Triple-negative breast cancer (TNBC) represents a heterogeneous breast cancer subtype with a poor prognosis. The optimal adjuvant chemotherapy regimen is still unknown. Although numerous large randomized trials have established the benefit of adjuvant anthracyclines and/or taxanes in TNBC, there is no preferred regimen for these patients. There is currently no guideline. Moreover, without knowing the optimal treatment backbone, it will not be possible to evaluate whether adding agents such as platinum or other novel therapies is beneficial for TNBC patients. Furthermore, the best duration of adjuvant treatment in TNBC is still unknown. This review will focus on results of clinical trials that analyzed the benefits of extending the duration of adjuvant treatment in TNBCs with maintenance treatments. We will further discuss promising results in favor of other new agents including capecitabine, metronomic treatment, and biological drugs.

1.
Trivers KF, Lund MJ, Porter PL, Liff JM, Flagg EW, Coates RJ, Eley JW: The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control 2009;20:1071-1082.
2.
Lin NU, Vanderplas A, Hughes ME, Theriault RL, Edge SB, Wong YN, Blayney DW, Joyce CN, Winer EP, Weeks JC: Clinico-pathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 2012;118:5463-5472.
3.
Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006;295:1658-1667.
4.
Villarreal-Garza C, Khalaf D, Bouganim N, Clemons M, Peña Curiel O, Baez-Revueltas B, Kiss A, Kassam F, Enright K, Verma S, Pritchard K, Myers J, Dent R: Platinum based chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat 2014;146:567-572.
5.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarrthy AB, Shyr Y, Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-2767.
6.
Bron S, Henry L, Faes-van't Hull E, Turrini R, Vanhecke D, Guex N, Ifticene-Treboux A, Iancu EM, Semilietof A, Rufer N, Lehr HA, Xenarios I, Coukos G, Delaloye JF, Doucey MA: TIE-2-expressing monocytes are lymphangiogenic and associate specifically with lymphatics of human breast cancer. Oncoimmunology 2016;5:e1073882.
7.
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzales-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275-1281.
8.
Von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S: Definition and impact of pCR on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-1804.
9.
Von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, Zahm DM, Kümmel S, Eidtmann H, Klare P, Huober J, Costa S, Tesch H, Hanusch C, Hilfrich J, Khandan F, Fasching PA, Sinn BV, Engels K, Mehta K, Nekljudova V, Untch M: Neoadjuvant carboplatin in patients with triple-negative and HER-2 positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014;15:747-756.
10.
Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930-942.
11.
Henderson JC, Berry D, Demeteri G, Cirrincione C, Goldstein L, Martino S, Ingle JN, Cooper MR, Canellos G, Borden E, Fleming G, Holland JF, Graziano S, Carpenter J, Muss H, Norton L: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (pts) with node positive primary breast cancer (BC). Proc Am Soc Oncol 1998;17:abstr 390a.
12.
Hanahan D, Bergers G, Bergsland E: Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clinical Invest 2000;105:1045-1047.
13.
Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15-R24.
14.
Hirata S, Matsubara T, Saura R, Hirohata K, Tateishi H: Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low-dose methotrexate. Arthritis Rheum 1989;32:1065-1073.
15.
Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A: Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: anti-tumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;13:73-80.
16.
André N, Carré M, Pasquier E: Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol 2014;11:413-431.
17.
Kerbel RS, Kamen BA: The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4:423-436.
18.
Toi M, Lee SJ, Lee ES, Ohtani S, Im YH, Im SA, Lim SB, Yanagita Y, Takao S, Ohno S, Aogi K, Iwata H, Kim A, Sasano H, Yokota I, Ohaschi Y, Masuda N: A phase III trial of adjuvant capecitabine in breast cancer patients with HER-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CRATE-X, JBCRG-04). Cancer Res 2016;76(suppl):abstr S1-07.
19.
Chen G, Guo Z, Liu M, Yao G, Dong J, Guo J, Ye C: Clinical value of capecitabine-based combination adjuvant chemotherapy in early breast cancer: a meta-analysis of randomized controlled trials. Oncol Res 2017DOI: 10.3727/096504017X14897173032733.
20.
Alagizy HA, Shehata MA, Hashem TA, Abdelaziz KK, Swiha MM: Metronomic capecitabine as extend adjuvant chemotherapy in women with triple negative breast cancer. Hematol Oncol Stem Cell Ther 2015;8:22-27.
