Challenges in Prognosis, Systemic Therapy, and Survival in Patients with HER2-Negative Metastatic Breast Cancer candidates to systemic chemotherapy
Main Article Content
Abstract
Abstract
In patients with HER2-negative metastatic breast cancer who are not candidates for endocrine therapy, several regimens are approved, but there is no consensus on which should be preferred. The impressive gains in progression-free survival achieved by combining two cytotoxic drugs or chemotherapy plus bevacizumab have not consistently translated into overall survival benefits. Survival in this population depends on a wide range of biological and clinical factors, some of which remain unclear. International guidelines recommend that combination regimens should be limited to clinically aggressive situations. However, an evidence-based definition that could help guide treatment decisions and trial design has not been established for so-called ‘poor-prognosis’ or ‘aggressive’ tumors. In this article, we summarize the current literature regarding prognosis and treatment of patients with no endocrine options for HER2-negative metastatic breast cancer. The choice of optimal systemic therapy should be based on robust prognostic factors, the biologic characteristics of the tumor, and the type and severity of comorbidities. Furthermore, we suggest that combination regimens (chemotherapy doublets or bevacizumab-based regimens) may be considered appropriate options for patients with well-defined criteria representing poor-prognosis disease.
Keywords:
Metastatic breast cancer, Chemotherapy, Clinical Prognostic Factor
Article Details
How to Cite
AGUIRRE, Elena et al.
Challenges in Prognosis, Systemic Therapy, and Survival in Patients with HER2-Negative Metastatic Breast Cancer candidates to systemic chemotherapy.
Medical Research Archives, [S.l.], v. 5, n. 12, dec. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1587>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v5i12.1587.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Dawood S, Broglio K, Gonzalez-Angulo AM et al. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J Clin Oncol 2008;26:4891–4898.
2. Giordano SH, Buzdar AU, Smith TL et al. Is breast cancer survival improving? Cancer 2004;100:44–52.
3. Mauri D, Polyzos N, Salanti G et al. Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst 2008;100:1780–1791.
4. Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009;7:122–192.
5. Higgins MJ, Baselga J. Breast cancer in 2010: novel targets and therapies for a personalized approach. Nat Rev Clin Oncol 2011;8:65–66.
6. Verma S, Miles D, Gianni L et al.; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783–1791.
7. Swain SM, Baselga J, Kim SB et al.; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724–734.
8. Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–529.
9. 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 2014;25:2357–2362
10. Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015;373:209–19.
11. Cardoso F, Costa A, Norton L et al. 1st international consensus guidelines for advanced breast cancer (ABC 1). Breast 2012;21:242–252.
12. Regierer AC, Wolters R, Ufen MP et al. An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients. Ann Oncol 2014;25:633–638.
13. Hortobagyi GN. Toward individualized breast cancer therapy: translating biological concepts to the bedside. Oncologist 2012;17:577–584.
14. Hayes DF. Prognostic and predictive factors revisited. Breast 2005;14:493–499.
15. Hortobagyi GN, Smith TL, Legha SS et al. Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol 1983;1:776–786.
16. Foukakis T, Fornander T, Lekberg T et al. Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm, Sweden. Breast Cancer Res Treat 2011;130:553–560.
17. Planchat E, Durando X, Abrial C et al. Prognostic value of initial tumor parameters after metastatic relapse. Cancer Invest 2011;29:635–643.
18. van de Water W, Markopoulos C, van de Velde CJ et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA 2012;307:590–597.
19. Alexandre J, Bleuzen P, Bonneterre J et al. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol 2000;18:562–573.
20. Nistico C, Cuppone F, Bria E et al. Ten years of experience with weekly chemotherapy in metastatic breast cancer patients: multivariate analysis of prognostic factors. Anticancer Drugs 2006;17:1193–1200.
21. Duffy MJ. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem 2006;52:345–351.
22. Nicolini A, Carpi A, Tarro G. Biomolecular markers of breast cancer. Front Biosci 2006;11:1818–1843.
23. Sandri MT, Salvatici M, Botteri E et al. Prognostic role of CA15.3 in 7942 patients with operable breast cancer. Breast Cancer Res Treat 2012;132:317–326.
24. Bidard FC, Peeters DJ, Fehm T et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014;15:406–414.
25. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005;104:1742–50.
26. Pierga JY, Robain M, Jouve M et al. Response to chemotherapy is a major parameter-influencing long-term survival of metastatic breast cancer patients. Ann Oncol 2001;12:231–237.
