title: Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer.
abstract: : Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%-20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs.
  
  
  
  Next-generation sequencing is now widely available in the clinic, but interpretation of the results is challenging, and its impact on treatment selection is often limited. This work provides an overview of frequently encountered molecular abnormalities in breast cancer and discusses their potential therapeutic implications. This review emphasizes the importance of administering investigational targeted therapies, or off-label use of approved targeted drugs, in the context of a formal clinical trial or registry programs to facilitate learning about the clinical utility of tumor target profiling.
authors.affiliation: Oncology Experimental Therapeutics, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Clinical and Research Institute, Milan, Italy libero.santarpia@humanitasresearch.it liberosantarpia@yahoo.it lajos.pusztai@yale.edu.
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
authors.affiliation: Oncology Experimental Therapeutics, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Clinical and Research Institute, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bottai
authors.affiliation: Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Kelly
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Borbala
authors.initials: B
authors.lastname: Székely
authors.affiliation: Yale Cancer Center, School of Medicine, Yale University, New Haven, Connecticut, USA libero.santarpia@humanitasresearch.it liberosantarpia@yahoo.it lajos.pusztai@yale.edu.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C508053:ERBB2 protein, human
keywords: Biomarkers of response to therapy; Breast cancer molecular subtypes; Drug resistance; Mutation-genomic landscape; Oncogenic signaling pathways; Potential therapeutic targets; Tumor heterogeneity