Targeted therapies in breast cancer: New challenges to fight against resistance

Table 1 Recapitulative breast cancer targeted therapy scheme cited in this article

Target pathway	Current therapy	Combination therapy
HER2 (HER2-positive breast cancer)	Trastuzumab/herceptin Pertuzumab lapatinib	Combination trastuzumab/lapatinib (EPHOS-B trial) trastuzumab/264RAD
m-TOR pathway	Everolimus	Possible combination everolimus/HER2 inhibitor
Angiogenesis (VEGF)	Bevacizumab paclitaxel Docetaxel	Targeting the placental growth factor and Bv8/Targeting the Notch pathway by anti-delta like ligands 4 and secretase inhibitors inhibiting simultaneously the VEGF pathway and the platelet derived growth factor receptor with a TK inhibitor
DNA repair mechanisms (TNBC) Notch-1 protein over-expression/breast cancer stem cells proliferation (TNBC)	Parp inhibitors/anthracyclins and taxanes	Possible combination cisplatin/gemcitabine/iniparib Possible combination of g-secretase inhibitor in addition to sunitinib
Immune system response Cell cycle checkpoints	Immunotherapeutic agents Antibodies against PD-1 T-cell inhibitory molecule or its ligand PD-L1	Nelipepimut-S(human leukocyte antigen)/GM-CSF Pembrolizumab in TNBC/PD-L1 positive (KEYNOTE-086 trial)

HER2: Human epidermal growth factor receptor 2; DII4: Delta like ligands 4; TNBC: Triple negative breast cancer; GM-CSF: Granulocyte-macrophage colony stimulating factor; VEGF: Vascular endothelial growth factor.

Table 2 Some of the current clinical trials in breast cancer targeted immunotherapy (http://www.cancerresearch.org./cancer-immunotherapy/impacting-all-cancers/breast-cancer)

Title of clinical trial	Type of breast cancer
Phase III clinical trial: NEUVAX: nelipepimut-S or E75NCT01479244	HER1+ HER2+
Phase II clinical trial: NEUVAX NCTO1570036	Node positive or TNBC
Phase I clinical trial: Pembrolizumab PD1 antibody + dendritic cell vaccine NCTO2479230	Metastatic breast cancer
Phase II trial: Pembrolizumab PD1 antibody + HDAC inhibitor and anti-estrogen therapy NCT02395627	Breast cancer
Phase II first line neo adjuvant trial: Atezolizumab + chemotherapy NCTO2530489	TNBC
Phase I clinical trial: Atezolizumab and HER2 inhibitors NCTO2605915	HER2+
Phase I/II clinical trial: PDR001(PD1 antibody)	Advanced breast cancer, TNBC
Phase I/II clinical trial: MEDI6469 anti OX40 antibody NCTO1642290	Stage 4 breast cancer (patients with prior failure of hormone or chemotherapy)
Pilot study of QBX258 targeting IL-4 and IL-13 NTCO2494206	Advanced TNBC whose cancer cells make a protein called glycoprotein NMB to which CDX-011 binds

IL: Interleukin; HER2: Human epidermal growth factor receptor 2; TNBC: Triple negative breast cancer.

Table 3 Some of the current clinical trials in breast cancer targeted therapy (http://www.breastcancertrials.org)

Title of clinical trial	Type of cancer
Randomized open label Phase II trial: Kadcyla, tykerb and abraxane vs herceptin, tykerb and taxol before Surgery for HER2+ tumors NCT02073487	HER2+
Phase III randomised, placebo controlled clinical trial: Chemotherapy and a PARP-inhibitor for BRCA1/2+, HER2- advanced breast cancer NCTO2163694	HER2-, BRCA1/2+ metastatic or locally advanced unresectable breast cancer
Phase II, multicenter, randomized clinical trial: Alisertib with taxol for advanced ER+/HER2- or TNBC NCTO2187991	ER+/HER2- TNBC
Phase II Clinical trial: Gemzar, herceptin and perjeta for HER2+ metastatic breast cancer NCTO2252887	HER2+ metastatic breast cancer
Phase I clinical trial: CD-839 for advanced breast tumors NCTO2071862	Advanced breast cancer and solid tumors
Phase I clinical trial: Saracatinib and anastrozole for ER-positive disease NCTO1216176	ER+
Randomised Phase III clinical trial: Hormone therapy with or without ibrance for HR+, HER2- stage II-III breast cancer NCTO2513394	HR+, HER2-
Phase II clinical trial: CDK-inhibitor for previously treated metastatic disease NCTO1037790	Previously treated metastatic breast cancer
Phase I clinical trial: GS-5745 in metastatic HER2- breast cancer and other solid tumors NCTO1813282	Metastatic HER2- breast cancer not responding to other treatments