Clinical implications of routine genomic mutation sequencing in PIK3CA/AKT1 and KRAS/NRAS/BRAF in metastatic breast cancer

• Published in: Breast cancer research and treatment Vol. 160; no. 1; pp. 69 - 77
• Main Authors: Cejalvo, Juan Miguel, Pérez-Fidalgo, J. Alejandro, Ribas, Gloria, Burgués, Octavio, Mongort, Cristina, Alonso, Elisa, Ibarrola-Villava, Maider, Bermejo, Begoña, Martínez, María Teresa, Cervantes, Andrés, Lluch, Ana
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2016; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Biomarkers, Tumor; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer genetics; Cancer metastasis; Cancer research; Cancer therapies; Cancer treatment; Care and treatment; Clinical Trial; DNA Mutational Analysis; Female; Gene Frequency; Gene mutation; Genetic aspects; Genetic research; Genetic testing; Genomes; Genomics; Health aspects; Humans; Immunohistochemistry; Medical screening; Medicine; Medicine & Public Health; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Oncology; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-akt - genetics; ras Proteins - genetics; Targeted cancer therapy; Clinical trials; PI3K pathway; Breast cancer; Genomic mutation sequencing
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-016-3980-z

Background 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. Methods 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. Results 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. Conclusions 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.