients. J Am Coll Surg 191 (1): 1-6; discussion 6-8, 2000. [PUBMED Abstract]
  24. Greco M, Agresti R, Cascinelli N, et al.: Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis. Ann Surg 232 (1): 1-7, 2000. [PUBMED Abstract]
  25. Kern KA: Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg 189 (6): 539-45, 1999. [PUBMED Abstract]
  26. Rubio IT, Korourian S, Cowan C, et al.: Sentinel lymph node biopsy for staging breast cancer. Am J Surg 176 (6): 532-7, 1998. [PUBMED Abstract]
  27. Veronesi U, Paganelli G, Galimberti V, et al.: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349 (9069): 1864-7, 1997. [PUBMED Abstract]
  28. Albertini JJ, Lyman GH, Cox C, et al.: Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276 (22): 1818-22, 1996. [PUBMED Abstract]
  29. Krag D, Weaver D, Ashikaga T, et al.: The sentinel node in breast cancer--a multicenter validation study. N Engl J Med 339 (14): 941-6, 1998. [PUBMED Abstract]
  30. Veronesi U, Paganelli G, Viale G, et al.: Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 91 (4): 368-73, 1999. [PUBMED Abstract]
  31. Mansel RE, Fallowfield L, Kissin M, et al.: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst 98 (9): 599-609, 2006. [PUBMED Abstract]
  32. Krag DN, Anderson SJ, Julian TB, et al.: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 11 (10): 927-33, 2010. [PUBMED Abstract]
  33. Giuliano AE, Hunt KK, Ballman KV, et al.: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305 (6): 569-75, 2011. [PUBMED Abstract]
  34. Galimberti V, Cole BF, Zurrida S, et al.: Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 14 (4): 297-305, 2013. [PUBMED Abstract]
  35. Donker M, van Tienhoven G, Straver ME, et al.: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 15 (12): 1303-10, 2014. [PUBMED Abstract]
  36. Cunningham BL: Breast reconstruction following mastectomy. In: Najarian JS, Delaney JP, eds.: Advances in Breast and Endocrine Surgery. Chicago, Ill: Year Book Medical Publishers, 1986, pp 213-226.
  37. Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991. [PUBMED Abstract]
  38. Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991. [PUBMED Abstract]
  39. Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986. [PUBMED Abstract]
  40. Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. Int J Radiat Oncol Biol Phys 21 (2): 339-46, 1991. [PUBMED Abstract]
  41. Clarke M, Collins R, Darby S, et al.: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366 (9503): 2087-106, 2005. [PUBMED Abstract]
  42. Eifel P, Axelson JA, Costa J, et al.: National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93 (13): 979-89, 2001. [PUBMED Abstract]
  43. Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011. [PUBMED Abstract]
  44. Romestaing P, Lehingue Y, Carrie C, et al.: Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 15 (3): 963-8, 1997. [PUBMED Abstract]
  45. Bartelink H, Horiot JC, Poortmans P, et al.: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345 (19): 1378-87, 2001. [PUBMED Abstract]
  46. Bartelink H, Maingon P, Poortmans P, et al.: Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 16 (1): 47-56, 2015. [PUBMED Abstract]
  47. Wazer DE, Kramer B, Schmid C, et al.: Factors determining outcome in patients treated with interstitial implantation as a radiation boost for breast conservation therapy. Int J Radiat Oncol Biol Phys 39 (2): 381-93, 1997. [PUBMED Abstract]
  48. Whelan TJ, Pignol JP, Levine MN, et al.: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362 (6): 513-20, 2010. [PUBMED Abstract]
  49. Haviland JS, Owen JR, Dewar JA, et al.: The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 14 (11): 1086-94, 2013. [PUBMED Abstract]
  50. Hickey BE, James ML, Lehman M, et al.: Fraction size in radiation therapy for breast conservation in early breast cancer. Cochrane Database Syst Rev 7: CD003860, 2016. [PUBMED Abstract]
  51. Whelan TJ, Olivotto IA, Parulekar WR, et al.: Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med 373 (4): 307-16, 2015. [PUBMED Abstract]
  52. Poortmans PM, Collette S, Kirkove C, et al.: Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med 373 (4): 317-27, 2015. [PUBMED Abstract]
  53. Budach W, Bölke E, Kammers K, et al.: Adjuvant radiation therapy of regional lymph nodes in breast cancer - a meta-analysis of randomized trials- an update. Radiat Oncol 10: 258, 2015. [PUBMED Abstract]
  54. Ragaz J, Jackson SM, Le N, et al.: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337 (14): 956-62, 1997. [PUBMED Abstract]
  55. Overgaard M, Hansen PS, Overgaard J, et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337 (14): 949-55, 1997. [PUBMED Abstract]
  56. Fowble B, Gray R, Gilchrist K, et al.: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6 (7): 1107-17, 1988. [PUBMED Abstract]
  57. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 355 (9217): 1757-70, 2000. [PUBMED Abstract]
  58. McGale P, Taylor C, Correa C, et al.: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383 (9935): 2127-35, 2014. [PUBMED Abstract]
  59. Taghian AG, Jeong JH, Mamounas EP, et al.: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 24 (24): 3927-32, 2006. [PUBMED Abstract]
  60. Recht A, Come SE, Henderson IC, et al.: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334 (21): 1356-61, 1996. [PUBMED Abstract]
  61. Fisher B, Brown AM, Dimitrov NV, et al.: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8 (9): 1483-96, 1990. [PUBMED Abstract]
  62. Wallgren A, Bernier J, Gelber RD, et al.: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35 (4): 649-59, 1996. [PUBMED Abstract]
  63. Hickey BE, Francis DP, Lehman M: Sequencing of chemotherapy and radiotherapy for early breast cancer. Cochrane Database Syst Rev 4: CD005212, 2013. [PUBMED Abstract]
  64. Halyard MY, Pisansky TM, Dueck AC, et al.: Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol 27 (16): 2638-44, 2009. [PUBMED Abstract]
  65. Lingos TI, Recht A, Vicini F, et al.: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21 (2): 355-60, 1991. [PUBMED Abstract]
  66. Paszat LF, Mackillop WJ, Groome PA, et al.: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 16 (8): 2625-31, 1998. [PUBMED Abstract]
  67. Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61 (6): 866-8, 1990. [PUBMED Abstract]
  68. Darby SC, McGale P, Taylor CW, et al.: Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6 (8): 557-65, 2005. [PUBMED Abstract]
  69. Højris I, Overgaard M, Christensen JJ, et al.: Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 354 (9188): 1425-30, 1999. [PUBMED Abstract]
  70. Nixon AJ, Manola J, Gelman R, et al.: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16 (4): 1374-9, 1998. [PUBMED Abstract]
  71. Giordano SH, Kuo YF, Freeman JL, et al.: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97 (6): 419-24, 2005. [PUBMED Abstract]
  72. Harris EE, Correa C, Hwang WT, et al.: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24 (25): 4100-6, 2006. [PUBMED Abstract]
  73. Meek AG: Breast radiotherapy and lymphedema. Cancer 83 (12 Suppl American): 2788-97, 1998. [PUBMED Abstract]
  74. Larson D, Weinstein M, Goldberg I, et al.: Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 12 (9): 1575-82, 1986. [PUBMED Abstract]
  75. Swedborg I, Wallgren A: The effect of pre- and postmastectomy radiotherapy on the degree of edema, shoulder-joint mobility, and gripping force. Cancer 47 (5): 877-81, 1981. [PUBMED Abstract]
  76. Powell S, Cooke J, Parsons C: Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 18 (3): 213-20, 1990. [PUBMED Abstract]
  77. Boice JD Jr, Harvey EB, Blettner M, et al.: Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326 (12): 781-5, 1992. [PUBMED Abstract]
  78. Storm HH, Andersson M, Boice JD Jr, et al.: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84 (16): 1245-50, 1992. [PUBMED Abstract]
  79. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11 (3): 485-97, 1985. [PUBMED Abstract]
  80. Taghian A, de Vathaire F, Terrier P, et al.: Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 361-7, 1991. [PUBMED Abstract]
  81. Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 86 (13): 983-8, 1994. [PUBMED Abstract]
  82. Senkus E, Kyriakides S, Penault-Llorca F, et al.: Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24 (Suppl 6): vi7-23, 2013. [PUBMED Abstract]
  83. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): 1687-717, 2005. [PUBMED Abstract]
  84. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352 (9132): 930-42, 1998. [PUBMED Abstract]
  85. Pritchard KI, Shepherd LE, O'Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354 (20): 2103-11, 2006. [PUBMED Abstract]
  86. Gennari A, Sormani MP, Pronzato P, et al.: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100 (1): 14-20, 2008. [PUBMED Abstract]
  87. De Laurentiis M, Cancello G, D'Agostino D, et al.: Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26 (1): 44-53, 2008. [PUBMED Abstract]
  88. Henderson IC, Berry DA, Demetri GD, et al.: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21 (6): 976-83, 2003. [PUBMED Abstract]
  89. Mamounas EP, Bryant J, Lembersky B, et al.: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23 (16): 3686-96, 2005. [PUBMED Abstract]
  90. Martin M, Pienkowski T, Mackey J, et al.: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352 (22): 2302-13, 2005. [PUBMED Abstract]
  91. Perez EA: TAC--a new standard in adjuvant therapy for breast cancer? N Engl J Med 352 (22): 2346-8, 2005. [PUBMED Abstract]
  92. Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358 (16): 1663-71, 2008. [PUBMED Abstract]
  93. Citron ML, Berry DA, Cirrincione C, et al.: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21 (8): 1431-9, 2003. [PUBMED Abstract]
  94. Hudis C, Citron M, Berry D, et al.: Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-41, 2005.
  95. Citron ML, Berry DA, Cirrincione C, et al.: Dose-dense (DD) AC followed by paclitaxel is associated with moderate, frequent anemia compared to sequential (S) and/or less DD treatment: update by CALGB on Breast Cancer Intergroup Trial C9741 with ECOG, SWOG, & NCCTG. [Abstract] J Clin Oncol 23 (Suppl 16): A-620, 33s, 2005.
  96. Del Mastro L, De Placido S, Bruzzi P, et al.: Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet 385 (9980): 1863-72, 2015. [PUBMED Abstract]
  97. Petrelli F, Cabiddu M, Coinu A, et al.: Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat 151 (2): 251-9, 2015. [PUBMED Abstract]
  98. Blackwell K, Semiglazov V, Krasnozhon D, et al.: Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol 26 (9): 1948-53, 2015. [PUBMED Abstract]
  99. Jones SE, Savin MA, Holmes FA, et al.: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24 (34): 5381-7, 2006. [PUBMED Abstract]
  100. Jones S, Holmes FA, O'Shaughnessy J, et al.: Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 27 (8): 1177-83, 2009. [PUBMED Abstract]
  101. Gagliato Dde M, Gonzalez-Angulo AM, Lei X, et al.: Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol 32 (8): 735-44, 2014. [PUBMED Abstract]
  102. Pritchard KI, Paterson AH, Paul NA, et al.: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14 (10): 2731-7, 1996. [PUBMED Abstract]
  103. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19 (14): 3306-11, 2001. [PUBMED Abstract]
  104. Smith RE, Bryant J, DeCillis A, et al.: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 21 (7): 1195-204, 2003. [PUBMED Abstract]
  105. Crump M, Tu D, Shepherd L, et al.: Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21 (16): 3066-71, 2003. [PUBMED Abstract]
  106. Praga C, Bergh J, Bliss J, et al.: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23 (18): 4179-91, 2005. [PUBMED Abstract]
  107. Schagen SB, Muller MJ, Boogerd W, et al.: Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst 98 (23): 1742-5, 2006. [PUBMED Abstract]
  108. Peto R, Davies C, Godwin J, et al.: Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379 (9814): 432-44, 2012. [PUBMED Abstract]
  109. Mehta RS: Dose-dense and/or metronomic schedules of specific chemotherapies consolidate the chemosensitivity of triple-negative breast cancer: a step toward reversing triple-negative paradox. J Clin Oncol 26 (19): 3286-8; author reply 3288, 2008. [PUBMED Abstract]
  110. Liedtke C, Mazouni C, Hess KR, et al.: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26 (8): 1275-81, 2008. [PUBMED Abstract]
  111. Silver DP, Richardson AL, Eklund AC, et al.: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28 (7): 1145-53, 2010. [PUBMED Abstract]
  112. Anders CK, Winer EP, Ford JM, et al.: Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res 16 (19): 4702-10, 2010. [PUBMED Abstract]
  113. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353 (16): 1659-72, 2005. [PUBMED Abstract]
  114. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al.: 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389 (10075): 1195-1205, 2017. [PUBMED Abstract]
  115. Romond EH, Perez EA, Bryant J, et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353 (16): 1673-84, 2005. [PUBMED Abstract]
  116. Perez E, Romond E, Suman V, et al.: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patiens with HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): 512, 6s, 2007.
  117. Perez EA, Romond EH, Suman VJ, et al.: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32 (33): 3744-52, 2014. [PUBMED Abstract]
  118. Slamon D, Eiermann W, Robert N, et al.: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365 (14): 1273-83, 2011. [PUBMED Abstract]
