Abstract
Treatment and management of breast cancer imposes a heavy burden on public health care, and incidence rates continue to increase. Breast cancer is the most common female neoplasia and primary cause of death among women worldwide. The recognition of breast cancer as a complex and heterogeneous disease, comprising different molecular entities, was a landmark in our understanding of this malignancy. Valuing the impact of the molecular characteristics on tumor behavior enabled a better assessment of a patient’s prognosis and increased the predictive power to therapeutic response and clinical outcome. Molecular heterogeneity is also prominent in the triple-negative breast cancer subtype, and is reflected by the distinct prognostic and patient’s sensitivity to treatment, being chemotherapy the only systemic treatment currently available. From a therapeutic perspective, gene expression profiling of triple-negative tumors has notably contributed to the exploration of new druggable targets and brought to light the need to align these patients to the various therapies according to their triple-negative subtype. Additionally, the higher amount of tumor infiltrating lymphocytes, and the prevalence of an increased expression of PD-1 receptor and its ligand, PD-L1, in triple-negative tumors, created a new treatment opportunity with immune checkpoint inhibitors. This manuscript addresses the current knowledge on the molecular and immune profiles of breast cancer, and its impact on the development of targeted therapies, with a particular emphasis on the triple-negative subtype.
Abbreviations
- BL1 :
-
basal-like 1
- BL2 :
-
basal-like 2
- CTLA-4 :
-
cytotoxic T-lymphocyte antigen 4
- ER :
-
estrogen receptor
- FDA :
-
food and drug administration
- HER2 :
-
human epidermal growth factor receptor 2
- IM :
-
immunomodulatory
- LAR :
-
luminal androgen receptor
- LHRH :
-
luteinizing hormone-releasing hormone
- M :
-
mesenchymal
- MSL :
-
mesenchymal stem-like
- PARP :
-
poly (adenosine diphosphate-ribose) polymerase
- pCR :
-
pathologic complete response
- PD-1 :
-
programmed death-1 receptor
- PD-L1 :
-
programmed death-ligand 1
- PR :
-
progesterone receptor
- TNBC :
-
triple-negative breast cancer
References
Tavassoli FA (1999) Pathology of the Breast. McGraw Hill Professional
Carter CL, Allen C, Henson DE (1989) Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63(1):181–187. https://doi.org/10.1002/1097-0142(19890101)63:1<181::AID-CNCR2820630129>3.0.CO;2-H
Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K, Spyratos F, Brunet M (1989) Prognostic value of histologic grade nuclear components of Scarff-Bloom-Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer 64(9):1914–1921. https://doi.org/10.1002/1097-0142(19891101)64:9<1914::AID-CNCR2820640926>3.0.CO;2-G
Sobin LH, Gospodarowicz MK, Wittekind C (2011) TNM classification of malignant tumours. Wiley
D'Eredita G, Giardina C, Martellotta M, Natale T, Ferrarese F (2001) Prognostic factors in breast cancer: the predictive value of the Nottingham Prognostic Index in patients with a long-term follow-up that were treated in a single institution. Eur J Cancer 37(5):591–596. https://doi.org/10.1016/S0959-8049(00)00435-4
Balslev I, Axelsson CK, Zedeler K, Rasmussen BB, Carstensen B, Mouridsen HT (1994) The Nottingham Prognostic Index applied to 9,149 patients from the studies of the Danish Breast Cancer Cooperative Group (DBCG). Breast Cancer Res Treat 32(3):281–290. https://doi.org/10.1007/BF00666005
Sinn HP, Kreipe H (2013) A Brief Overview of the WHO Classification of Breast Tumors, 4th Edition, Focusing on Issues and Updates from the 3rd Edition. Breast Care (Basel) 8(2):149–154. https://doi.org/10.1159/000350774
Elston CW, Ellis IO, Pinder SE (1999) Pathological prognostic factors in breast cancer. Crit Rev Oncol Hematol 31(3):209–223. https://doi.org/10.1016/S1040-8428(99)00034-7
Mohsin SK, Weiss H, Havighurst T, Clark GM, Berardo M, Roanh le D, To TV, Qian Z, Love RR, Allred DC (2004) Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study. Mod Pathol 17(12):1545–1554. https://doi.org/10.1038/modpathol.3800229
Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481. https://doi.org/10.1200/JCO.1999.17.5.1474
Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol 31(31):3997. https://doi.org/10.1200/Jco.2013.50.9984
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. https://doi.org/10.1038/35021093
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874. https://doi.org/10.1073/pnas.191367098
Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci 100(14):8418–8423
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7(1):96. https://doi.org/10.1186/1471-2164-7-96
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu ZY, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin YZ, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76. https://doi.org/10.1186/gb-2007-8-5-r76
Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68. https://doi.org/10.1186/bcr2635
Sabatier R, Finetti P, Guille A, Adelaide J, Chaffanet M, Viens P, Birnbaum D, Bertucci F (2014) Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization. Mol Cancer 13(1):228. https://doi.org/10.1186/1476-4598-13-228
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, Members P (2011) Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22(8):1736–1747. https://doi.org/10.1093/annonc/mdr304
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750. https://doi.org/10.1093/jnci/djp082
Inwald EC, Koller M, Klinkhammer-Schalke M, Zeman F, Hofstadter F, Gerstenhauer M, Brockhoff G, Ortmann O (2015) 4-IHC classification of breast cancer subtypes in a large cohort of a clinical cancer registry: use in clinical routine for therapeutic decisions and its effect on survival. Breast Cancer Res Treat 153(3):647–658. https://doi.org/10.1007/s10549-015-3572-3
Prat A, Cheang MCU, Martín M, Parker JS, Carrasco E, Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TO (2012) Prognostic significance of progesterone receptor–positive tumor cells within immunohistochemically defined luminal A breast cancer. Journal of Clinical Oncology:JCO. 2012.2043. 4134. doi:https://doi.org/10.1200/JCO.2012.43.4134
Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, Senn H-J, Albain KS, André F, Bergh J (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24(9):2206–2223. https://doi.org/10.1093/annonc/mdt303
Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, Nielsen TO, Foulkes WD (2007) Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 7(1):134. https://doi.org/10.1186/1471-2407-7-134
Rao C, Shetty J, Prasad KH (2013) Immunohistochemical profile and morphology in triple - negative breast cancers. Journal of clinical and diagnostic research : JCDR 7(7):1361–1365. https://doi.org/10.7860/JCDR/2013/5823.3129
Prat A, Adamo B, Cheang MCU, Anders CK, Carey LA, Perou CM (2013) Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 18(2):123–133
Pogoda K, Niwinska A, Murawska M, Olszewski W, Nowecki Z (2014) The outcome of special histologic types of triple-negative breast cancer (TNBC). In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 1122. doi:https://doi.org/10.1200/jco.2014.32.15_suppl.1122
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. https://doi.org/10.1158/1078-0432.CCR-04-0220
Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F, Committee EG (2015) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v8–30. https://doi.org/10.1093/annonc/mdv298
Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M (2015) Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 26(8):1533–1546. https://doi.org/10.1093/annonc/mdv221
Neuman HB, Morrogh M, Gonen M, Van Zee KJ, Morrow M, King TA (2010) Stage IV breast cancer in the era of targeted therapy: does surgery of the primary tumor matter? Cancer 116(5):1226–1233. https://doi.org/10.1002/cncr.24873
Rashaan ZM, Bastiaannet E, Portielje JEA, van de Water W, van der Velde S, Ernst MF, van de Velde CJH, Liefers GJ (2012) Surgery in metastatic breast cancer: Patients with a favorable profile seem to have the most benefit from surgery. Ejso-Eur J Surg Onc 38(1):52–56. https://doi.org/10.1016/j.ejso.2011.10.004
Ly BH, Vlastos G, Rapiti E, Vinh-Hung V, Nguyen NP (2010) Local-regional radiotherapy and surgery is associated with a significant survival advantage in metastatic breast cancer patients. Tumori 96(6):947–954
