| Abstract: |
Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents. ©2013 Macmillan Publishers Limited. All rights reserved. |
| Keywords: |
treatment response; unclassified drug; gene mutation; drug tolerability; review; placebo; cancer combination chemotherapy; cancer growth; drug efficacy; drug safety; nonhuman; solid tumor; antineoplastic agents; drug targeting; capecitabine; paclitaxel; adjuvant therapy; cancer adjuvant therapy; recurrent cancer; phenotype; unindexed drug; enzyme inhibition; breast cancer; protein targeting; neoplasm proteins; evolution; high throughput screening; breast neoplasms; cixutumumab; exemestane; temsirolimus; cancer hormone therapy; drug dose escalation; molecular cloning; drug mechanism; neoplastic stem cells; epigenetics; cancer cell; cancer stem cell; cell subpopulation; lymphoma; stroma; tamoxifen; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; target cell; protein deficiency; letrozole; genetic disorder; trastuzumab; anastrozole; breast metastasis; breast carcinogenesis; cell metabolism; everolimus; lapatinib; host cell; functional genomics; product development; genetic heterogeneity; fulvestrant; genetic selection; intracellular signaling; phosphatidylinositol 3 kinase inhibitor; intracellular space; tumor microenvironment; molecularly targeted therapy; phase 2 clinical trial (topic); phase 3 clinical trial (topic); disease activity; phase 1 clinical trial (topic); triple negative breast cancer; molecular targeted therapy; 1 (1 cyano 1 methylethyl) 3 methyl 8 (3 quinolinyl)imidazo[4,5 c]quinolin 2(1h,3h) one; cancer prognosis; experimentation; estrogen receptor positive breast cancer; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; xl 147; pictilisib; xl 765; buparlisib; byl 719; gdc 0032; azd 2014; azd 5363; gdc 0980; gsk 2126458; gsk 2636771; ink 128
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