27. Gersi D, Wilcken N, Simes J et al. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2005 Apr 18(2):CD003366.
28. Piccart-Gebhart MJ, Burzykowski T, Buyse M et al. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol 2008;26:1980–1986.
29. Bria E, Giannarelli D, Felici A et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005;103:672–679.
30. 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 2008;26:3950–3957.
31. 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 2002;20:2812–2823.
32. Miles D, Vukelja S, Moiseyenko V et al. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer 2004;5:273–278.
33. 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 2003;21:588–592.
34. Gennari A, Stockler M, Puntoni M et al. Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of randomized clinical trials. J Clin Oncol 2011;29:2144–2149.
35. Siziopikou KP, Ariga R, Proussaloglou KE et al. The challenging estrogen receptor-negative/progesterone receptor-negative/HER-2-negative patient: a promising candidate for epidermal growth factor receptor-targeted therapy? Breast J 2006;12:360–362.
36. Baselga J, Gomez P, Greil R et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 2013;31:2586–2592.
37. 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 2014;32:3840–3847.
38. O'Shaughnessy J, Osborne C, Pippen JE et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364:205–214.
39. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666–2676.
40. 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 2010;28:3239–3247.
41. Robert NJ, Dieras 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 2011;29:1252–1260.
42. Miles D, Cameron D, Bondarenko I, et al. First results from the double-blind placebo (PL)-controlled randomised phase III MERiDiAN trial prospectively evaluating plasma (p)VEGF-A in patients (pts) receiving first-line paclitaxel (PAC) ± bevacizumab (BV) for HER2-negative metastatic breast cancer (mBC). Eur J Cancer 2015;51(suppl S3):S287 (abstract 1866).
43. Lang I, Brodowicz T, Ryvo L et al.; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol 2013;14:125–133.
44. Rugo HS, Barry WT, Moreno-Aspitia A et al. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol 2015;33:2361–2369.
45. Miles DW, Diéras V, Cortés J et al. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013;24:2773–2780.
46. Schrader I, Foerster F, Schneeweiss A. Analysis according to prognostic factors in patients (pts) treated with first-line bevacizumab (BEV) combined with paclitaxel (PAC) for HER2-negative metastatic breast cancer (MBC) in a routine oncology practice study. J Clin Oncol 2012;30:Abstract 1077.
47. Smith IE, Pierga JY, Biganzoli L et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol 2011;22:595–602.
48. Biganzoli L, Di Vincenzo E, Jiang Z et al. First-line bevacizumab-containing therapy for breast cancer: results in patients aged ≥70 years treated in the ATHENA study. Ann Oncol 2012;23:111–118.
49. Llombart-Cussac A, Pivot X, Biganzoli L et al. A prognostic factor index for overall survival in patients receiving first-line chemotherapy for HER2-negative advanced breast cancer: an analysis of the ATHENA trial. The Breast 2014;23:656–662.
50. Brodowicz T, Lang I, Kahan Z et al. Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses. Br J Cancer 2014;111:2051–2057.
51. Robert NJ, Dieras V, Jackisch C et al. Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC). Poster presented at: American Association of Cancer Research Annual Meeting, April 5-9, 2014: San Diego, CA, USA. Abstract CT322.
52. Gligorov J, Doval D, Bines J et al. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1351-1360.
2. Giordano SH, Buzdar AU, Smith TL et al. Is breast cancer survival improving? Cancer 2004;100:44–52.
3. Mauri D, Polyzos N, Salanti G et al. Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst 2008;100:1780–1791.
4. Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009;7:122–192.
5. Higgins MJ, Baselga J. Breast cancer in 2010: novel targets and therapies for a personalized approach. Nat Rev Clin Oncol 2011;8:65–66.
6. Verma S, Miles D, Gianni L et al.; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783–1791.
7. Swain SM, Baselga J, Kim SB et al.; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724–734.
8. Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–529.
9. 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 2014;25:2357–2362
10. Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015;373:209–19.
11. Cardoso F, Costa A, Norton L et al. 1st international consensus guidelines for advanced breast cancer (ABC 1). Breast 2012;21:242–252.
12. Regierer AC, Wolters R, Ufen MP et al. An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients. Ann Oncol 2014;25:633–638.
13. Hortobagyi GN. Toward individualized breast cancer therapy: translating biological concepts to the bedside. Oncologist 2012;17:577–584.
14. Hayes DF. Prognostic and predictive factors revisited. Breast 2005;14:493–499.
15. Hortobagyi GN, Smith TL, Legha SS et al. Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol 1983;1:776–786.
16. Foukakis T, Fornander T, Lekberg T et al. Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm, Sweden. Breast Cancer Res Treat 2011;130:553–560.