Morrow M, Goldstein L (2006) Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted? J Clin Oncol 24(18):2694–2696. https://doi.org/10.1200/JCO.2006.05.9824
Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23(5):489–502. https://doi.org/10.1016/j.breast.2014.08.009
Pritchard KI (2003) Endocrine therapy of advanced disease: analysis and implications of the existing data. Clin Cancer Res 9(1 Pt 2):460S–467S
Lumachi F, Luisetto G, Basso SM, Basso U, Brunello A, Camozzi V (2011) Endocrine therapy of breast cancer. Curr Med Chem 18(4):513–522. https://doi.org/10.2174/092986711794480177
Olson E, Mullins DA (2013) When standard therapy fails in breast cancer: current and future options for HER2-positive disease. J Clin Trials 3:1000129. https://doi.org/10.4172/2167-0870.1000129
Singh JC, Jhaveri K, Esteva FJ (2014) HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. Br J Cancer 111(10):1888–1898. https://doi.org/10.1038/bjc.2014.388
Twelves C, Jove M, Gombos A, Awada A (2016) Cytotoxic chemotherapy: Still the mainstay of clinical practice for all subtypes metastatic breast cancer. Crit Rev Oncol Hematol 100:74–87. https://doi.org/10.1016/j.critrevonc.2016.01.021
Li BT, Wong MH, Pavlakis N (2014) Treatment and Prevention of Bone Metastases from Breast Cancer: A Comprehensive Review of Evidence for Clinical Practice. J Clin Med 3(1):1–24. https://doi.org/10.3390/jcm3010001
Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo JQ, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA (2011) Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor-Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype-ACOSOG Z1031. J Clin Oncol 29(17):2342–2349. https://doi.org/10.1200/Jco.2010.31.6950
Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, Dube P, de Oliveira CT (2006) Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer - The Pre-Operative "Arimidex" Compared to Tamoxilen (PROAC7) trial. Cancer 106(10):2095–2103. https://doi.org/10.1002/cncr.21872
Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A'Hern R, Salter J, Detre S, Hills M, Walsh G, Group IT (2007) Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 99(2):167–170. https://doi.org/10.1093/jnci/djk020
Dunbier AK, Anderson H, Ghazoui Z, Salter J, Parker JS, Perou CM, Smith IE, Dowsett M (2011) Association between breast cancer subtypes and response to neoadjuvant anastrozole. Steroids 76(8):736–740. https://doi.org/10.1016/j.steroids.2011.02.025
Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD (2005) Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol 23(25):5973–5982. https://doi.org/10.1200/JCO.2005.05.551
LHRH-agonists in Early Breast Cancer Overview group (2007) Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 369(9574):1711–1723
Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ (2015) Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372(5):436–446. https://doi.org/10.1056/NEJMoa1412379
McGuire WL (1978) Steroid receptors in human breast cancer. Cancer Res 38(11 Pt 2):4289–4291
Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE Jr, Wickerham DL, Wolmark N (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24(23):3726–3734. https://doi.org/10.1200/JCO.2005.04.7985
Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, Ravdin P, Bugarini R, Baehner FL, Davidson NE, Sledge GW, Winer EP, Hudis C, Ingle JN, Perez EA, Pritchard KI, Shepherd L, Gralow JR, Yoshizawa C, Allred DC, Osborne CK, Hayes DF, Breast Cancer Intergroup of North A (2010) Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 11(1):55–65. https://doi.org/10.1016/S1470-2045(09)70314-6
Dowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, Cuzick J, Houghton J, Williams N, Mallon E, Bishop H, Ellis I, Larsimont D, Sasano H, Carder P, Cussac AL, Knox F, Speirs V, Forbes J, Buzdar A (2008) Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the arimidex, tamoxifen, alone or in combination trial. J Clin Oncol 26(7):1059–1065. https://doi.org/10.1200/Jco.2007.12.9437