  119. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al.: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354 (8): 809-20, 2006. [PUBMED Abstract]
  120. Pivot X, Romieu G, Debled M, et al.: 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 14 (8): 741-8, 2013. [PUBMED Abstract]
  121. Mavroudis D, Saloustros E, Malamos N, et al.: Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol 26 (7): 1333-40, 2015. [PUBMED Abstract]
  122. Tan-Chiu E, Yothers G, Romond E, et al.: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23 (31): 7811-9, 2005. [PUBMED Abstract]
  123. Slamon D, Eiermann W, Robert N, et al.: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-52, 2006.
  124. Piccart-Gebhart M, Holmes E, Baselga J, et al.: Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol 34 (10): 1034-42, 2016. [PUBMED Abstract]
  125. von Minckwitz G, Procter M, de Azambuja E, et al.: Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 377 (2): 122-131, 2017. [PUBMED Abstract]
  126. Chan A, Delaloge S, Holmes FA, et al.: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17 (3): 367-77, 2016. [PUBMED Abstract]
  127. Martin M, Holmes FA, Ejlertsen B, et al.: Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18 (12): 1688-1700, 2017. [PUBMED Abstract]
  128. Burstein HJ, Temin S, Anderson H, et al.: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol 32 (21): 2255-69, 2014. [PUBMED Abstract]
  129. Pan H, Gray R, Braybrooke J, et al.: 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med 377 (19): 1836-1846, 2017. [PUBMED Abstract]
  130. Colleoni M, Gelber S, Goldhirsch A, et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24 (9): 1332-41, 2006. [PUBMED Abstract]
  131. Fisher B, Dignam J, Bryant J, et al.: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93 (9): 684-90, 2001. [PUBMED Abstract]
  132. Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 93 (6): 456-62, 2001. [PUBMED Abstract]
  133. Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88 (24): 1828-33, 1996. [PUBMED Abstract]
  134. Davies C, Pan H, Godwin J, et al.: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381 (9869): 805-16, 2013. [PUBMED Abstract]
  135. Albain KS, Barlow WE, Ravdin PM, et al.: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet 374 (9707): 2055-63, 2009. [PUBMED Abstract]
  136. Eisen A, Messersmith J, Franek M, et al.: Adjuvant ovarian ablation in the treatment of premenopausal women with early stage invasive breast cancer. Ontario, Canada: Cancer Care, 2010. Evidence-based Series # 1-9: Section 1. Available online. Last accessed January 31, 2019.
  137. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Lancet 341 (8856): 1293-8, 1993. [PUBMED Abstract]
  138. Schmid P, Untch M, Kossé V, et al.: Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol 25 (18): 2509-15, 2007. [PUBMED Abstract]
  139. Ejlertsen B, Mouridsen HT, Jensen MB, et al.: Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer. J Clin Oncol 24 (31): 4956-62, 2006. [PUBMED Abstract]
  140. Wolff AC, Davidson NE: Still waiting after 110 years: the optimal use of ovarian ablation as adjuvant therapy for breast cancer. J Clin Oncol 24 (31): 4949-51, 2006. [PUBMED Abstract]
  141. Boccardo F, Rubagotti A, Amoroso D, et al.: Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. boccardo@hp380.ist.unige.it. J Clin Oncol 18 (14): 2718-27, 2000. [PUBMED Abstract]
  142. Winer EP, Hudis C, Burstein HJ, et al.: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 20 (15): 3317-27, 2002. [PUBMED Abstract]
  143. Tevaarwerk AJ, Wang M, Zhao F, et al.: Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 32 (35): 3948-58, 2014. [PUBMED Abstract]
  144. Francis PA, Regan MM, Fleming GF, et al.: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372 (5): 436-46, 2015. [PUBMED Abstract]
  145. Gnant M, Mlineritsch B, Stoeger H, et al.: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12 (7): 631-41, 2011. [PUBMED Abstract]
  146. Pagani O, Regan MM, Walley BA, et al.: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371 (2): 107-18, 2014. [PUBMED Abstract]
  147. Bernhard J, Luo W, Ribi K, et al.: Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol 16 (7): 848-58, 2015. [PUBMED Abstract]
  148. Dowsett M, Forbes JF, Bradley R, et al.: Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 386 (10001): 1341-52, 2015. [PUBMED Abstract]
  149. The ATAC Trialists' Group. Arimidex, tamoxifen alone or in combination: 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 randomised trial. Lancet 359 (9324): 2131-9, 2002. [PUBMED Abstract]
  150. Howell A, Cuzick J, Baum M, et al.: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 (9453): 60-2, 2005. [PUBMED Abstract]
  151. Thürlimann B, Keshaviah A, Coates AS, et al.: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26): 2747-57, 2005. [PUBMED Abstract]
  152. Coates AS, Keshaviah A, Thürlimann B, et al.: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25 (5): 486-92, 2007. [PUBMED Abstract]
  153. Boccardo F, Rubagotti A, Guglielmini P, et al.: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 17 (Suppl 7): vii10-4, 2006. [PUBMED Abstract]
  154. Jakesz R, Jonat W, Gnant M, et al.: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366 (9484): 455-62, 2005 Aug 6-12. [PUBMED Abstract]
  155. Boccardo F, Rubagotti A, Aldrighetti D, et al.: Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer 109 (6): 1060-7, 2007. [PUBMED Abstract]
  156. Coombes RC, Hall E, Gibson LJ, et al.: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350 (11): 1081-92, 2004. [PUBMED Abstract]
  157. Coombes RC, Kilburn LS, Snowdon CF, et al.: Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 (9561): 559-70, 2007. [PUBMED Abstract]
  158. van de Velde CJ, Rea D, Seynaeve C, et al.: Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377 (9762): 321-31, 2011. [PUBMED Abstract]
  159. Regan MM, Neven P, Giobbie-Hurder A, et al.: Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol 12 (12): 1101-8, 2011. [PUBMED Abstract]
  160. De Placido S, Gallo C, De Laurentiis M, et al.: Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol 19 (4): 474-485, 2018. [PUBMED Abstract]
  161. Goss PE, Ingle JN, Pritchard KI, et al.: Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol 31 (11): 1398-404, 2013. [PUBMED Abstract]
  162. Goss PE, Hershman DL, Cheung AM, et al.: Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. Lancet Oncol 15 (4): 474-82, 2014. [PUBMED Abstract]
  163. Smith I, Yardley D, Burris H, et al.: Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J Clin Oncol 35 (10): 1041-1048, 2017. [PUBMED Abstract]
  164. Goss PE, Ingle JN, Martino S, et al.: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349 (19): 1793-802, 2003. [PUBMED Abstract]
  165. Bryant J, Wolmark N: Letrozole after tamoxifen for breast cancer--what is the price of success? N Engl J Med 349 (19): 1855-7, 2003. [PUBMED Abstract]
  166. Burstein HJ: Beyond tamoxifen--extending endocrine treatment for early-stage breast cancer. N Engl J Med 349 (19): 1857-9, 2003. [PUBMED Abstract]
  167. Goss PE, Ingle JN, Martino S, et al.: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97 (17): 1262-71, 2005. [PUBMED Abstract]
  168. Mamounas EP, Jeong JH, Wickerham DL, et al.: Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol 26 (12): 1965-71, 2008. [PUBMED Abstract]
  169. Goss PE, Ingle JN, Pritchard KI, et al.: Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med 375 (3): 209-19, 2016. [PUBMED Abstract]
  170. Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al.: Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05). J Natl Cancer Inst 110 (1): , 2018. [PUBMED Abstract]
  171. Coleman R, Powles T, Paterson A, et al.: Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386 (10001): 1353-61, 2015. [PUBMED Abstract]
  172. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97 (3): 188-94, 2005. [PUBMED Abstract]
  173. Bear HD, Anderson S, Brown A, et al.: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21 (22): 4165-74, 2003. [PUBMED Abstract]
  174. Smith IE, Dowsett M, Ebbs SR, et al.: Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23 (22): 5108-16, 2005. [PUBMED Abstract]
  175. Cortazar P, Zhang L, Untch M, et al.: Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384 (9938): 164-72, 2014. [PUBMED Abstract]
  176. Carlson RW, Allred DC, Anderson BO, et al.: Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 7 (2): 122-92, 2009. [PUBMED Abstract]
  177. Boughey JC, Suman VJ, Mittendorf EA, et al.: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA 310 (14): 1455-61, 2013. [PUBMED Abstract]
  178. Kuehn T, Bauerfeind I, Fehm T, et al.: Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 14 (7): 609-18, 2013. [PUBMED Abstract]
  179. Alvarado R, Yi M, Le-Petross H, et al.: The role for sentinel lymph node dissection after neoadjuvant chemotherapy in patients who present with node-positive breast cancer. Ann Surg Oncol 19 (10): 3177-84, 2012. [PUBMED Abstract]
  180. Lyman GH, Temin S, Edge SB, et al.: Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 32 (13): 1365-83, 2014. [PUBMED Abstract]
  181. Smith IC, Heys SD, Hutcheon AW, et al.: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20 (6): 1456-66, 2002. [PUBMED Abstract]
  182. von Minckwitz G, Kümmel S, Vogel P, et al.: Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst 100 (8): 552-62, 2008. [PUBMED Abstract]
  183. Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16 (8): 2672-85, 1998. [PUBMED Abstract]
  184. Fisher ER, Wang J, Bryant J, et al.: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95 (4): 681-95, 2002. [PUBMED Abstract]
  185. Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008. [PUBMED Abstract]
  186. van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19 (22): 4224-37, 2001. [PUBMED Abstract]
  187. Vriens BE, Aarts MJ, de Vries B, et al.: Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer 49 (15): 3102-10, 2013. [PUBMED Abstract]
  188. Untch M, Jackisch C, Schneeweiss A, et al.: Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 17 (3): 345-56, 2016. [PUBMED Abstract]
  189. von Minckwitz G, Rezai M, Loibl S, et al.: Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 28 (12): 2015-23, 2010. [PUBMED Abstract]
  190. von Minckwitz G, Schneeweiss A, Loibl S, et al.: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15 (7): 747-56, 2014. [PUBMED Abstract]
  191. Sikov WM, Berry DA, Perou CM, et al.: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33 (1): 13-21, 2015. [PUBMED Abstract]
  192. Rastogi P, Buyse ME, Swain SM, et al.: Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group. Clin Breast Cancer 11 (4): 228-34, 2011. [PUBMED Abstract]
  193. Untch M, Loibl S, Bischoff J, et al.: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13 (2): 135-44, 2012. [PUBMED Abstract]
  194. Buzdar AU, Ibrahim NK, Francis D, et al.: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23 (16): 3676-85, 2005. [PUBMED Abstract]
  195. Untch M, Rezai M, Loibl S, et al.: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28 (12): 2024-31, 2010. [PUBMED Abstract]
  196. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010. [PUBMED Abstract]
  197. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15 (6): 640-7, 2014. [PUBMED Abstract]
  198. Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14 (13): 1317-25, 2013. [PUBMED Abstract]
  199. Ismael G, Hegg R, Muehlbauer S, et al.: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13 (9): 869-78, 2012. [PUBMED Abstract]
  200. Gianni L, Pienkowski T, Im YH, et al.: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13 (1): 25-32, 2012. [PUBMED Abstract]
  201. Baselga J, Bradbury I, Eidtmann H, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379 (9816): 633-40, 2012. [PUBMED Abstract]
  202. Gianni L, Pienkowski T, Im YH, et al.: 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17 (6): 791-800, 2016. [PUBMED Abstract]
  203. Schneeweiss A, Chia S, Hickish T, et al.: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24 (9): 2278-84, 2013. [PUBMED Abstract]
  204. Carey LA, Berry DA, Cirrincione CT, et al.: Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol 34 (6): 542-9, 2016. [PUBMED Abstract]
  205. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15 (10): 1137-46, 2014. [PUBMED Abstract]
  206. Lenihan D, Suter T, Brammer M, et al.: Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 23 (3): 791-800, 2012. [PUBMED Abstract]
  207. Valachis A, Nearchou A, Polyzos NP, et al.: Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Int J Cancer 133 (9): 2245-52, 2013. [PUBMED Abstract]
  208. Eiermann W, Paepke S, Appfelstaedt J, et al.: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12 (11): 1527-32, 2001. [PUBMED Abstract]
  209. Preece PE, Wood RA, Mackie CR, et al.: Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. Br Med J (Clin Res Ed) 284 (6319): 869-70, 1982. [PUBMED Abstract]
  210. Masuda N, Lee SJ, Ohtani S, et al.: Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 376 (22): 2147-2159, 2017. [PUBMED Abstract]
  211. Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271 (20): 1587-92, 1994. [PUBMED Abstract]
  212. Rosselli Del Turco M, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271 (20): 1593-7, 1994. [PUBMED Abstract]
  213. Khatcheressian JL, Wolff AC, Smith TJ, et al.: American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 24 (31): 5091-7, 2006. [PUBMED Abstract]