17. Planchat E, Durando X, Abrial C et al. Prognostic value of initial tumor parameters after metastatic relapse. Cancer Invest 2011;29:635–643.
18. van de Water W, Markopoulos C, van de Velde CJ et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA 2012;307:590–597.
19. Alexandre J, Bleuzen P, Bonneterre J et al. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol 2000;18:562–573.
20. Nistico C, Cuppone F, Bria E et al. Ten years of experience with weekly chemotherapy in metastatic breast cancer patients: multivariate analysis of prognostic factors. Anticancer Drugs 2006;17:1193–1200.
21. Duffy MJ. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem 2006;52:345–351.
22. Nicolini A, Carpi A, Tarro G. Biomolecular markers of breast cancer. Front Biosci 2006;11:1818–1843.
23. Sandri MT, Salvatici M, Botteri E et al. Prognostic role of CA15.3 in 7942 patients with operable breast cancer. Breast Cancer Res Treat 2012;132:317–326.
24. Bidard FC, Peeters DJ, Fehm T et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014;15:406–414.
25. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005;104:1742–50.
26. Pierga JY, Robain M, Jouve M et al. Response to chemotherapy is a major parameter-influencing long-term survival of metastatic breast cancer patients. Ann Oncol 2001;12:231–237.
27. Gersi D, Wilcken N, Simes J et al. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2005 Apr 18(2):CD003366.
28. Piccart-Gebhart MJ, Burzykowski T, Buyse M et al. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol 2008;26:1980–1986.
29. Bria E, Giannarelli D, Felici A et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005;103:672–679.
30. 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 2008;26:3950–3957.
31. 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 2002;20:2812–2823.
32. Miles D, Vukelja S, Moiseyenko V et al. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer 2004;5:273–278.
33. 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 2003;21:588–592.
34. Gennari A, Stockler M, Puntoni M et al. Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of randomized clinical trials. J Clin Oncol 2011;29:2144–2149.
35. Siziopikou KP, Ariga R, Proussaloglou KE et al. The challenging estrogen receptor-negative/progesterone receptor-negative/HER-2-negative patient: a promising candidate for epidermal growth factor receptor-targeted therapy? Breast J 2006;12:360–362.
36. Baselga J, Gomez P, Greil R et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 2013;31:2586–2592.
37. 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 2014;32:3840–3847.
38. O'Shaughnessy J, Osborne C, Pippen JE et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364:205–214.
39. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666–2676.
40. 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 2010;28:3239–3247.
41. Robert NJ, Dieras 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 2011;29:1252–1260.
42. Miles D, Cameron D, Bondarenko I, et al. First results from the double-blind placebo (PL)-controlled randomised phase III MERiDiAN trial prospectively evaluating plasma (p)VEGF-A in patients (pts) receiving first-line paclitaxel (PAC) ± bevacizumab (BV) for HER2-negative metastatic breast cancer (mBC). Eur J Cancer 2015;51(suppl S3):S287 (abstract 1866).
43. Lang I, Brodowicz T, Ryvo L et al.; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol 2013;14:125–133.
44. Rugo HS, Barry WT, Moreno-Aspitia A et al. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol 2015;33:2361–2369.
45. Miles DW, Diéras V, Cortés J et al. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013;24:2773–2780.
46. Schrader I, Foerster F, Schneeweiss A. Analysis according to prognostic factors in patients (pts) treated with first-line bevacizumab (BEV) combined with paclitaxel (PAC) for HER2-negative metastatic breast cancer (MBC) in a routine oncology practice study. J Clin Oncol 2012;30:Abstract 1077.
47. Smith IE, Pierga JY, Biganzoli L et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol 2011;22:595–602.
48. Biganzoli L, Di Vincenzo E, Jiang Z et al. First-line bevacizumab-containing therapy for breast cancer: results in patients aged ≥70 years treated in the ATHENA study. Ann Oncol 2012;23:111–118.
49. Llombart-Cussac A, Pivot X, Biganzoli L et al. A prognostic factor index for overall survival in patients receiving first-line chemotherapy for HER2-negative advanced breast cancer: an analysis of the ATHENA trial. The Breast 2014;23:656–662.
50. Brodowicz T, Lang I, Kahan Z et al. Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses. Br J Cancer 2014;111:2051–2057.
51. Robert NJ, Dieras V, Jackisch C et al. Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC). Poster presented at: American Association of Cancer Research Annual Meeting, April 5-9, 2014: San Diego, CA, USA. Abstract CT322.
52. Gligorov J, Doval D, Bines J et al. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1351-1360.