Johnston S, Pippen J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M (2009) Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol 27(33):5538–5546. https://doi.org/10.1200/Jco.2009.23.3734
Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A (2009) Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 27(33):5529–5537. https://doi.org/10.1200/JCO.2008.20.6847
Koeberle D, Ruhstaller T, Jost L, Pagani O, Zaman K, von Moos R, Oehlschlegel C, Crowe S, Pilop C, Thuerlimann B, Swiss Group for Clinical Cancer R (2011) Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03). Endocr Relat Cancer 18(2):257–264. https://doi.org/10.1530/ERC-10-0317
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726. https://doi.org/10.1200/Jco.20.3.719
Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R, Herceptin Adjuvant Trial Study T (2011) Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 12(3):236–244. https://doi.org/10.1016/S1470-2045(11)70033-X
Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N (2014) 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):3744–3752. https://doi.org/10.1200/Jco.2014.55.5730
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J, Breast Cancer International Research G (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283. https://doi.org/10.1056/NEJMoa0910383
Tan-Chiu E, Yothers G, Romond E, Geyer CE, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005) 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):7811–7819. https://doi.org/10.1200/Jco.2005.02.4091
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281. https://doi.org/10.1200/JCO.2007.14.4147
Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685. https://doi.org/10.1158/1078-0432.CCR-04-2421
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334. https://doi.org/10.1158/1078-0432.CCR-06-1109
Peshkin BN, Alabek ML, Isaacs C (2010) BRCA1/2 mutations and triple negative breast cancers. Breast Dis 32(1-2):25–33. https://doi.org/10.3233/BD-2010-0306
Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, Mierzwa T, Szwiec M, Wisniowski R, Siolek M, Dent R, Lubinski J, Narod S (2010) Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28(3):375–379. https://doi.org/10.1200/JCO.2008.20.7019
Gronwald J, Byrski T, Huzarski T, Dent R, Bielicka V, Zuziak D, Wisniowski R, Lubinski J, Narod S (2009) Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. In: ASCO Annual Meeting Proceedings. vol 15S. p 502. doi:https://doi.org/10.1200/jco.2009.27.15s.502
Leone JP, Guardiola V, Venkatraman A, Pegram MD, Welsh C, Silva O, Larrieux R, Franchesci D, Gomez C, Hurley J (2009) Neoadjuvant platinum-based chemotherapy (CT) for triple-negative locally advanced breast cancer (LABC): retrospective analysis of 125 patients. In: ASCO Annual Meeting Proceedings. vol 15S. p 625. doi:https://doi.org/10.1200/jco.2009.27.15_suppl.625
Sirohi B, Arnedos M, Popat S, Ashley S, Nerurkar A, Walsh G, Johnston S, Smith IE (2008) Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol 19(11):1847–1852. https://doi.org/10.1093/annonc/mdn395
Liu M, Mo QG, Wei CY, Qin QH, Huang Z, He J (2013) Platinum-based chemotherapy in triple-negative breast cancer: A meta-analysis. Oncol Lett 5(3):983–991. https://doi.org/10.3892/ol.2012.1093
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767. https://doi.org/10.1172/JCI45014
Bertucci F, Finetti P, Cervera N, Charafe-Jauffret E, Mamessier E, Adelaide J, Debono S, Houvenaeghel G, Maraninchi D, Viens P, Charpin C, Jacquemier J, Birnbaum D (2006) Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res 66(9):4636–4644. https://doi.org/10.1158/0008-5472.CAN-06-0031
Marginean F, Rakha EA, Ho BC, Ellis IO, Lee AH (2010) Histological features of medullary carcinoma and prognosis in triple-negative basal-like carcinomas of the breast. Mod Pathol 23(10):1357–1363. https://doi.org/10.1038/modpathol.2010.123
Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, Liu W, Stivers D, Baggerly K, Carey M, Lluch A, Monteagudo C, He X, Weigman V, Fan C, Palazzo J, Hortobagyi GN, Nolden LK, Wang NJ, Valero V, Gray JW, Perou CM, Mills GB (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69(10):4116–4124. https://doi.org/10.1158/0008-5472.CAN-08-3441
Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, Macgrogan G, Bergh J, Cameron D, Goldstein D, Duss S, Nicoulaz AL, Brisken C, Fiche M, Delorenzi M, Iggo R (2005) Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24(29):4660–4671. https://doi.org/10.1038/sj.onc.1208561
Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, Valero V, Lehmann BD, Pietenpol JA, Hortobagyi GN, Symmans WF, Ueno NT (2013) Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular Subtypes. Clin Cancer Res 19(19):5533–5540. https://doi.org/10.1158/1078-0432.CCR-13-0799
Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, Savage MI, Osborne CK, Hilsenbeck SG, Chang JC, Mills GB, Lau CC, Brown PH (2015) Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 21(7):1688–1698. https://doi.org/10.1158/1078-0432.CCR-14-0432
Jezequel P, Loussouarn D, Guerin-Charbonnel C, Campion L, Vanier A, Gouraud W, Lasla H, Guette C, Valo I, Verriele V, Campone M (2015) Gene-expression molecular subtyping of triple-negative breast cancer tumours: importance of immune response. Breast Cancer Res 17(1):43. https://doi.org/10.1186/s13058-015-0550-y
The Cancer Genome Atlas Network (TCGA) (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70
Abramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA (2015) Subtyping of triple-negative breast cancer: implications for therapy. Cancer 121(1):8–16. https://doi.org/10.1002/cncr.28914
Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, Carey M, Agarwal R, Meric-Berstam F, Traina TA, Hudis C, Hortobagyi GN, Gerald WL, Mills GB, Hennessy BT (2009) Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res 15(7):2472–2478. https://doi.org/10.1158/1078-0432.CCR-08-1763
Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, Chen X, Balko JM, Gomez H, Arteaga CL, Mills GB, Sanders ME, Pietenpol JA (2014) PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 16(4):406. https://doi.org/10.1186/s13058-014-0406-x
De Summa S, Pinto R, Sambiasi D, Petriella D, Paradiso V, Paradiso A, Tommasi S (2013) BRCAness: a deeper insight into basal-like breast tumors. Ann Oncol 24(suppl 8):viii13–viii21
Kenemans P, Verstraeten RA, Verheijen RH (2004) Oncogenic pathways in hereditary and sporadic breast cancer. Maturitas 49(1):34–43. https://doi.org/10.1016/j.maturitas.2004.06.005
Audeh MW (2014) Novel treatment strategies in triple-negative breast cancer: specific role of poly(adenosine diphosphate-ribose) polymerase inhibition. Pharmgenomics Pers Med 7:307–316. https://doi.org/10.2147/PGPM.S39765
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134. https://doi.org/10.1056/NEJMoa0900212
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12(9):852–861. https://doi.org/10.1016/S1470-2045(11)70214-5
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–244. https://doi.org/10.1016/S0140-6736(10)60892-6
Isakoff SJ, Overmoyer B, Tung NM, Gelman RS, Giranda VL, Bernhard KM, Habin KR, Ellisen LW, Winer EP, Goss PE (2010) A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 1019. doi:https://doi.org/10.1200/jco.2010.28.15_suppl.1019
O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364(3):205–214. https://doi.org/10.1056/NEJMoa1011418
O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP (2014) 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):3840–3847. https://doi.org/10.1200/JCO.2014.55.2984
Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, Singer CF, Lowe ES, Watkins CL, Carmichael J (2013) 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 15(5):R88. https://doi.org/10.1186/bcr3484
Watkins J, Weekes D, Shah V, Gazinska P, Joshi S, Sidhu B, Gillett C, Pinder S, Vanoli F, Jasin M, Mayrhofer M, Isaksson A, Cheang MCU, Mirza H, Frankum J, Lord CJ, Ashworth A, Vinayak S, Ford JM, Telli ML, Grigoriadis A, Tutt ANJ (2015) Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers. Cancer Discovery 5(5):488–505. https://doi.org/10.1158/2159-8290.CD-14-1092
Mayer IA, Jovanovic B, Abramson VG, Mayer EL, Sanders ME, Bardia A, Dillon PM, Kuba MG, Carpenter JT, Chang JC, Lehmann BD, Meszoely IM, Grau A, Shyr Y, Arteaga CL, Chen X, Pietenpol JA (2013) A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus (an mTOR inhibitor) in patients with stage II/III triple-negative breast cancer (TNBC). Cancer Res 73 (24 Supplement):PD1-6-PD1-6. doi:https://doi.org/10.1158/0008-5472.SABCS13-PD1-6
