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

Abstract

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. Methods: 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. Results: 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. Conclusions: 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. Gene Exon Mutation analysis Mutation code Response to T. CNS metastases HER2 20 insertion P780_H781insC PD YES 20 insertion P780_H781insC SD YES 21 missense S856P CR YES EGFR 18 missense T710I CR NO 20 missense L815P PD NO 20 missense S784F CR YES 20 missense V765M PR YES 21 missense E872K; CR YES 21 missense E866K PR YES H835P PIK3CA 9 missense D549N PR YES 20 missense H1048Y PD YES 20 missense A987V PR NO 20 missense M1004I; PR NO 20 missense H1048Y SD YES L1026P No significant financial relationships to disclose.