Locally Advanced or Inflammatory Breast Cancer

Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer

On the basis of the available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.
The standard treatment options for locally advanced or inflammatory breast cancer may include the following:
  1. Breast-conserving surgery or total mastectomy with axillary lymph node dissection.
  2. Chemotherapy.
  3. Radiation therapy.
  4. Hormone therapy.
Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.
The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting (refer to the Postoperative Systemic Therapy section of this summary for more information), although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy.[1]
For patients who respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy.[2] Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.
Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.
Evidence (multimodality therapy):
  1. In a retrospective series, 70 patients with locally advanced breast cancer and supraclavicular metastases received preoperative chemotherapy. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection or breast-conserving surgery and axillary lymph node dissection before or after radiation therapy. Patients who did not respond to preoperative chemotherapy were treated with surgery and/or radiation therapy. After completion of local therapy, chemotherapy was continued for 4 to 15 cycles, followed by radiation therapy.[3]
    • Approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined-modality therapy.
    • These results have been confirmed in a separate series of patients treated in British Columbia.[4]
  2. A series of 178 patients with inflammatory breast cancer were treated with a combined-modality approach. Patients were treated with induction chemotherapy, then local therapy (radiation therapy or mastectomy), followed by chemotherapy, and, if mastectomy was performed, radiation therapy.[5][Level of evidence: 3iiiDii]
Subsequent trials have confirmed that patients with locally advanced and inflammatory breast cancer can experience long-term DFS when treated with initial chemotherapy.[1]
All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Petrelli F, Coinu A, Lonati V, et al.: Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27 (7): 702-8, 2016. [PUBMED Abstract]
  2. Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994. [PUBMED Abstract]
  3. Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001. [PUBMED Abstract]
  4. Olivotto IA, Chua B, Allan SJ, et al.: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21 (5): 851-4, 2003. [PUBMED Abstract]
  5. Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997. [PUBMED Abstract]

Locoregional Recurrent Breast Cancer

Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.
The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy.[1] The rates are somewhat higher (up to 10%) for those treated with mastectomy.[2] Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.[3-5]
Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated. Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if known.
ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence.[6] Patients in this study had no interval treatment. If ER and PR statuses are unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in the selection of chemotherapy or hormone therapy.[7]
Treatment options for locoregional recurrent breast cancer include the following:
  1. Chemotherapy.
  2. Hormone therapy.
  3. Radiation therapy.
  4. Surgery.
  5. Targeted therapy (e.g., trastuzumab).
Patients with locoregional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.[4]
Treatment options also depend on the site of recurrence, as follows:
  • Cutaneous: A phase III randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[8][Level of evidence: 1iiDiii]
  • Chest wall: Local chest wall recurrence after mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.[9,10] Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater-than-2-year disease-free interval before recurrence have the best chance for prolonged survival.[10] The 5-year disease-free survival (DFS) rate in one series of such patients was 25%, with a 10-year rate of 15%.[11] The locoregional control rate was 57% at 10 years. Systemic therapy should be considered in patients with locoregional recurrence.
  • Breast: In the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR[NCT00074152]) trial, patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.[12][Level of evidence: 1iiDii]
    • In ER-negative patients, the HR for DFS for chemotherapy versus no chemotherapy was 0.29 (95% CI, 0.13–0.67; 10 years DFS, 70% vs. 34%), whereas in ER-positive patients, the HR was 1.07 (95% CI, 0.57–2.00; 10 years DFS, 50% vs. 59%). The interaction between chemotherapy and ER status with respect to DFS was significant (P = .013).[13]
    • This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer in patients with ER-negative tumors.
(Refer to the Metastatic (systemic) disease section of this summary for information about treatment for recurrent metastatic breast cancer.) All patients with recurrent breast cancer are considered candidates for ongoing clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011. [PUBMED Abstract]
  2. Buchanan CL, Dorn PL, Fey J, et al.: Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg 203 (4): 469-74, 2006. [PUBMED Abstract]
  3. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986. [PUBMED Abstract]
  4. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993. [PUBMED Abstract]
  5. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991. [PUBMED Abstract]
  6. Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996. [PUBMED Abstract]
  7. Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987. [PUBMED Abstract]
  8. Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001. [PUBMED Abstract]
  9. Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991. [PUBMED Abstract]
  10. Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992. [PUBMED Abstract]
  11. Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990. [PUBMED Abstract]
  12. Aebi S, Gelber S, Anderson SJ, et al.: Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 15 (2): 156-63, 2014. [PUBMED Abstract]
  13. Wapnir IL, Price KN, Anderson SJ, et al.: Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol 36 (11): 1073-1079, 2018. [PUBMED Abstract]

Metastatic Breast Cancer

Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months,[1] some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[2][Level of evidence: 3iiDiii]
Treatment options for metastatic breast cancer include the following:
  1. Hormone therapy (tamoxifen, aromatase inhibitors).
  2. Targeted therapy (e.g., trastuzumab, lapatinib, pertuzumab, mammalian target of rapamycin [mTOR] inhibitors, and cyclin-dependent kinases (CDK4/6) inhibitors).
  3. Chemotherapy.
  4. Surgery, for patients with limited symptomatic metastases.
  5. Radiation therapy, for patients with limited symptomatic metastases.
  6. Bone modifier therapy, for patients with bone metastases.
Cytologic or histologic documentation of metastatic disease is obtained whenever possible.
Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.

