The Community Resource in Targeted Therapies
Driving Knowledge. Empowering Change. Optimizing Outcomes.
ONCAlert | Upfront Therapy for mRCC

Evolving Paradigms in Triple-Negative Breast Cancer: References

Published Online: Feb 20,2017
  1. 1. Wahba HA, El-hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med. 2015;12(2):106-116.
  2. Tomao F, Papa A, Zaccarelli E, et al. Triple-negative breast cancer: new perspectives for targeted therapies. Onco Targets Ther. 2015;8:177-193.
  3. Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol. 2014;232(2):142-150.
  4. De Ruijter TC, Veeck J, De Hoon JP, Van Engeland M, Tjan-heijnen VC. Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol. 2011;137(2):183-192.
  5. Boyle P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann Oncol. 2012;23(suppl 6):vi7-vi12.
  6. Abramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA. Subtyping of triple-negative breast cancer: implications for therapy. Cancer. 2015;121(1):8-16.
  7. Choi Y, Park SK, Ahn KJ, et al. Being overweight or obese increases the risk of progression in triple-negative breast cancer after surgical resection. J Korean Med Sci. 2016;31(6):886-91.
  8. ElShamy WM. The protective effect of longer duration of breastfeeding against pregnancy-associated triple negative breast cancer. Oncotarget. 2016. doi: 10.18632/oncotarget.9690. [Epub ahead of print]
  9. Hyslop T, Michael Y, Avery T, Rui H. Population and target considerations for triplenegative breast cancer clinical trials. Biomark Med. 2013;7(1):11-21.
  10. Penault-Llorca F, Viale G. Pathological and molecular diagnosis of triple-negative breast cancer: a clinical perspective. Ann Oncol. 2012;23(suppl 6):vi19–vi22. doi: 10.1093/annonc/mds190.
  11. Schmadeka R, Harmon BE, Singh M. Triple-negative breast carcinoma: current and emerging concepts. Am J Clin Pathol. 2014;141(4):462-477.
  12. Jiang HS, Kuang XY, Sun WL, et al. Androgen receptor expression predicts differ- ent clinical outcomes for breast cancer patients strati ed by hormone receptor status. Oncotarget. 2016. doi: 10.18632/oncotarget.9778. [Epub ahead of print]
  13. Maric G, Rose AA, Annis MG, Siegel PM. Glycoprotein non-metastatic b (gpNMB): a metastatic mediator and emerging therapeutic target in cancer. Onco Targets Ther. 2013;6:839-852.
  14. Wang CQ, Tang CH, Chang HT, et al. Fascin-1 as a novel diagnostic marker of triple-negative breast cancer. Cancer Med. 2016;5(8):1983-1988.
  15. Eiermann W, Vallis KA. Locoregional treatments for triple-negative breast cancer. Ann Oncol. 2012;23(suppl 6):vi30-vi34.
  16. Anders CK, Zagar TM, Carey LA. The management of early-stage and metastatic triplenegative breast cancer: a review. Hematol Oncol Clin North Am. 2013;27(4):737-749, viii.
  17. Yadav BS, Sharma SC, Chanana P, Jhamb S.  Systemic treatment strategies for triplenegative breast cancer. World J Clin Oncol. 2014;5:125-133.
  18. Zhang P, Yin Y, Mo H, et al. Better pathologic complete response and relapse-free survival after carboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial. Oncotarget. 2016. doi: 10.18632/oncotarget.10607. [Epub ahead of print]
  19. Yardley DA, Weaver R, Melisko ME, et al. EMERGE: A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol. 2015;33(14):1609-1619.
  20. Celldex Therapeutics. A Randomized Multicenter Pivotal Study of CDX-011 (CR011- vcMMAE)in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (The METRIC Study). In: ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/ct2/show/study/NCT01997333:
  21. Crown J, O’Shaughnessy J, Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol. 2012;23(suppl 6):vi56-vi65.
  22. Singh J, Novik Y, Stein S, et al. Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res. 2014;16(2):R32.
  23. Yunokawa M, Koizumi F, Kitamura Y, et al. Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells. Cancer Sci. 2012;103(9):1665-1671.
  24. Puma Biotechnology, Inc. A phase I/II trial of temsirolimus plus neratinib for patients with metastatic HER2-amplified or triple negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01111825.
  25. Gordon V, Banerji S. Molecular pathways: PI3K pathway targets in triple-negative breast cancers. Clin Cancer Res. 2013;19(14):3738-3744.