Gonzalez-Angulo AM, Green MC, Murray JL, Palla SL, Koenig KH, Brewster AM, Valero V, Ibrahim NK, Moulder SL, Litton JK (2011) Open label, randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC (T-FEC) versus the combination of paclitaxel and RAD001 followed by FEC (TR-FEC) in women with triple receptor-negative breast cancer (TNBC). In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 1016. doi:https://doi.org/10.1200/jco.2011.29.15_suppl.1016
Singh J, Novik Y, Stein S, Volm M, Meyers M, Smith J, Omene C, Speyer J, Schneider R, Jhaveri K, Formenti S, Kyriakou V, Joseph B, Goldberg JD, Li X, Adams S, Tiersten A (2014) Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res 16(2):R32. https://doi.org/10.1186/bcr3634
Edelman G, Bedell C, Shapiro G, Pandya SS, Kwak EL, Scheffold C, Nguyen LT, Laird A, Baselga J, Rodon J (2010) A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies. J Clin Oncol 28(15):3004. https://doi.org/10.1200/jco.2010.28.15_suppl.3004
Jimeno A, Herbst RS, Falchook GS, Messersmith WA, Hecker S, Peterson S, Hausman DF, Kurzrock R, Eckhardt SG, Hong DS (2010) Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 3089. doi:https://doi.org/10.1200/jco.2010.28.15_suppl.3089
Patnaik A, Appleman LJ, Mountz JM, Ramanathan RK, Beeram M, Tolcher AW, Papadopoulos KP, Lotze MT, Petro DP, Laymon C (2011) A first-in-human phase I study of intravenous PI3K inhibitor BAY 80-6946 in patients with advanced solid tumors: Results of dose-escalation phase. In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 3035. doi:https://doi.org/10.1200/jco.2011.29.15_suppl.3035
Von Hoff DD, LoRusso P, Demetri GD, Weiss GJ, Shapiro G, Ramanathan RK, Ware JA, Raja R, Jin J, Levy GG (2011) A phase I dose-escalation study to evaluate GDC-0941, a pan-PI3K inhibitor, administered QD or BID in patients with advanced or metastatic solid tumors. In: ASCO annual meeting proceedings. vol 15_suppl. p 3052
Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan ZY, Hong R, Kassees R, Lee LB, Risom T, Gross S, Liederer BM, Koeppen H, Skelton NJ, Wallin JJ, Belvin M, Punnoose E, Friedman LS, Lin K (2013) Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models. Clin Cancer Res 19(7):1760–1772. https://doi.org/10.1158/1078-0432.CCR-12-3072
Oliveira M, Saura C, Gonzalez-Martin A, Andersen JC, Fisher JG, Calvo I, Ciruelos E, Gil M, De La Pena L, Llobet-Canela M (2015) FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (Ipat, GDC-0068) in combination with paclitaxel (Pac) as neoadjuvant treatment for early stage triple-negative breast cancer (TNBC). In: ASCO Annual Meeting Proceedings. vol 15_suppl. p TPS1112. doi:https://doi.org/10.1200/jco.2015.33.15_suppl.tps1112
Kim S, Tan AR, Im S-A, Villanueva R, Valero V, Saura C, Oliveira M, Isakoff SJ, Singel SM, Dent RA (2015) LOTUS: A randomized, phase II, multicenter, placebo-controlled study of ipatasertib (Ipat, GDC-0068), an inhibitor of Akt, in combination with paclitaxel (Pac) as front-line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC). In: ASCO Annual Meeting Proceedings. vol 15_suppl. p TPS1111. doi:https://doi.org/10.1200/jco.2015.33.15_suppl.tps1111
Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, Anton P, Cozar P, Guzman M, Grueso J, Rodriguez O, Calvo MT, Aura C, Diez O, Rubio IT, Perez J, Rodon J, Cortes J, Ellisen LW, Scaltriti M, Baselga J (2012) PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition. Cancer Discovery 2(11):1036–1047. https://doi.org/10.1158/2159-8290.CD-11-0348
McNamara KM, Moore NL, Hickey TE, Sasano H, Tilley WD (2014) Complexities of androgen receptor signalling in breast cancer. Endocr Relat Cancer 21(4):T161–T181. https://doi.org/10.1530/ERC-14-0243
Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH, Park BW, Lee KS (2010) Expression of androgen receptors in primary breast cancer. Ann Oncol 21(3):488–492. https://doi.org/10.1093/annonc/mdp510