21.
Lluch A, Torrecillas L, Barrios CH, Bines J, Gomez H, Getulio J, Ruiz-Borrego M, de la Haba J, Torres R, Ruiz A. CIBOMA/2004-01: a randomized phase III trial assessing adjuvant capecitabine (X) maintenance therapy after standard chemotherapy for triple-negative early breast cancer (EBC). Eur J Cancer Suppl 2009;7:304.
22.
Lluch A, Gomez H, Ruiz-Borrego M, Bines J, Llombart A, Ramos M: First safety data from a randomized phase III (CIBOMA 2004-01/GEICAM/2003-11) trial assessing adjuvant capecitabine maintenance therapy after standard chemotherapy for triple-negative breast cancer. Proc SABCS 2010;abstr P5-10-15.
23.
Zhong-yu Yuan: Phase III study of adjuvant capecitabine metronomic chemotherapy in triple-negative operable breast cancer. clinicaltrials.gov/show/NCT01112826.
24.
Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger GG, Suter TM, Masaku T, Parmar M, Laeufle R, Im YH, Romieu G, Harvey V, Lipatov O, Pienkowski T, Cottu P, Chan A, Im SA, Hall PS, Babuteishvilli-Pacaud L, Henschel V, Deurloo RJ, Pallaud C, Bell R: Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013;14:933-942.
25.
Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Denkert C, Savas P, Combs S., Rimm DL, Giltnane JM, Estrada MV, Sanchez V, Sanders ME, Cook RS, Pilkinton MA, Mallal SA, Wang K, Miller VA, Stephens PJ, Yelensky R, Doimi FD, Gomez H, Ryzhov SV, Darcy PK, Arteaga CL, Balko JM: RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD1/PDL1 immune checkpoint inhibitors. Clin Cancer Res 2016;22:1499-1509.
26.
Issa-Nummer Y, Darb-Esfahani S, Loibl S, Kunz G, Nekljudova V, Schrader I, Sinn BV, Ulmer HU, Kronenwett R, Just M, Kühn T, Diebold K, Untch M, Holms F, Blohmer JU, Habeck JO, Dietel M, Overkamp F, Krabisch P, von Minckwitz G, Denkert C: Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer - a substudy of the neoadjuvant GeparQuinto trial. PLoS One 2013;8:e79775.
27.
Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu MC, Delaloge S, Curigliano G, Andre F: Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol 2014;25:611-618.
28.
Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, Holt RA: Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 2014;24:743-750.
29.
Ludwig Breast Cancer Study Group: Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single peri-operative cycle. N Engl J Med 1988;319:677-683.
30.
Ludwig Breast Cancer Study Group: Prolonged disease-free survival after on course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med 1989;320:491-496.
31.
Colleoni M, Litman HJ, Castiglione-Gertsch M, Sauerbrei W, Gelber RD, Bonetti M, Coates AS, Schumacher M, Bastert G, Rudenstam CM, Schmoor C, Lindtner J, Collins J, Thurlimann B, Holmberg SB, Crivellari D, Beyerle C, Neumann RLA, Goldhirsch A; for the International Breast Cancer Study Group and the German Breast Cancer Study Group: Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomized trials investigating three versus six courses of CMF. Br J Cancer 2002;86:1705-1714.
32.
Saurerbrei W, Bastert G, Bojar H, Beyerle C, Neumann RL, Schmoor C, Schumacher M: Randomized 2 × 2 trial evaluating hormonal treatment and the duration of CT in node-positive BC patients: an update based on 10 years' follow up. J Clin Oncol 2000;18:94-99.
33.
International Breast Cancer Study Group: Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol 1996;14:1885-1894.
34.
Fischer B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluoruracil in positive-node breast cancer patients with tamoxifen-non responsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483-1496.
35.
Clahsen PC, van de Velde CJ, Welvaart K, van Driel OJ, Sylvester RJ: Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organization for Research and Treatment of Cancer-Dutch Breast Cancer Working Party study. J Clin Oncol 1995;13:33-41.
36.
Nasr KE, Osman MA, Elkady MS, Ellithy MA: Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study. Ann Transl Med 2015;3:284-294.
37.
Colleoni M, Gray K P, Gelber S, Làng I, Thurlimann B, Gianni L, Abdi Ehtesham AA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Golhirsch A: Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group Trial 22-00. J Clin Oncol 2016;34:3400-3408.
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