Hormone Receptor-Positive or Hormone Receptor-Unknown Breast Cancer

Tamoxifen and aromatase inhibitor (AI) therapy

Initial hormone therapy
Initial hormone therapy depends, in part, on the patient's menopausal status.
For postmenopausal patients with newly diagnosed metastatic disease and estrogen receptor (ER)–positive tumors, progesterone receptor (PR)–positive tumors, or ER/PR–unknown tumors, hormone therapy is generally used as initial treatment. Hormone therapy is especially indicated if the patient’s disease involves only bone and soft tissue and the patient either has not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year.
While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER positive, PR positive, or ER/PR unknown, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the AI compared with tamoxifen.[3-5][Level of evidence: 1iiDiii]
Evidence (initial hormone therapy in postmenopausal women):
  1. A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).[6][Level of evidence: 1iA]
    • Patients who received an AI as either their first or second hormone therapy for metastatic disease and were randomly assigned to receive a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HRdeath], 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).
  2. Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant (refer to the discussion of second-line hormone therapy for more information about this drug) and anastrozole with anastrozole alone in the first-line treatment of hormone receptor-positive postmenopausal patients with recurrent or metastatic disease.[7,8] In both studies, fulvestrant was administered as a 500-mg loading dose on day 1; 250 mg was administered on days 15 and 29, and monthly thereafter; plus, 1 mg of anastrozole was administered daily. The Southwest Oncology Group (SWOG) trial included more patients who presented with metastatic disease; the Fulvestrant and Anastrozole Combination Therapy (FACT [NCT00256698]) study enrolled more patients who had previously received tamoxifen.[7,8]
    • The SWOG trial (SWOG-0226 [NCT00075764]), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and overall survival (OS) (HR, 0.81; 95% CI, 0.65–1.00; P = .05).[7][Level of evidence: 1iA]
    • In contrast, the FACT trial , which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).[8][Level of evidence: 1iA]
Another initial treatment option for postmenopausal women is AI therapy combined with CDK inhibitor therapy (refer to the Cyclin-dependent kinase inhibitor therapy section of this summary for more information).
In premenopausal women, several randomized but underpowered trials have tried to determine whether combined hormone therapy (luteinizing hormone–releasing hormone [LH-RH] agonists plus tamoxifen) is superior to either approach alone. Results have been inconsistent.[9-11]
Evidence (initial hormone therapy in premenopausal women):
  1. The best study design compared buserelin (an LH-RH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor-positive tumors.[12][Level of evidence: 1iiA]
    • Patients who received buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those who received tamoxifen alone (median survival, 2.9 years) or buserelin alone (median survival, 2.5 years) (P = .01).[12][Level of evidence: 1iiA]
    • Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.
Second-line hormone therapy
Women whose tumors are ER positive or ER unknown, with bone or soft tissue metastases only, and who have been treated with tamoxifen, may be offered second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective AI, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens;[13-21] and fulvestrant, an ER down-regulator.[22,23]
Evidence (second-line hormone therapy):
  1. Compared with megestrol acetate, all three currently available AI have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[13-19,24]
  2. In a meta-analysis that included randomized trials of patients who received an AI as either their first or second hormone therapy for metastatic disease, those who were randomly assigned to receive a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[6][Level of evidence: 1iA]
  3. Two randomized trials that enrolled 400 and 451 patients whose disease had progressed after they received tamoxifen demonstrated that fulvestrant yielded results similar to those of anastrozole in terms of its impact on PFS.[25,26] The proper sequence of these therapies is currently not known.[24,27]
  4. No benefit has been found in combining anastrozole and fulvestrant in patients who had previously been treated with an AI.[28]

Mammalian target of rapamycin (mTOR) inhibitor therapy

Endocrine therapy is recommended for patients with metastatic hormone receptor–positive disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mTOR inhibitors might enhance the efficacy of endocrine therapies.
Evidence (mTOR inhibitor therapy):
  1. The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor-positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.[29][Level of evidence: 1iDiii]
    • At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001).
    • The addition of everolimus to exemestane was more toxic than was placebo plus exemestane, with the most-common grade 3 or 4 adverse events being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).
    • The results of this study reported a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy, but there were more side effects.
    • There was no OS benefit to the combination after further follow-up.[30]
  2. Evidence of mTOR inhibitor activity in human epidermal growth factor receptor 2 (HER2)–positive breast cancer was shown in the double-blind, placebo-controlled, phase III BOLERO-3 (NCT01007942) trial.[31][Level of evidence: 1iDiii] In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant, breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine, or placebo plus trastuzumab plus vinorelbine.
    • At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067).
    • Serious adverse events were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group.
    • Final OS outcomes for this trial have not yet been reported.
Cyclin-dependent kinase inhibitor therapy
CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor-positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in both first- and later-line treatment of advanced hormone receptor-positive HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib, ribociclib, and abemaciclib.
Palbociclib
Evidence (palbociclib):
  1. PALOMA-2 (NCT01740427) confirmed the results of the PALOMA-1 trial.[32] This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666).[33] Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    • The primary endpoint (investigator-assessed PFS) was met with a median PFS of 24.8 months in the palbociclib-plus-letrozole group compared with 14.5 months in the placebo-plus-letrozole group (HR, 0.58; 95% CI, 0.46–0.72; P < .001).[33][Level of evidence: 1iDiii]
    • OS data are not yet mature.
    • Patients who received palbociclib experienced more frequent cytopenias (66.4% grade 3 to 4 in palbociclib-treated patients vs. 1.4% in placebo-treated patients). Other common adverse events included nausea, arthralgia, fatigue, and alopecia. The most common grade 3 to 4 adverse events other than neutropenia included leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).
    • The FDA granted accelerated approval to palbociclib beause of these results.
  2. PALOMA-3 (NCT01942135) is a double-blind, phase III trial of 521 patients with hormone receptor–positive, HER2/neu–negative, advanced breast cancer who had relapsed after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin. The preplanned stopping boundary was crossed at the time of the first interim analysis of investigator-assessed PFS.[34][Level of Evidence: 1iC]
    • The final analysis showed a median PFS of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm (HR, 0.46; 95% CI, 0.36–0.59; P < .0001).[35][Level of Evidence: 1iC]
    • Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (1%) in both groups. Patients receiving palbociclib had more-frequent fatigue, nausea, and headache.
    • Tumor PIK3CA mutational status did not significantly affect the magnitude of benefit associated with fulvestrant plus palbociclib (two-sided Pinteraction = .83).
    • Global quality of life as assessed by the European Organisation for Research and Treatment of Cancer questionnaire, QLQ-C30, was better maintained on the palbociclib-fulvestrant arm (mean change, -0.9 points vs. -4.0 points; P = 0.03).[34]
    • A prespecified analysis of OS was made after 310 patients had died. A 6.9 month difference in median OS favoring the palbociclib-fulvestrant arm (34.9 months vs. 28.0 months) was found, which did not reach statistical significance (HR, 0.81; 95% CI, 0.64–1.03, P = .09).[36]
Ribociclib
Evidence (ribociclib):
  1. Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with hormone receptor-positive and HER2-negative recurrent or metastatic breast cancer. A phase III, placebo-controlled trial (NCT01958021) randomly assigned 668 patients to receive ribociclib plus letrozole or placebo plus letrozole.[37] Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    1. The primary endpoint (investigator-assessed PFS) was met. A preplanned interim analysis was performed after 243 patients had disease progression or died, and median duration of follow-up was 15.3 months. After 18 months, the PFS rate was 63.0% (95% CI, 54.6–70.3) in the ribociclib group and 42.2% (95% CI, 34.8–49.5) in the placebo group.[37][Level of evidence: 1iDiii]
    2. No OS data are available.
    3. Adverse events in patients included neutropenia in the ribociclib group (74.3%) and in the placebo group (5.2%), nausea (51.5% and 28.5%), infection (50.3% and 42.4%), fatigue (36.5% and 30.0%), and diarrhea (35.0% and 22.1%).
      • These events were mostly grade 1 to 2 with the exception of cytopenia.
      • Grade 3 to 4 neutropenia occurred in 59.3% of patients in the ribociclib group and 0.9% of patients in the placebo group.
      • The rate of febrile neutropenia was 1.5% in the ribociclib group and 0% in the placebo group.
      • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in nine patients (2.7%) in the ribociclib arm compared with zero patients in the placebo arm.
  2. Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with hormone receptor-positive and HER2-negative recurrent or metastatic breast cancer. Patients who had received either no or one previous endocrine therapy for advanced disease were included in the MONALEESA-3 (NCT02422615) trial, a phase III, placebo-controlled trial that randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.[38] Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    1. The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 20.5 months versus 12.8 months in the placebo group (HR, .593; 95% CI, .480–.732; P <.001).[38][Level of evidence: 1iDiii]
    2. OS data are immature.
    3. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
      • Grade 3 to 4 neutropenia occurred in 53.4% of patients in the ribociclib group and 0.0% of patients in the placebo group.
      • The rate of febrile neutropenia was 1.0% in the ribociclib group and 0% in the placebo group.
      • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in 6.5% of patients in the ribociclib arm and 0.4% in the placebo arm.
  3. Ribociclib was also assessed in a study conducted solely in premenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor plus goserelin.[39] In the MONALEESA-7 (NCT02278120) trial, 672 premenopausal patients with hormone receptor-positive and HER2-negative recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo. Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    1. The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 23.8 months versus 13.0 months in the placebo group (HR, .55; 95% CI, 0.44–0.69; P < .0001).[39][Level of evidence: 1iC]
    2. Median time-to-definitive deterioration (≥10%) as measured by the global health status/quality-of-life scale score of the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire, QLQ-C30, was not reached in the ribociclib group, compared with 21.2 months in the placebo group (HR, 0.70; 95% CI, 0.53–0.92; P = .004).
    3. OS data are immature.
    4. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
      • Grade 3 to 4 neutropenia occurred in 61% of patients in the ribociclib group and 4% of patients in the placebo group.
      • The rate of febrile neutropenia was 2.0% in the ribociclib group and 1.0% in the placebo group.
      • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in 10.0 % of patients in the ribociclib arm and 2.0% in the placebo arm. Sixty-millisecond increases were more common in patients receiving tamoxifen (16% on ribociclib and 7% on placebo).
Abemaciclib
Evidence (abemaciclib):
  1. MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with hormone receptor-positive and HER2-negative advanced breast cancer.[40]
    • The primary endpoint, investigator-assessed PFS, was met. After a median follow-up of 17.8 months, the PFS was not reached in the abemaciclib arm and was reached at 14.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41–0.72, P = .000021).
    • OS data are not yet mature.
    • The side effect profile of abemaciclib differs from the other CDK4/6 inhibitors. Diarrhea was the most frequent adverse event in the abemaciclib arm, although most of the diarrhea cases were grade 1.
    • Neutropenia was more common in the abemaciclib arm; however, only 21.1% of participants experienced grade 3 to 4 neutropenia.
  2. The MONARCH 2 (NCT02107703) study tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with hormone receptor-positive and HER2-negative advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.[41]
    1. The primary endpoint (investigator-assessed PFS) was met, with median duration of follow-up of 19.5 months. The median PFS was 16.4 months for the abemaciclib-fulvestrant arm versus 9.3 months for the placebo-fulvestrant arm (HR, 0.55; 95% CI, 0.45–0.68; P < .001).[41][Level of evidence: 1iDiii]
    2. No OS data are available.
    3. Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).
      • These events were mostly grade 1 to 2. Grade 1 to 2 diarrhea occurred in 73% of the patients in the abemaciclib group and in 24.2% of the placebo group. Anti-diarrheal medicine effectively managed this symptom in most cases, according to the study report.
      • Grade 3 diarrhea occurred in 13.4% of patients in the abemaciclib group and 0.4% of patients in the placebo group. No grade 4 diarrhea was reported.
      • Grade 3 to 4 neutropenia occurred in 25.5% of patients in the abemaciclib group and 1.7% of patients in the placebo group. Febrile neutropenia was reported in six patients in the abemaciclib arm.
  3. Single-agent abemaciclib was approved by the FDA for use in hormone receptor–positive, HER2–negative breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 (NCT02102490) trial.[42] Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with hormone receptor–positive and HER2–negative advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated and most participants had visceral disease.
    • The primary endpoint, investigator-assessed objective response rate, was 19.7% at 12 months (95% CI, 13.3–27.5%).
    • The clinical benefit rate was 42.4%.
    • Median PFS was 6.0 months (95% CI, 4.2–7.5 months).
    • The most common adverse event was diarrhea, which occurred in 90.2% of the participants. However, the majority was grade 1 to 2 and only 19.7% of participants experienced grade 3 diarrhea. There was no grade 4 diarrhea.
    • Neutropenia occurred in 97.7% of participants, however, the majority was grade 1 to 2 and only 26.9% of participants experienced grade 3 to 4 neutropenia.