  26. O’Shaughnessy J, Romieu G, Diéras V, Byrtek M, Duenne AA, Miles D. Meta-analysis of patients with triple-negative breast cancer (TNBC) from three randomized trials of first-line bevacizumab (BV) and chemotherapy treatment for metastatic breast cancer Evolving Paradigms in TNBC 13 (MBC). Cancer Res. 2010;70(suppl 24):P6-12-03.
  27. 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(20):3239-3247.
  28. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebocontrolled, 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(10):1252-1260.
  29. Gerber B, Loibl S, Eidtmann H, et al. Neoadjuvant bevacizumab and anthracyclinetaxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Ann Oncol. 2013;24(12):2978-2984.
  30. Eli Lilly and Company. A multicenter, multinational, randomized, double-blind, phase III study of IMC-1121B plus docetaxel versus placebo plus docetaxel in previously untreated patients with HER2-negative, unresectable, locally-recurrent or metastatic breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials. gov/show/NCT00703326.
  31. Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26(11):1810-1816.
  32. Baselga J, Segalla JG, Roché H, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. 2012;30(13):1484-1491.
  33. Fudan University. A single-institutional phase IIa trial and a multi-institutional phase IIb trial of apatinib in metastatic triple-negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01176669: NCT NCT01176669.
  34. National Cancer Institute (NCI). Phase I/II study of cediranib and olaparib in combination for treatment of recurrent papillary-serous ovarian, fallopian tube, or peritoneal cancer or for treatment of recurrent triple-negative breast cancer. ClinicalTrials. gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01116648.
  35. Turner N, Lambros MB, Horlings HM, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29(14):2013-2023.
  36. André F, Cortés J. Rationale for targeting fibroblast growth factor receptor signaling in breast cancer. Breast Cancer Res Treat. 2015;150(1):1-8.
  37. Bello E, Taraboletti G, Colella G, et al. The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of advanced-stage triple-negative breast cancer xenografts. Mol Cancer Ther. 2013;12(2):131-140.
  38. Baselga J, Gómez 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(20):2586-2592.
  39. Linklater ES, Tovar EA, Essenburg CJ, et al. Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers. Oncotarget. 2016. doi: 10.18632/onco- target.12065. [Epub ahead of print]
  40. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012;30(21):2615-2623.
  41. The Methodist Hospital System. Randomized open-label neo-adjuvant phase II study comparing ixabepilone (I) vs. ixabepilone plus cetuximab (IC) in triple negative breast cancer patients. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01097642.
  42. Memorial Sloan Kettering Cancer Center. Bicalutamide for the treatment of androgen receptor positive (AR(+)), estrogen receptor negative, progesterone receptor negative (ER(-)/PR(-)) metastatic breast cancer patients: a phase II feasibility study. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT00468715.
  43. Mirzania M. Approach to the triple negative breast cancer in new drugs area. Int J Hematol Oncol Stem Cell Res. 2016;10(2):115-119.
  44. Dent RA, Lindeman GJ, Clemons M, et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res. 2013;15(5):R88.
  45. AstraZeneca. Phase I/II randomised, double-blind, multi-centre study to assess the efficacy of AZD2281 when given in combination with paclitaxel in the 1st or 2nd line treatment of patients with metastatic triple negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT00707707.
  46. AstraZeneca. A phase I, open-label study to assess the safety and tolerability of KU-0059436 in combination with carboplatin, KU-0059436 in combination with a paclitaxel/carboplatin T/C doublet and KU-0059436 in combination with paclitaxel in the treatment of patients with advanced solid tumours. ClinicalTrials.gov: National Library of Medicine https://clinicaltrials.gov/show/NCT00516724.
  47. AstraZeneca. A phase I open label, multi centre study of AZD2281 administered orally in combination with cisplatin, to assess the safety and tolerability in patients with advanced solid tumours. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT00782574.
  48. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin. Oncol. 2010;28(suppl): Abstract 1019.
  49. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205-214.
  50. Sanofi. Randomized, open-label, phase 2 study of the efficacy and safety of weekly paclitaxel single-agent and two different regimens of the PARP-1 inhibitor SAR240550 (BSI-201) in combination with weekly paclitaxel, as neoadjuvant therapy in patients with stage II-IIIA triple negative breast cancer (TNBC). ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01204125.
  51. Hoosier Cancer Research Network. PARP inhibition after preoperative chemotherapy in patients with triple negative breast cancer or ER/PR +, HER2 negative with known BRCA1/2 mutations: Hoosier Oncology Group BRE09-146. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01074970.
