Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

Abstract

In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.

Keywords: breast cancer; molecular biomarker; targeted therapy; treatment resistance.

Figure 1

The crosstalking network of signaling pathways involved in breast cancer development and progression: estrogen receptor (ER) signaling pathway, receptor tyrosine kinase (RTK) pathway, PIK3/AKT/mTOR pathway, MAPK signaling pathway, angiogenic pathway, SRC pathway and JAK/STAT pathway. ER: estrogen receptor, RAS: rat sarcoma viral oncogene homolog, B-RAF: murine sarcoma viral oncogene homolog, MEK1/2: MAPK/Erk kinase 1/2, ERK1/2: extracellular-signal-regulated kinase 1/2, SRC: rous sarcoma, RTKs: receptor tyrosine kinases, JAK: Janus kinase, STAT: Signal Transducer and Activator of Transcription, PI3K: Phosphoinositide 3-kinase, PTEN: Phosphatase and tensin homolog, AKT: protein kinase B, NFκB: nuclear factor κ-light-chain-enhancer of activated B cells, GSK3A/B: Glycogen synthase kinase-3 α/β, mTORC1/2: mammalian target of rapamycin complex 1/2, PIP: phosphatidylinositol phosphate, P: phosphorylated. Solid arrow: activation. Dashed arrow: activation of nuclear transcription factors. T-bar: inhibition.

Figure 2

The RB-E2F and p53 pathways. INK4A: p16 protein, RB: retinoblastoma, E2F: E2 factor, CDK: cyclin dependent kinase, ARF: p14 protein, MDM2: Mouse double minute 2 homolog, ATM: ataxia-telangiectasia mutated, ATR: ATM- and Rad3-Related, CHK1: cell cycle checkpoint kinase 1, CHK2: cell cycle checkpoint kinase 2, P53: tumor suppressor P53, WAF1: cyclin-dependent kinase inhibitor 1, BAX: BCL2 Associated X. Arrow with +: activation. T-bar: inhibition.

Figure 3

HSP90 mechanism of action. The binding of a client protein to HSP90 requires the co-operation of another chaperone (HSP70 and its co-factor HSP40). HOP mediates interaction between HSP70 and HSP90. The exchange of ADP to ATP induces dissociation of HSP70 and its co-chaperones from the complex that associate then with p23, forming a mature complex. Under stressful conditions, HSP90 protects oncoproteins (such as HER2, AKT, c-MYC, etc.) from degradation. HSP90: heat shock protein 90 kDa, HSP70: Heat-shock protein of 70-kDa, HSP40: heat shock protein 40 kDA, HOP: Hsp organizing protein, ADP: Adenosine diphosphate, ATP: Adenosine triphosphate.

Figure 4

DNA repair mechanisms and the role of PARP enzymes. PARP: Poly (ADP-ribose) polymerase.

Figure 5

Immune pathway and the immune-checkpoints. TCR: T cell receptor, CTLA4: T-lymphocyte-associated antigen 4, B7.1: Cluster of differentiation 80, B7.2: Cluster of differentiation 86, MHC: Major histocompatibility complex, PD1: programmed cell death protein 1, PDL: PD1 ligand.