Hormone Receptor-Negative Breast Cancer

The treatment for hormone receptor-negative breast cancer is chemotherapy. (Refer to the Chemotherapy section of this summary for more information.)

HER2/neu–Positive Breast Cancer

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Monoclonal antibody therapy

Trastuzumab
Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu.[43] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[43] In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[44][Level of evidence: 3iiiDiv]
Evidence (trastuzumab):
  1. In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab.[45][Level of evidence: 1iiA]
    • Patients treated with chemotherapy plus trastuzumab had an OS advantage over those who received chemotherapy alone (25.1 months vs. 20.3 months, P= .05).[45][Level of evidence: 1iiA]
Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[46]
Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.
  • In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone.[47][Level of evidence: 1iDiii]
  • However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007[NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.[48][Level of evidence: 1iiA]
Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.
Pertuzumab
Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.
Evidence (pertuzumab):
  1. The phase III CLEOPATRA (NCT00567190) trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2-positive metastatic setting.[49,50][Level of evidence: 1iA]
    • With a median follow-up of 50 months, the median OS was 40.8 months in the control group versus 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months by the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80).
    • Median OS was 56.5 months in the pertuzumab group compared with 40.8 months in the placebo group (HR, 0.68; 95% CI, 0.57–0.84; P < .001).[50]
    • The toxicity profile was similar in both treatment groups, with no increase in cardiac toxic effects seen in the pertuzumab combination arm.
Ado-trastuzumab emtansine
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.
Evidence (T-DM1):
  1. The phase III EMILIA or TDM4370g (NCT00829166) study was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[51][Level of evidence: 1iiA] Patients were randomly assigned to receive either T-DM1 or lapatinib plus capecitabine.
    • Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P < .001).
    • Median OS was longer with trastuzumab emtansine versus lapatinib plus capecitabine (29.9 months vs. 25.9 months; HR, 0.75 [95% CI, 0.64–0.88].[52]
    • The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar syndrome were higher in patients who received lapatinib plus capecitabine.
  2. Further evidence of T-DM1’s activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.[53][Level of evidence: 1iiDiii] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.
    • At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97).
    • Preliminary OS results were similar between treatment arms.
    • T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 adverse events (46.4% vs. 90.9%), adverse events leading to treatment discontinuations (7.2% vs. 40.9%), and serious adverse events (20.3% vs. 25.8%).
  3. Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized phase III TH3RESA (NCT01419197) study of T-DM1 versus physician’s choice of treatment.[54][Level of evidence: 1iiA] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1.
    • At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s choice group (HR, 0.528; 95% CI, 0.422–0.661; P < .0001).
    • OS was significantly longer with trastuzumab emtansine versus the treatment of physician’s choice (median OS, 22.7 months vs. 15.8 months; HR, 0.68; 95% CI, 0.54–0.85; P = .0007).[55]
  4. The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE (NCT01120184) trial.[56][Level of evidence: 1iDiii] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.
    • The median PFS for these treatment groups was 13.7 months for the trastuzumab-plus-taxane group, 14.1 months for the T-DM1-plus-placebo group, and 15.2 months for the T-DM1-plus-pertuzumab group.
    • There was no significant difference in PFS with T-DM1 plus placebo compared with trastuzumab plus taxane (HR, 0.91; 97.5% CI, 0.73–1.13), or with T-DM1 plus pertuzumab compared with trastuzumab plus taxane (HR, 0.87; 97.5% CI, 0.69–1.08).
    • Therefore, neither T-DM1 plus placebo nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane.

Tyrosine kinase inhibitor therapy

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.
Evidence (lapatinib):
  1. A nonblinded randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[57][Level of evidence: 1iiA]
    • Median time-to-disease progression in the lapatinib-plus-capecitabine arm was 8.4 months compared with 4.4 months in the capecitabine-alone arm (HR, 0.49; 95% CI, 0.34–0.71; P < .001).
    • There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[57][Level of evidence: 1iiA]
    • Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. (Refer to the PDQ summary on Gastrointestinal Complicationsfor more information about diarrhea.)
    • No data are available on quality of life or treatment after disease progression.

Germline BRCA Mutation

For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly (adenosine diphosphate-ribose) polymerase (PARP) has shown activity.BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.

Olaparib

Evidence (olaparib):
  1. The OlympiAD (NCT02000622) trial was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine).[58] All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor-positive disease had also received endocrine therapy previously.
    • Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 months vs. 4.2. months; HR for disease progression or death, 0.58; 95% CI, 0.43–0.80; P < .001).[58][Level of evidence: 1iiA]
    • OS did not differ between the two treatment groups with median time to death (HRdeath, 0.90; 95% CI, 0.63–1.29; P = .57).
    • Olaparib was less toxic than standard therapy, with a rate of grade 3 or higher adverse events of 36.6% in the olaparib group and 50.5% in the standard therapy group, with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib; neutropenia, palmar-plantar erythrodysesthesia, and liver-function test abnormalities occurred more commonly with chemotherapy.
    • Of note, subset analysis suggested that PFS improvement with olaparib appeared greater in the TNBC subgroup (HR, 0.43; 95% CI, 0.29–0.63) than in the hormone receptor-positive subgroup (HR, 0.82; 95% CI, 0.55–1.26).

Talazoparib

Evidence (Talazoparib):
  1. The EMBRACA (NCT01945775) trial was a randomized, open label, phase III trial that assigned 431 patients with a deleterious germline BRCA or BRCA2 mutation and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine).[59] All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor-positive and hormone receptor-negative patients were enrolled.
    • Median PFS was significantly longer in the talazoparib group than in the standard therapy group (8.6 months vs. 5.6 months; HR for disease progression or death, 0.54; 95% CI, 0.41–0.71; P < .001).
    • Benefits were observed in all subgroups, although CIs were wide in the subgroup of patients who had received previous platinum therapy.
    • Median OS did not differ between the two groups (22.3 months vs. 19.5 months; HR for death, 0.76; 95% CI, 0.55–1.06; P = .11), although survival data are not yet mature.
    • The primary toxicity observed with talazoparib was myelosuppression, especially anemia.
    • Patient-reported outcome data demonstrated more favorable effects of talazoparib than standard chemotherapy on quality-of-life meaures.
(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Chemotherapy

Patients on hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with hormone receptor-negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.[60]
Single agents that have shown activity in metastatic breast cancer include the following:
  • Anthracyclines.
    • Doxorubicin.
    • Epirubicin.
    • Liposomal doxorubicin.[61-64]
    • Mitoxantrone.
  • Taxanes.
    • Paclitaxel.[65,66]
    • Docetaxel.
    • Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[67,68]
  • Alkylating agents.
    • Cyclophosphamide.
  • Fluoropyrimidines.
    • Capecitabine.[69-71]
    • 5-Fluorouracil (5-FU).
  • Antimetabolites.
    • Methotrexate.
  • Vinca alkaloids.
    • Vinorelbine.[72]
    • Vinblastine.
    • Vincristine.
  • Platinum.
    • Carboplatin.
    • Cisplatin.
  • Other.
    • Gemcitabine.[73]
    • Mitomycin C.
    • Eribulin mesylate.[74,75]
    • Ixabepilone.[76]
Combination regimens that have shown activity in metastatic breast cancer include the following:
  • AC: Doxorubicin and cyclophosphamide.[77]
  • EC: Epirubicin and cyclophosphamide.[78]
  • Docetaxel and doxorubicin.[79]
  • CAF: Cyclophosphamide, doxorubicin, and 5-FU.[80]
  • CMF: Cyclophosphamide, methotrexate, and 5-FU.[81]
  • Doxorubicin and paclitaxel.[82,83]
  • Docetaxel and capecitabine.[84]
  • Vinorelbine and epirubicin.[85]
  • Capecitabine and ixabepilone.[86]
  • Carboplatin and gemcitabine.[87]
  • Gemcitabine and paclitaxel.[88]
There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An Eastern Cooperative Oncology intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially.[89] Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[89][Level of evidence: 1iiA]; [90,91]
The selection of therapy in individual patients is influenced by the following:
  • Rate of disease progression.
  • Presence or absence of comorbid medical conditions.
  • Physician/patient preference.
Currently, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[1,92] A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[93][Level of evidence: 1iiA]
Decisions regarding the duration of chemotherapy may consider the following:
  • Patient preference and goals of treatment.
  • Presence of toxicities from previous therapies.
  • Availability of alternative treatment options.
The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.[94,95][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies,[95] survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation [96] or a different chemotherapy regimen given at higher versus lower doses.[97][Level of evidence: 1iiA] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.[98][Level of evidence: 1iiA] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Chemotherapy plus immunotherapy