  52. Arnedos M, Bihan C, Delaloge S, Andre F. Triple-negative breast cancer: are we making headway at least? Ther Adv Med Oncol. 2012;4(4):195-210.
  53. Pichot CS, Hartig SM, Xia L, et al. Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer. 2009;101(1):38- 47.
  54. Kim EM, Mueller K, Gartner E, Boerner J. Dasatinib is synergistic with cetuximab and cisplatin in triple-negative breast cancer cells. J Surg Res. 2013;185(1):231-239.
  55. M.D. Anderson Cancer Center. Phase II short-term adjuvant therapy and biomarker studies with targeted agents in women with estrogen receptor negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/ct2/show/ study/NCT01471106.
  56. Sprycel Web site. About SPRYCEL (dasatinib). http://www.sprycel.com/About. Accessed August 2015.
  57. Tate CR, Rhodes LV, Segar HC, et al. Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Res. 2012;14(3):R79.
  58. Alliance for Clinical Trials in Oncology. Phase I/II study of panobinostat (LBH589) and letrozole in patients with triple negative metastatic breast cancer. ClinicalTrials. gov: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01105312.
  59. NCI Drug Dictionary: trametinib. National Cancer Institute Web site: http://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=599034. Accessed August 2015.
  60. UNC Lineberger Comprehensive Cancer Center. Defining the triple negative breast cancer kinome response to GSK1120212. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01467310.
  61. National Cancer Institute (NCI). A single arm, phase II study of single agent trametinib followed by trametinib in combination with GSK2141795 in patients with advanced triple negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01964924.
  62. Ma CX, Ellis MJ, Petroni GR, et al. A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat. 2013;137(2):483-492.
  63. Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW, Chen KF. CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res. 2012;14(2):R68.
  64. Shen S, Du XJ, Liu J, Sun R, Zhu YH, Wang J. Delivery of bortezomib with nanoparticles for basal-like triple-negative breast cancer therapy. J Control Release. 2015;208:14-24.
  65. Kren BT, Unger GM, Abedin MJ, et al. Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy. Breast Cancer Res. 2015;17:19.
  66. Mita MM, Joy AA, Mita A, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014;14(3):169-176.
  67. Mitri Z, Karakas C, Wei C, et al. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. Invest New Drugs. 2015;33(4):890-894. 14 Evolving Paradigms in TNBC
  68. Sandeep Rajput, Zhanfang Guo, Cynthia Ma. CDKs inhibitor: potential monotherapy for treatment of triple-negative breast cancer. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 April 18-22; Philadelphia, PA. Cancer Res. 2015;75(suppl 15: abstract 3097).
  69. Shawn F. Johnson, Neil Johnson, David Chi, et al. The CDK inhibitor dinaciclib sensitizes triple-negative breast cancer cells to PARP inhibition. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 April 6-10; Washington, DC. Cancer Res. 2013;73(suppl 8: abstract 1788).
  70. Geyer FC, Lacroix-triki M, Savage K, et al. β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol. 2011;24(2):209-231.
  71. Maubant S, Tesson B, Maire V, et al. Transcriptome analysis of Wnt3a-treated triplenegative breast cancer cells. PLoS One. 2015;10(4):e0122333.
  72. Leris AC, Roberts TR, Jiang WG, Newbold RF, Mokbel K. WNT5A expression in human breast cancer. Anticancer Res. 2005;25(2A):731-734.
  73. Soerensen PG, Andersson T, Buhl U. Phase I dose-escalating study to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of Foxy-5 in patients with metastatic breast, colorectal, or prostate cancer. J Clin Oncol. 2014;32:5s (suppl): Abstract TPS1140.
  74. Liu J, Pan S, Hsieh MH, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013;110(50):20224-20229.
  75. Solzak JP, Atale R, Hancock B, Radovich M. Dual PI3K and Wnt pathway inhibition is a synergistic combination against triple-negative breast cancer. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 April 18-22; Philadelphia, PA. Cancer Res. 2015;75(suppl 15: abstract 5340).
  76. Novartis Pharmaceuticals. A phase I, open-label, dose escalation study of oral LGK974 in patients with malignancies dependent on Wnt ligands. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/show/NCT01351103.