Traina TA, Miller K, Yardley DA, O'Shaughnessy J, Cortes J, Awada A, Kelly CM, Trudeau ME, Schmid P, Gianni L (2015) Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 1003. doi: https://doi.org/10.1200/jco.2015.33.15_suppl.1003
Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, Asahi S, Miki H, Tasaka A, Kusaka M (2012) Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol 129(3-5):115–128. https://doi.org/10.1016/j.jsbmb.2012.01.001
Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA, Translational Breast Cancer Research C (2013) Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res 19(19):5505–5512. https://doi.org/10.1158/1078-0432.CCR-12-3327
Hu X, Zhang J, Xu B, Jiang Z, Ragaz J, Tong Z, Zhang Q, Wang X, Feng J, Pang D, Fan M, Li J, Wang B, Wang Z, Zhang Q, Sun S, Liao C (2014) Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer. Int J Cancer 135(8):1961–1969. https://doi.org/10.1002/ijc.28829
Baselga J, Gomez P, Greil R, Braga S, Climent MA, Wardley AM, Kaufman B, Stemmer SM, Pego A, Chan A, Goeminne JC, Graas MP, Kennedy MJ, Ciruelos Gil EM, Schneeweiss A, Zubel A, Groos J, Melezinkova H, Awada A (2013) 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 31(20):2586–2592. https://doi.org/10.1200/JCO.2012.46.2408
Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu WK, Ferraro M, Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP (2012) TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 30(21):2615–2623. https://doi.org/10.1200/JCO.2010.34.5579
Tolaney SM, Tan S, Guo H, Barry W, Van Allen E, Wagle N, Brock J, Larrabee K, Paweletz C, Ivanova E, Janne P, Overmoyer B, Wright JJ, Shapiro GI, Winer EP, Krop IE (2015) Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer. Investig New Drugs 33(5):1108–1114. https://doi.org/10.1007/s10637-015-0269-8
Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027. https://doi.org/10.1200/JCO.2005.06.081
Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtio J, Lewensohn R (2009) Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol 20(10):1639–1646. https://doi.org/10.1093/annonc/mdp062
Robert NJ, Diéras V, Glaspy J, Brufsky A, Bondarenko I, Lipatov O, Perez E, Yardley D, Zhou X, Phan S (2009) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). In: ASCO Annual Meeting Proceedings. vol 15S. p 1005. doi:https://doi.org/10.1200/jco.2009.27.15s.1005
Miles D, Chan A, Romieu G, Dirix LY, Cortes J, Pivot X, Tomczak P, Taran T, Harbeck N, Steger GG (2008) Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. In: ASCO Annual Meeting Proceedings. vol 15_suppl. p LBA1011. doi: https://doi.org/10.1200/jco.2008.26.15_suppl.lba1011
Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676. https://doi.org/10.1056/NEJMoa072113
Brufsky A, Valero V, Tiangco B, Dakhil SR, Brize A, Bousfoul N, Rugo HS, Yardley DA (2011) Impact of bevacizumab (BEV) on efficacy of second-line chemotherapy (CT) for triple-negative breast cancer (TNBC): Analysis of RIBBON-2. In: ASCO Annual Meeting Proceedings. vol 15_suppl. p 1010. doi:https://doi.org/10.1200/jco.2011.29.15_suppl.1010
Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger GG, Suter TM, Toi M, Parmar M, Laeufle R, Im YH, Romieu G, Harvey V, Lipatov O, Pienkowski T, Cottu P, Chan A, Im SA, Hall PS, Bubuteishvili-Pacaud L, Henschel V, Deurloo RJ, Pallaud C, Bell R (2013) Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 14(10):933–942. https://doi.org/10.1016/S1470-2045(13)70335-8
Carpenter D, Kesselheim AS, Joffe S (2011) Reputation and precedent in the bevacizumab decision. N Engl J Med 365(2):e3. https://doi.org/10.1056/NEJMp1107201
Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19(2):264–271. https://doi.org/10.1038/modpathol.3800528
De Luca A, D'Alessio A, Maiello MR, Gallo M, Chicchinelli N, Pergameno M, Piccirilli MS, Normanno N (2015) Evaluation of the pharmacokinetics of ixabepilone for the treatment of breast cancer. Expert Opin Drug Metab Toxicol 11(7):1177–1185. https://doi.org/10.1517/17425255.2015.1057497
Trédan O, Campone M, Jassem J, Vyzula R, Coudert B, Pacilio C, Prausova J, Hardy-Bessard A-C, Arance A, Mukhopadhyay P (2015) Ixabepilone alone or with cetuximab as first-line treatment for advanced/metastatic triple-negative breast cancer. Clin Breast Cancer 15(1):8–15. https://doi.org/10.1016/j.clbc.2014.07.007