The addition of atezolizumab, an anti-programmed death ligand 1 (PD-L1) + antibody, to first-line chemotherapy for patients with hormone-receptor–negative and human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer was evaluated in the phase III randomized placebo-controlled IMpassion130 trial (NCT02425891).[99] Participants (N = 902) were randomly assigned 1:1 to atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel or to placebo plus nab-paclitaxel. Participants were stratified according to the presence of liver metastases (yes/no), receipt of previous taxane therapy (yes/no), and PD-L1 status (positive or negative). PD-L1 score of 1% or greater was defined as positive. Co-primary endpoints included PFS and OS, both of which were evaluated in the intention-to-treat population and in the PD-L1–positive population (n = 369).
  1. PFS data are final with a median follow-up of 12.9 months and included the following:
    • In the intention-to-treat population, PFS was improved with the addition of atezolizumab (median PFS, 7.2 months vs. 5.5 months; HR, 0.80; 95% CI, 0.69–0.92; P = .0025).
    • In the PD-L1–positive population, PFS was improved with the addition of atezolizumab (median PFS, 7.5 months vs. 5 months; HR, 0.62; 95% CI, 0.49–0.78; P < .001).
  2. OS data are not yet mature. Results of the first interim analysis for OS, performed at the time of the final PFS analysis, included the following:
    • In the intention-to-treat population, there was a nonsignificant trend towrd improved OS with the addition of atezolizumab (median OS, 21.3 months vs. 17.6 months; HR, 0.84; 95% CI, 0.69–1.02; P = .08).
    • The study design used hierarchical testing for OS requiring that the OS be statistically significantly improved with atezolizumab in the intention-to-treat population before OS could be compared between the arms in the PD-L1–positive population. Because this requirement was not met at the time of the first interim analysis, a P-value could not be determined at that time for the comparison of OS between the two arms in the PD-L1–positive population. Median OS was, however, 9.5 months longer in the atezolizumab arm in the PD-L1–positive population (25 months vs. 15.5 months; HR, 0.62; 95% CI, 0.45–0.86).[99][Level of evidence: 1iDiii]
  3. Adverse events occurred as expected. Adverse events that were potentially immune-related were more frequent in the atezolizumab arm.
Atezolizumab is not currently approved by the FDA for use in breast cancer in the United States.

Cardiac toxic effects with anthracyclines

The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:
  • Advanced age.
  • Previous chest-wall radiation therapy.
  • Previous anthracycline exposure.
  • Hypertension and known underlying heart disease.
  • Diabetes.
The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin.[100-103] The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[104] The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 or more when further treatment with an anthracycline is likely to be of benefit.[105] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[106]

Surgery

Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:
  • Fungating/painful breast lesions (mastectomy).
  • Parenchymal brain or vertebral metastases with spinal cord compression.
  • Isolated lung metastases.
  • Pathologic (or impending) fractures.
  • Pleural or pericardial effusions.
(Refer to the PDQ summary on Cancer Pain for more information; refer to the PDQ summary on Cardiopulmonary Syndromes for information about pleural and pericardial effusions.)

Radiation Therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases.[107] Indications for external-beam radiation therapy include the following:
  • Painful bony metastases.
  • Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
  • Bronchial obstruction.
  • Fungating/painful breast or chest wall lesions.
  • After surgery for decompression of intracranial or spinal cord metastases.
  • After fixation of pathologic fractures.
Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[108,109]

Bone Modifier Therapy

The use of bone modifier therapy to reduce skeletal morbidity in patients with bone metastases should be considered.[110] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[111-113][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[114]
The optimal dosing schedule for zoledronate was studied in CALGB-70604 [Alliance; NCT00869206], which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks.[115] Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority).[115][Level of evidence: 1iiD] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.
The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.[116]
(Refer to the PDQ summary on Cancer Pain for more information on bisphosphonates.)

