HER2, EGFR, PIK3CA mutations in HER2+ metastatic breast cancer (MBC) patients (pts) treated with trastuzumab (T): Incidence and correlation with response.

1031 Background: Resistence mechanisms to T are still undefined. EGFR, pMAPK, pAKT and PTEN status by IHC were not correlated with response to T in our previously series of 45 HER2+ MBC pts. No data are reported about incidence of HER2, EGFR and PIK3CA genes mutations and their correlations with response to T. in HER2+ MBC pts.,From 4/1999 to 3/2006, 133 consecutive pts were treated with T. Tumor tissues for this analysis were available from 41 pts. Genomic DNA was isolated from paraffin-embedded tumor specimens, amplified for HER2 (exons 19, 20, 21 and 22, encoding the kinase domain), EGFR (exons 18, 19, 20 and 21) and PIK3CA (exons 9 and 20, encoding a part of elical and kinase domains, respectively) genes by nested polymerase chain reaction and sequenced in both sense and antisense directions.,We found mutations of HER2 in 3 pts (7.3%), of EGFR in 6 pts (14.6 %) and PIK3CA in 5 pts (12.2%) with HER2+ tumors ( Table ); correlations with response to T are reported ( Table ). The same HER2 mutation in exon 20 was identified in 2 pts with pAKT+ tumor (IHC) and no response to T. PIK3CA mutations were associated with pAKT+ status only in 2 pts. In all 5 tumors with PIK3CA mutations, a PTEN+ status (IHC) was observed, consistent with the speculation that PIK3CA mutations and loss of PTEN expression are mutually exclusive. A pt presented 2 mutations: 1 in ex 20 of HER2 (P780_H781insC) and 1 in ex 20 of PIK3CA (L1026P). CNS metastases developed in 9/13 (69.2%) pts with mutations of these genes, but only in 12/28 (42.8%) pts without mutations.,In our series of HER2+ MBC pts the incidence of HER2, EGFR and PIK3CA mutations is relatively low and therefore any correlation with response to T is difficult. An intriguing observation is the higher incidence of CNS metastases reported in the 13 pts with these mutations. If confirmed in larger studies, these data could help to identify HER2+ pts with a higher risk of brain metastases. [Table: see text] No significant financial relationships to disclose.