  77. Shrivastava S, Jeengar MK, Thummuri D, et al. Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/ ß-catenin signaling cascades and reversal of epithelial-mesenchymal transition. Biofactors. 2016. doi: 10.1002/biof.1315. [Epub ahead of print]
  78. Tian XS, Cong MH, Zhou WH, Zhu J, Chen YZ, Liu Q. Clinicopathologic and prognostic characteristics of triple-negative breast cancer. Onkologie. 2008;31(11):610-614.
  79. 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. 2008;26(8):1275- 1281.
  80. Rhee J, Han SW, Oh DY, et al. The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer. BMC Cancer. 2008;8:307.
  81. Parikh RR, Housman D, Yang Q, Toppmeyer D, Wilson LD, Haffty BG. Prognostic value of triple-negative phenotype at the time of locally recurrent, conservatively treated breast cancer. Int J Radiat Oncol Biol Phys. 2008;72(4):1056-1063.
  82. Kaplan HG, Malmgren JA. Impact of triple negative phenotype on breast cancer prognosis. Breast J. 2008;14(5):456-463.
  83. Nishimura R, Arima N. Is triple negative a prognostic factor in breast cancer? Breast Cancer. 2008;15(4):303-308.
  84. Tseng LM, Hsu NC, Chen SC, et al. Distant metastasis in triple-negative breast cancer. Neoplasma. 2013;60(3):290-294.
  85. Chikarmane SA, Tirumani SH, Howard SA, Jagannathan JP, DiPiro PJ. Metastatic patterns of breast cancer subtypes: What radiologists should know in the era of personalized cancer medicine. Clin Radiol. 2015;70(1):1-10.
  86. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 pt 1):4429-4434.
  87. Liedtke C, Hess KR, Karn T, et al. The prognostic impact of age in patients with triplenegative breast cancer. Breast Cancer Res Treat. 2013;138(2):591-599.
  88. Le du F, Eckhardt BL, Lim B, et al. Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype? Oncotarget. 2015;6(15):12890-12908.
  89. Lehmann BD, Pietenpol JA, Tan AR. Triple-negative breast cancer: molecular subtypes and new targets for therapy. Am Soc Clin Oncol Educ Book. 2015;35:e31-e39.
  90. NCI Drug Dictionary: gamma secretase inhibitor PF-03084014. National Cancer Institute Web site: http://www.cancer.gov/publications/dictionaries/cancerdrug?cdrid=641472. Accessed August 2015.
  91. Jules Bordet Institute. Biomarker research study for PF-03084014 in chemoresistant triple-negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https:// clinicaltrials.gov/ct2/show/NCT02338531.
  92. Dana-Farber Cancer Institute. Phase II study of combination ruxolitinib (INCB018242) with preoperative chemotherapy for triple negative inflammatory breast cancer following completion of a phase I combination study in recurrent/ metastatic breast cancer. ClinicalTrials.gov: National Library of Medicine. https:// clinicaltrials.gov/ct2/show/NCT02041429.
  93. Immunomedics, Inc. Randomized phase II study of IMMU-132 alone or in combination with carboplatin in patients with relapsed/refractory triple-negative breast cancer. ClinicalTrials.gov: National Library of Medicine. https://clinicaltrials.gov/ct2/ show/NCT02161679.
  94. Santa-maria CA, Gradishar WJ. Changing treatment paradigms in metastatic breast cancer: lessons learned. JAMA Oncol. 2015;1(4):528-534.
  95. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 December 9-13; San Antonio, TX. Cancer Res. 2015;75(suppl 9: abstract S1-09).
  96. Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combi- nation with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016;34(suppl): Abstract 1009.
  97. A Study of Atezolizumab Administered in Combination With Bevacizumab and/ or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors. ClinicalTrials.gov website. https://clinicaltrials.gov/show/NCT01633970.
  98. Ma F, Li H, Wang H, et al. Enriched CD44(+)/CD24(-) population drives the aggressive phenotypes presented in triple-negative breast cancer (TNBC). Cancer Lett. 2014;353(2):153-159.
  99. Samanta S, Sun H, Goel HL, et al. IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene. doi:10.1038/onc.2015.164.
  100. Marzec KA, Baxter RC, Martin JL. Targeting insulin-like growth factor binding protein-3 signaling in triple-negative breast cancer. Biomed Res Int. 2015;2015:638526.
  101. Turner NC, Reis-filho JS. Tackling the diversity of triple-negative breast cancer. Clin Cancer Res. 2013;19(23):6380-6388.



Clinical Articles

Evolving Paradigms in Triple-Negative Breast Cancer: References
Copyright © TargetedOnc 2018 Intellisphere, LLC. All Rights Reserved.