Carey LA, O'Shaughnessy JA, Hoadley K, Khambata-Ford S, Horak CE, Xu LA, Awad M, Brickman D, Muller S, Donato J, Asmar L, Stiljeman I, Ebbert M, Bernard P, Perou CM (2009) Potential Predictive Markers of Benefit from Cetuximab in Metastatic Breast Cancer: An Analysis of Two Randomized Phase 2 Trials. Cancer Res 69(24):596s–596s. https://doi.org/10.1158/0008-5472.SABCS-09-2014
Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, Owens P, Sanders ME, Kuba MG, Sanchez V, Kurupi R, Moore PD, Pinto JA, Doimi FD, Gomez H, Horiuchi D, Goga A, Lehmann BD, Bauer JA, Pietenpol JA, Ross JS, Palmer GA, Yelensky R, Cronin M, Miller VA, Stephens PJ, Arteaga CL (2014) Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 4(2):232–245. https://doi.org/10.1158/2159-8290.CD-13-0286
Marotta LLC, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gonen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. J Clin Investig 121(7):2723–2735. https://doi.org/10.1172/JCI44745
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013
Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in Previously Untreated Melanoma without BRAF Mutation. N Engl J Med 372(4):320–330. https://doi.org/10.1056/Nejmoa1412082
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387(10031):1909–1920. https://doi.org/10.1016/S0140-6736(16)00561-4
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375(19):1856–1867. https://doi.org/10.1056/NEJMoa1602252
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373(2):123–135. https://doi.org/10.1056/NEJMoa1504627
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate I (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373(19):1803–1813. https://doi.org/10.1056/NEJMoa1510665
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, Investigators K (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028. https://doi.org/10.1056/NEJMoa1501824
Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, Holt RA (2014) Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 24(5):743–750. https://doi.org/10.1101/gr.165985.113
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31(7):860–867. https://doi.org/10.1200/JCO.2011.41.0902
Wimberly H, Brown JR, Schalper K, Haack H, Silver MR, Nixon C, Bossuyt V, Pusztai L, Lannin DR, Rimm DL (2015) PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunol Res 3(4):326–332. https://doi.org/10.1158/2326-6066.CIR-14-0133
Ali HR, Glont SE, Blows FM, Provenzano E, Dawson SJ, Liu B, Hiller L, Dunn J, Poole CJ, Bowden S, Earl HM, Pharoah PDP, Caldas C (2015) PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol 26(7):1488–1493. https://doi.org/10.1093/annonc/mdv192
Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F (2015) Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6(7):5449–5464. 10.18632/oncotarget.3216
Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L (2014) Trial Watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 3(1):e27878. https://doi.org/10.4161/onci.27878
Ramakrishnan R, Gabrilovich DI (2011) Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer. Cancer Immunol, Immunother : CII 60(3):419–423. https://doi.org/10.1007/s00262-010-0930-1
Drake CG, Lipson EJ, Brahmer JR (2014) Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol 11(1):24–37. https://doi.org/10.1038/nrclinonc.2013.208
Acknowledgements
Ana Cristina Leal Gregório is student of the international PhD program in Experimental Biology and Biomedicine (PDBEB) from the Institute for Interdisciplinary Research, University of Coimbra and recipient of the fellowship SFRH/BD/51190/2010 from the Portuguese Foundation for Science and Technology (FCT). The work was supported by the grants PTDC/SAU-BMA/121028/2010 and POCI-01-0145-FEDER-007440 (FEDER/COMPETE 2020/FCT).
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Gregório, A.C., Lacerda, M., Figueiredo, P. et al. Therapeutic Implications of the Molecular and Immune Landscape of Triple-Negative Breast Cancer. Pathol. Oncol. Res. 24, 701–716 (2018). https://doi.org/10.1007/s12253-017-0307-2
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DOI: https://doi.org/10.1007/s12253-017-0307-2