title: Clinical implications of routine genomic mutation sequencing in PIK3CA/AKT1 and KRAS/NRAS/BRAF in metastatic breast cancer.
abstract: There is increasing interest in the molecular profiling of tumour tissues in order to investigate alternative breast cancer (BC) therapies. However, the impact of genomic screening for druggable mutations with targeted gene panel sequencing (TGPS) in routine practice remains controversial.
  
  
  
  This is a retrospective analysis of data from a genomic screening programme at our institution, in which we performed simplified TGPS for mutations in PIK3CA, AKT1, KRAS, NRAS, and BRAF in order to select patients for targeted therapy clinical trials. The genomes of archived samples of primary (PT) and/or metastatic (MT) tumours from advanced BC patients were analysed with MassARRAY technology (Sequenom MassARRAY, OncoCarta v1.0). The level of PTEN expression was assessed by immunohistochemistry. The primary endpoint was to identify the proportion of BC patients with PI3 K and MAPK alterations who were included in clinical trials using targeted therapies against these pathways.
  
  
  
  Two hundred and fifteen metastatic BC patients (65 PT and 168 MT) were included. Fifty-two patients (24.19 %) were enrolled in tailored clinical trials, of whom 29 (55.77, 13.49 % of all patients screened) harboured mutations targeted by the study drug. Moreover, 12 wild-type patients out of the 215 (5.58 %) were included in the clinical trials for which mutation analysis was an inclusion criteria. All the patients received drugs targeting the PI3K-AKT pathway and only two were given combinations directed against the PI3K and MAPK pathways. PI3KCA mutations were present in 33.7 % (61/181) of the patients, 45.83 % in PTs and 29.32 % in MTs. AKT1 mutations were detected in 5.48 % (8/146) of patients and PTEN loss in 34.67 % (52/150). KRAS, NRAS, and BRAF mutations were present in 12.06, 5.67, and 3.18 % of patients, respectively.
  
  
  
  Genomic screening with a simplified TGPS is feasible, and was used to identify 13.49 % of patients who were included in clinical trials using targeted therapy against the mutations they harboured; PI3KCA mutations were the most frequent aberration in our series.
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain. juanmiguel.cejalvo@irbbarcelona.org.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Cejalvo
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Pérez-Fidalgo
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ribas
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: Octavio
authors.initials: O
authors.lastname: Burgués
authors.affiliation: Department of Pathology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mongort
authors.affiliation: Department of Pathology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Alonso
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: Maider
authors.initials: M
authors.lastname: Ibarrola-Villava
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Bermejo
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Martínez
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain. lluch_ana@gva.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
keywords: Breast cancer; Clinical trials; Genomic mutation sequencing; PI3K pathway