Bevacizumab

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor–A. Its role in the treatment of metastatic breast cancer remains controversial.
Evidence (bevacizumab for metastatic breast cancer):
  1. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.[117] The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab.[117][Level of evidence: 1iiA]
    • The study failed to demonstrate a statistically significant effect on PFS (4.9 months with combination therapy vs. 4.2 months with capecitabine alone; HR, 0.98) or OS (15.1 months vs. 14.5 months).[117][Level of Evidence: 1iiA]
  2. ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab.[118][Level of evidence: 1iiA]
    • The trial demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR, 0.60; P < .001).[118][Level of Evidence: 1iiA]
    • The addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months; P = .16).
    • Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.
  3. The AVADO (NCT00333775) trial randomly assigned 736 patients to receive docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer.[119][Level of evidence: 1iiA]
    • The combination of docetaxel plus bevacizumab at 15 mg/kg, but not 7.5 mg/kg, modestly improved median PFS compared with placebo (10.1 mo vs. 8.1 mo) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[119][Level of Evidence: 1iiA]
    • More toxicity was seen in patients in the bevacizumab-containing arms, with significantly higher rates of bleeding and hypertension compared with patients in the placebo arms.
  4. The RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[120][Level of evidence: 1iiA]
    • Median PFS was longer for each bevacizumab-containing combination (capecitabine cohort: increased from 5.7 months to 8.6 months; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and taxane-anthracycline cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[120][Level of Evidence: 1iiA]
    • No statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed.
    • Toxicities associated with bevacizumab were similar to those seen in previous bevacizumab clinical trials.
  5. The RIBBON 2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer. This trial randomly assigned 684 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[121][Level of evidence: 1iA]
    • Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64–0.93; P = .0072).
    • However, no statistically significant difference in OS was seen (16.4 months for chemotherapy plus placebo vs. 18.0 months for chemotherapy plus bevacizumab, P = .3741).[121][Level of evidence: 1iA]
    • Toxicities associated with bevacizumab were similar to those seen in previous clinical trials.
In November 2011, because of the consistent finding that bevacizumab improved PFS only modestly but did not improve OS, and given bevacizumab’s considerable toxicity profile, the FDA revoked approval of bevacizumab for the treatment of metastatic breast cancer.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Honig SF: Hormonal therapy and chemotherapy. In: Harris JR, Morrow M, Lippman ME, et al., eds.: Diseases of the Breast. Lippincott-Raven Publishers: Philadelphia, Pa, 1996, pp 669-734.
  2. Greenberg PA, Hortobagyi GN, Smith TL, et al.: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14 (8): 2197-205, 1996. [PUBMED Abstract]
  3. Bonneterre J, Thürlimann B, Robertson JF, et al.: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18 (22): 3748-57, 2000. [PUBMED Abstract]
  4. Nabholtz JM, Buzdar A, Pollak M, et al.: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18 (22): 3758-67, 2000. [PUBMED Abstract]
  5. Mouridsen H, Gershanovich M, Sun Y, et al.: Phase III 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 21 (11): 2101-9, 2003. [PUBMED Abstract]
  6. Mauri D, Pavlidis N, Polyzos NP, et al.: Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 98 (18): 1285-91, 2006. [PUBMED Abstract]
  7. Mehta RS, Barlow WE, Albain KS, et al.: Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 367 (5): 435-44, 2012. [PUBMED Abstract]
  8. Bergh J, Jönsson PE, Lidbrink EK, et al.: FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 30 (16): 1919-25, 2012. [PUBMED Abstract]
  9. Boccardo F, Rubagotti A, Perrotta A, et al.: Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol 5 (4): 337-42, 1994. [PUBMED Abstract]
  10. Jonat W, Kaufmann M, Blamey RW, et al.: A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer 31A (2): 137-42, 1995. [PUBMED Abstract]
  11. Klijn JG, Blamey RW, Boccardo F, et al.: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 19 (2): 343-53, 2001. [PUBMED Abstract]
  12. Klijn JG, Beex LV, Mauriac L, et al.: Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 92 (11): 903-11, 2000. [PUBMED Abstract]
  13. Buzdar AU, Jones SE, Vogel CL, et al.: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer 79 (4): 730-9, 1997. [PUBMED Abstract]
  14. Dombernowsky P, Smith I, Falkson G, et al.: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16 (2): 453-61, 1998. [PUBMED Abstract]
  15. Jonat W, Howell A, Blomqvist C, et al.: A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A (3): 404-12, 1996. [PUBMED Abstract]
  16. Gershanovich M, Chaudri HA, Campos D, et al.: Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol 9 (6): 639-45, 1998. [PUBMED Abstract]
  17. Peethambaram PP, Ingle JN, Suman VJ, et al.: Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 54 (2): 117-22, 1999. [PUBMED Abstract]
  18. Kaufmann M, Bajetta E, Dirix LY, et al.: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18 (7): 1399-411, 2000. [PUBMED Abstract]
  19. Kvinnsland S, Anker G, Dirix LY, et al.: High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment. Eur J Cancer 36 (8): 976-82, 2000. [PUBMED Abstract]
  20. Buzdar A, Douma J, Davidson N, et al.: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19 (14): 3357-66, 2001. [PUBMED Abstract]
  21. Gibson LJ, Dawson CK, Lawrence DH, et al.: Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev (1): CD003370, 2007. [PUBMED Abstract]
  22. Howell A, Robertson JF, Abram P, et al.: Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 22 (9): 1605-13, 2004. [PUBMED Abstract]
  23. Perey L, Paridaens R, Hawle H, et al.: Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol 18 (1): 64-9, 2007. [PUBMED Abstract]
  24. Henderson IC: A rose is no longer a rose. J Clin Oncol 20 (16): 3365-8, 2002. [PUBMED Abstract]
  25. Osborne CK, Pippen J, Jones SE, et al.: Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20 (16): 3386-95, 2002. [PUBMED Abstract]
  26. Howell A, Robertson JF, Quaresma Albano J, et al.: Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20 (16): 3396-403, 2002. [PUBMED Abstract]
  27. Flemming J, Madarnas Y, Franek JA: Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review. Breast Cancer Res Treat 115 (2): 255-68, 2009. [PUBMED Abstract]
  28. Johnston SR, Kilburn LS, Ellis P, et al.: Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol 14 (10): 989-98, 2013. [PUBMED Abstract]
  29. Baselga J, Campone M, Piccart M, et al.: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366 (6): 520-9, 2012. [PUBMED Abstract]
  30. Piccart M, Hortobagyi GN, Campone M, et al.: Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Ann Oncol 25 (12): 2357-62, 2014. [PUBMED Abstract]
  31. André F, O'Regan R, Ozguroglu M, et al.: Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15 (6): 580-91, 2014. [PUBMED Abstract]
  32. Finn RS, Crown JP, Lang I, et al.: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16 (1): 25-35, 2015. [PUBMED Abstract]
  33. Finn RS, Martin M, Rugo HS, et al.: Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 375 (20): 1925-1936, 2016. [PUBMED Abstract]
  34. Turner NC, Ro J, André F, et al.: Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 373 (3): 209-19, 2015. [PUBMED Abstract]
  35. Cristofanilli M, Turner NC, Bondarenko I, et al.: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17 (4): 425-39, 2016. [PUBMED Abstract]
  36. Turner NC, Slamon DJ, Ro J, et al.: Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 379 (20): 1926-1936, 2018. [PUBMED Abstract]
  37. Hortobagyi GN, Stemmer SM, Burris HA, et al.: Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 375 (18): 1738-1748, 2016. [PUBMED Abstract]
  38. Slamon DJ, Neven P, Chia S, et al.: Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 36 (24): 2465-2472, 2018. [PUBMED Abstract]
  39. Tripathy D, Im SA, Colleoni M, et al.: Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 19 (7): 904-915, 2018. [PUBMED Abstract]
  40. Goetz MP, Toi M, Campone M, et al.: MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 35 (32): 3638-3646, 2017. [PUBMED Abstract]
  41. Sledge GW Jr, Toi M, Neven P, et al.: MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol 35 (25): 2875-2884, 2017. [PUBMED Abstract]
  42. Dickler MN, Tolaney SM, Rugo HS, et al.: MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer. Clin Cancer Res 23 (17): 5218-5224, 2017. [PUBMED Abstract]
  43. Pegram MD, Pauletti G, Slamon DJ: HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52 (1-3): 65-77, 1998. [PUBMED Abstract]
  44. Cobleigh MA, Vogel CL, Tripathy D, et al.: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17 (9): 2639-48, 1999. [PUBMED Abstract]
  45. Slamon DJ, Leyland-Jones B, Shak S, et al.: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344 (11): 783-92, 2001. [PUBMED Abstract]
  46. Seidman A, Hudis C, Pierri MK, et al.: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20 (5): 1215-21, 2002. [PUBMED Abstract]
  47. Robert N, Leyland-Jones B, Asmar L, et al.: Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24 (18): 2786-92, 2006. [PUBMED Abstract]
  48. Valero V, Forbes J, Pegram MD, et al.: Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol 29 (2): 149-56, 2011. [PUBMED Abstract]
  49. Baselga J, Cortés J, Kim SB, et al.: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366 (2): 109-19, 2012. [PUBMED Abstract]
  50. Swain SM, Baselga J, Kim SB, et al.: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372 (8): 724-34, 2015. [PUBMED Abstract]
  51. Verma S, Miles D, Gianni L, et al.: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367 (19): 1783-91, 2012. [PUBMED Abstract]
  52. Diéras V, Miles D, Verma S, et al.: Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 18 (6): 732-742, 2017. [PUBMED Abstract]
  53. Hurvitz SA, Dirix L, Kocsis J, et al.: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31 (9): 1157-63, 2013. [PUBMED Abstract]
  54. Krop IE, Kim SB, González-Martín A, et al.: Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (7): 689-99, 2014. [PUBMED Abstract]
  55. Krop IE, Kim SB, Martin AG, et al.: Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 18 (6): 743-754, 2017. [PUBMED Abstract]
  56. Perez EA, Barrios C, Eiermann W, et al.: Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol 35 (2): 141-148, 2017. [PUBMED Abstract]
  57. Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (26): 2733-43, 2006. [PUBMED Abstract]
  58. Robson M, Im SA, Senkus E, et al.: Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 377 (6): 523-533, 2017. [PUBMED Abstract]
  59. Litton JK, Rugo HS, Ettl J, et al.: Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 379 (8): 753-763, 2018. [PUBMED Abstract]
  60. Wilcken N, Dear R: Chemotherapy in metastatic breast cancer: A summary of all randomised trials reported 2000-2007. Eur J Cancer 44 (15): 2218-25, 2008. [PUBMED Abstract]
  61. Ranson MR, Carmichael J, O'Byrne K, et al.: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 15 (10): 3185-91, 1997. [PUBMED Abstract]
  62. Harris L, Batist G, Belt R, et al.: Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94 (1): 25-36, 2002. [PUBMED Abstract]
  63. Keller AM, Mennel RG, Georgoulias VA, et al.: Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22 (19): 3893-901, 2004. [PUBMED Abstract]
  64. Sparano JA, Makhson AN, Semiglazov VF, et al.: Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol 27 (27): 4522-9, 2009. [PUBMED Abstract]
  65. Seidman AD, Berry D, Cirrincione C, et al.: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26 (10): 1642-9, 2008. [PUBMED Abstract]
  66. Gonzalez-Angulo AM, Hortobagyi GN: Optimal schedule of paclitaxel: weekly is better. J Clin Oncol 26 (10): 1585-7, 2008. [PUBMED Abstract]
  67. Gradishar WJ, Tjulandin S, Davidson N, et al.: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23 (31): 7794-803, 2005. [PUBMED Abstract]
  68. Ibrahim NK, Samuels B, Page R, et al.: Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 23 (25): 6019-26, 2005. [PUBMED Abstract]
  69. Blum JL, Jones SE, Buzdar AU, et al.: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17 (2): 485-93, 1999. [PUBMED Abstract]
  70. Blum JL, Dieras V, Lo Russo PM, et al.: Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92 (7): 1759-68, 2001. [PUBMED Abstract]
  71. Venturini M, Paridaens R, Rossner D, et al.: An open-label, multicenter study of outpatient capecitabine monotherapy in 631 patients with pretreated advanced breast cancer. Oncology 72 (1-2): 51-7, 2007. [PUBMED Abstract]
  72. Degardin M, Bonneterre J, Hecquet B, et al.: Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol 5 (5): 423-6, 1994. [PUBMED Abstract]
  73. Carmichael J, Walling J: Advanced breast cancer: investigational role of gemcitabine. Eur J Cancer 33 (Suppl 1): S27-30, 1997. [PUBMED Abstract]
  74. Vahdat LT, Pruitt B, Fabian CJ, et al.: Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 27 (18): 2954-61, 2009. [PUBMED Abstract]
  75. Cortes J, O'Shaughnessy J, Loesch D, et al.: Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377 (9769): 914-23, 2011. [PUBMED Abstract]
  76. Smith JW 2nd, Vukelja S, Rabe A, et al.: Phase II randomized trial of weekly and every-3-week ixabepilone in metastatic breast cancer patients. Breast Cancer Res Treat 142 (2): 381-8, 2013. [PUBMED Abstract]
  77. Tranum BL, McDonald B, Thigpen T, et al.: Adriamycin combinations in advanced breast cancer. A Southwest Oncology Group Study. Cancer 49 (5): 835-9, 1982. [PUBMED Abstract]
  78. Langley RE, Carmichael J, Jones AL, et al.: Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol 23 (33): 8322-30, 2005. [PUBMED Abstract]
  79. Misset JL, Dieras V, Gruia G, et al.: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10 (5): 553-60, 1999. [PUBMED Abstract]
  80. Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol 12 (2): 123-8, 1989. [PUBMED Abstract]
  81. Tormey DC, Gelman R, Band PR, et al.: Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group Trial. Cancer 50 (7): 1235-44, 1982. [PUBMED Abstract]
  82. Jassem J, Pieńkowski T, Płuzańska A, et al.: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19 (6): 1707-15, 2001. [PUBMED Abstract]
  83. Biganzoli L, Cufer T, Bruning P, et al.: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol 20 (14): 3114-21, 2002. [PUBMED Abstract]
  84. O'Shaughnessy J, Miles D, Vukelja S, et al.: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20 (12): 2812-23, 2002. [PUBMED Abstract]
  85. Serin D, Verrill M, Jones A, et al.: Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study. Br J Cancer 92 (11): 1989-96, 2005. [PUBMED Abstract]
  86. Thomas ES, Gomez HL, Li RK, et al.: Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25 (33): 5210-7, 2007. [PUBMED Abstract]
  87. O'Shaughnessy J, Schwartzberg L, Danso MA, et al.: Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol 32 (34): 3840-7, 2014. [PUBMED Abstract]
  88. Albain KS, Nag SM, Calderillo-Ruiz G, et al.: Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 26 (24): 3950-7, 2008. [PUBMED Abstract]
  89. Sledge GW, Neuberg D, Bernardo P, et al.: Phase III 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 21 (4): 588-92, 2003. [PUBMED Abstract]
  90. Seidman AD: Sequential single-agent chemotherapy for metastatic breast cancer: therapeutic nihilism or realism? J Clin Oncol 21 (4): 577-9, 2003. [PUBMED Abstract]
  91. Overmoyer B: Combination chemotherapy for metastatic breast cancer: reaching for the cure. J Clin Oncol 21 (4): 580-2, 2003. [PUBMED Abstract]
  92. Perez EA: Current management of metastatic breast cancer. Semin Oncol 26 (4 Suppl 12): 1-10, 1999. [PUBMED Abstract]
  93. Jones D, Ghersi D, Wilcken N: Addition of drug/s to a chemotherapy regimen for metastatic breast cancer. Cochrane Database Syst Rev 3: CD003368, 2006. [PUBMED Abstract]
  94. Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16 (5): 1669-76, 1998. [PUBMED Abstract]
  95. Peters WP, Jones RB, Vrendenburgh J, et al.: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-149, 121, 1996.
  96. Muss HB, Case LD, Richards F 2nd, et al.: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 325 (19): 1342-8, 1991. [PUBMED Abstract]
  97. Falkson G, Gelman RS, Glick J, et al.: Metastatic breast cancer: higher versus low dose maintenance treatment when only a partial response or a no change status is obtained following doxorubicin induction treatment. An Eastern Cooperative Oncology Group study. Ann Oncol 3 (9): 768-70, 1992. [PUBMED Abstract]
  98. Park YH, Jung KH, Im SA, et al.: Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol 31 (14): 1732-9, 2013. [PUBMED Abstract]
  99. Schmid P, Adams S, Rugo HS, et al.: Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 379 (22): 2108-2121, 2018. [PUBMED Abstract]
  100. Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15 (4): 1333-40, 1997. [PUBMED Abstract]
  101. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997. [PUBMED Abstract]
  102. Hensley ML, Schuchter LM, Lindley C, et al.: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17 (10): 3333-55, 1999. [PUBMED Abstract]
  103. Marty M, Espié M, Llombart A, et al.: Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17 (4): 614-22, 2006. [PUBMED Abstract]
  104. Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63 (1): 37-45, 1989. [PUBMED Abstract]
  105. Hensley ML, Hagerty KL, Kewalramani T, et al.: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27 (1): 127-45, 2009. [PUBMED Abstract]
  106. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996. [PUBMED Abstract]
  107. Hartsell WF, Scott CB, Bruner DW, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97 (11): 798-804, 2005. [PUBMED Abstract]
  108. Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993. [PUBMED Abstract]
  109. Quilty PM, Kirk D, Bolger JJ, et al.: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31 (1): 33-40, 1994. [PUBMED Abstract]
  110. Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21 (21): 4042-57, 2003. [PUBMED Abstract]
  111. Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11 (1): 59-65, 1993. [PUBMED Abstract]
  112. Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16 (6): 2038-44, 1998. [PUBMED Abstract]
  113. Powles T, Paterson A, McCloskey E, et al.: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8 (2): R13, 2006. [PUBMED Abstract]
  114. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003. [PUBMED Abstract]
  115. Himelstein AL, Foster JC, Khatcheressian JL, et al.: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317 (1): 48-58, 2017. [PUBMED Abstract]
  116. Lipton A, Fizazi K, Stopeck AT, et al.: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48 (16): 3082-92, 2012. [PUBMED Abstract]
  117. Miller KD, Chap LI, Holmes FA, et al.: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23 (4): 792-9, 2005. [PUBMED Abstract]
  118. Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357 (26): 2666-76, 2007. [PUBMED Abstract]
  119. Miles DW, Chan A, Dirix LY, et al.: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28 (20): 3239-47, 2010. [PUBMED Abstract]
  120. Robert NJ, Diéras V, Glaspy J, et al.: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29 (10): 1252-60, 2011. [PUBMED Abstract]
  121. Brufsky AM, Hurvitz S, Perez E, et al.: RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29 (32): 4286-93, 2011. [PUBMED Abstract]

