Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer

Abstract

BackgroundTriple Negative Breast Cancer (TNBC) accounts for 12–24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20–40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.Materials and MethodsPIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.ResultsPIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.ConclusionsOur data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer

“…PIK3CA mutations are very frequent (20%-40%) genetic alterations in MBC, particularly in node-negative, ER þ and HER2 À breast cancer, and are generally related to a good clinical outcome with a lower recurrence and mortality rate (35). Nevertheless, tissue-based NGS had already demonstrated that at least 33% of TN breast cancer have deregulated PI3K/AKT pathways, making these pathways an attractive target for pharmacologic treatment (e.g., everolimus) and highlighting the importance of mutation profiling for individualized therapies (36). In our population, maybe because enriched in IBC (64% of the patients), with a rate of 40% in the entire population and of 31% in the TN subgroup, PIK3CA/mTOR pathway (altered in 22 patients, including 12 patients with IBC) appears the second most altered pathway, immediately after TP53 (52% and 61%, in the entire population and TN subgroup respectively).…”

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

“…In ER-positive tumors with mutated PIK3CA, indicators of PI3K pathway activation (e.g., phosphorylated AKT and mTOR) were no different as compared to tumors without mutations [12], unless associated with PTEN loss, then both indicators were increased. In TNBC, both mutations were associated with overexpression of phosphorylated AKT [13]. Therefore, the functional effects of PI3K pathway alterations are probably subtype specific.…”

“…PIK3CAm are most common in luminal estrogen receptor (ER)-positive tumors, especially in luminal A (49 vs 32 % in luminal B), approximately 25 % of HER2-positive tumors, and up to 23 % in triple negative breast cancers (TNBCs) [12][13][14]. PIK3CA is most frequently mutated at Bhot spots^in exons 9 and 20, corresponding to the helical (E542K and E545G) and kinase (H1047R) domains of the catalytic subunit p110a, respectively [15], accounting for up to 87.5 % of all mutations in PIK3CA [16].…”

“…While associated with increased signaling through AKT in cell lines [20], PIK3CAm have been associated with low mTORC1 output, and increased ESR1 signaling in some human tumors, especially ERpositive tumors, but increased AKT phosphorylation in others, particularly TNBC [12,13]. In ER-positive tumors with mutated PIK3CA, indicators of PI3K pathway activation (e.g., phosphorylated AKT and mTOR) were no different as compared to tumors without mutations [12], unless associated with PTEN loss, then both indicators were increased.…”

“…Therefore, the functional effects of PI3K pathway alterations are probably subtype specific. To complicate matters further, while PTEN mutations are rare in breast cancer, PTEN loss and PIK3CAm are not mutually exclusive [13].…”