Ductal Carcinoma In Situ

Introduction

Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to invasive cancer, but estimates of the probability of this vary widely. Some reports include DCIS in breast cancer statistics. In 2015, DCIS is expected to account for about 16% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.[1] For invasive and noninvasive tumors detected by screening, DCIS accounts for approximately 25% of all cases.
The frequency of a DCIS diagnosis has increased markedly in the United States since the use of screening mammography became widespread. Very few cases of DCIS present as a palpable mass, with more than 90% being diagnosed by mammography alone.[2]
DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into the following subtypes primarily because of architectural pattern:
  • Micropapillary.
  • Papillary.
  • Solid.
  • Cribriform.
  • Comedo.
Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.[3]

Treatment Options for Patients With DCIS

Treatment options for DCIS include the following:
  1. Breast-conserving surgery or mastectomy plus radiation therapy with or without tamoxifen.
  2. Total mastectomy with or without tamoxifen.
In the past, the customary treatment for DCIS was mastectomy.[4] The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy after wide excision alone, and a 25% to 50% incidence of in-breast recurrence after limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma.[4,5] The combined local and distant recurrence rate after mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation therapy are available.
Because breast-conserving surgery combined with breast radiation therapy is successful for invasive carcinoma, this conservative approach was extended to DCIS. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins after excisional biopsy were randomly assigned to receive either breast radiation therapy (50 Gy) or no further therapy.[6-9]
Evidence (breast-conserving surgery plus radiation therapy to the breast):
  1. Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or smaller. Results were reported at the 12-year actuarial follow-up interval.[7]; [9][Level of evidence: 1iiDii]
    • The overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005).
    • Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).
    • Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.
  2. Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. Results were reported at a median follow-up of 10.5 years.[9][Level of evidence: 1iiDii]
    • The overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P< .001), with a similarly effective reduction of invasive recurrence rates (13% to 8%, P = .065) and noninvasive recurrence rates (14% to 7%, P = .001).
    • In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[10]
    In both studies, the effect of radiation therapy was consistent across all assessed risk factors.
  3. The benefit of administering radiation therapy has been confirmed in a systematic review of four randomized trials (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41–0.58; P < .00001). In this study, the number needed to treat with radiation therapy was nine women to prevent one ipsilateral breast recurrence.[11]
  4. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804[NCT00003857]) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed because of poor accrual (636 of planned 1,790 patients accrued). Patients with good-risk DCIS (defined as mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins of 3 mm or more) were enrolled.[12]
    • With a median follow-up of 7 years, the ipsilateral local failure rate was low with observation (6.7%; 95% CI, 3.2%–9.6%) but was decreased significantly with the addition of radiation therapy (0.9%; 95% CI, 0.0%–2.2%).[12]
The results of the NSABP-B-17 and EORTC-10853 trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (HR, 0.49; 95% CI, 0.41–0.58; P < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; P = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; P = .03).[13][Level of evidence: 1iiD] After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.[11]
To identify a favorable group of patients for whom postoperative radiation therapy could be omitted, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[14-17]
The Van Nuys Prognostic Index is one pathologic staging system that combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification). It was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy.[17] Using this prognostic index, patients with favorable lesions who received surgical excision alone had a low recurrence rate (i.e., 2%, with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control.[18] Patients whose excised lesions had margin widths of 10 mm or more in every direction had an extremely low probability of local recurrence with surgery alone (4%, with a mean follow-up of 8 years).
Both reviews are retrospective, noncontrolled, and subject to substantial selection bias. In contrast, the prospective NSABP trial did not identify any subset of patients who did not benefit from the addition of radiation therapy to breast-conserving surgery in the management of DCIS.[3,6,13,19]
To determine whether tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24).
Evidence (adjuvant endocrine therapy):
  1. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 years).[20] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured ≤1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.
    • Women in the tamoxifen group had fewer breast cancer events at 5 years than did those treated with a placebo (8.2% vs. 13.4%; P = .009).[20][Level of evidence: 1iDii]
    • With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03).
    • Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01).
    • The benefit of tamoxifen extended to patients with positive or uncertain margins.[21] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
    • No survival advantage was demonstrated for the use of tamoxifen.
  2. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 y).[20] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured ≤1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.
    • No survival advantage was demonstrated for the use of tamoxifen.
  3. In the NSABP-B35 double-blind study, 3,104 postmenopausal women with DCIS who were treated with breast-conserving surgery were randomly assigned to receive either adjuvant tamoxifen or anastrozole, in addition to adjuvant radiation therapy.
    • The use of anastrozole was associated with significantly fewer breast cancer events (HR, 0.73; P = .023) but no improvement in survival.[22][Level of evidence: 1iDi]
  4. The Second International Breast Cancer Intervention Study (IBIS II DCIS[NCT00078832]) trial enrolled 2,980 postmenopausal women in a double-blind comparison of tamoxifen with anastrozole as adjuvant therapy. All of the women had breast conserving surgery, and 71% of them had radiation therapy.[23]
    • No difference in the rate of breast cancer recurrence in favor of anastrozole was found (HR, 0.89; 95% CI, 0.64–1.23; P = .49), and there was no difference in survival.
The decision to prescribe endocrine therapy after a diagnosis of DCIS often involves a discussion with the patient about the potential benefits and side effects of each agent.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed September 21, 2018.
  2. Siegel R, Ward E, Brawley O, et al.: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61 (4): 212-36, 2011 Jul-Aug. [PUBMED Abstract]
  3. Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999. [PUBMED Abstract]
  4. Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997. [PUBMED Abstract]
  5. Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982. [PUBMED Abstract]
  6. Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998. [PUBMED Abstract]
  7. Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001. [PUBMED Abstract]
  8. Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000. [PUBMED Abstract]
  9. Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006. [PUBMED Abstract]
  10. Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001. [PUBMED Abstract]
  11. Correa C, McGale P, Taylor C, et al.: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010 (41): 162-77, 2010. [PUBMED Abstract]
  12. McCormick B, Winter K, Hudis C, et al.: RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33 (7): 709-15, 2015. [PUBMED Abstract]
  13. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev 11: CD000563, 2013. [PUBMED Abstract]
  14. Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995. [PUBMED Abstract]
  15. Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75 (6): 1223-1227, 1995.
  16. Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994. [PUBMED Abstract]
  17. Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996. [PUBMED Abstract]
  18. Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999. [PUBMED Abstract]
  19. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast--a systematic review of the randomised trials. Breast 18 (3): 143-9, 2009. [PUBMED Abstract]
  20. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999. [PUBMED Abstract]
  21. Houghton J, George WD, Cuzick J, et al.: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362 (9378): 95-102, 2003. [PUBMED Abstract]
  22. Margolese RG, Cecchini RS, Julian TB, et al.: Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet 387 (10021): 849-56, 2016. [PUBMED Abstract]
  23. Forbes JF, Sestak I, Howell A, et al.: Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet 387 (10021): 866-73, 2016. [PUBMED Abstract]

Changes to This Summary (02/28/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Breast Cancer
Updated statistics with estimated new cases and deaths for 2019 (cited American Cancer Society as reference 1).
Stage Information for Breast Cancer
This section was extensively revised.
Locoregional Recurrent Breast Cancer
Revised text to state that in estrogen‒receptor (ER)-negative patients, the hazard ratio (HR) for disease-free survival (DFS) for chemotherapy versus no chemotherapy was 0.29, whereas in ER-positive patients, the HR was 1.07. Added that this trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer in patients with ER-negative tumors.
Metastatic Breast Cancer
Added text about palbociclib in the Paloma-3 trial to state that a prespecified analysis of overall survival (OS) was made after 310 patients had died. A 6.9 month difference in median OS favoring the palbociclib-fulvestrant arm was found, which did not reach statistical significance (cited Turner et al. as reference 36).
Added Chemotherapy plus immunotherapy as a new subsection.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Breast Cancer Treatment are:
  • Joseph L. Pater, MD (NCIC-Clinical Trials Group)
  • Karen L. Smith, MD, MPH (Johns Hopkins University at Sibley Memorial Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389406]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
  • Updated: February 28, 2019
Posted by at

No comments:

Post a Comment

Subscribe to: Post Comments (Atom)