17P Assessment of the Intratumoral Heterogeneity in Metastatic Breast Cancer (Mbc) Through the Analysis of the Frequency of Pik3Ca Mutant Alleles

Abstract

ABSTRACT Introduction The phosphatidylinositol-3-kinase (PI3K) pathway has an important prognostic and predictive significance in MBC. Mutations of PI3KCA could be heterogeneously distributed within the tumor and this could have clinical implications. In this study, we sought to assess the frequency of PIK3CA mutant alleles in different MBC phenotypes taking into account that formalin-fixed paraffin-embedded (FFPE) samples contain non-tumor and tumor areas (TA). Methods The OncoCarta Panel v1.0 (Sequenom) was used to profile 67 consecutive MBC FFPE tumor samples. The relative ratio between the mutant and wild-type alleles (% mutant allele, mA) of PIK3CA mutations was quantified by the MassARRAY® System. The viable tumor zone was scored to determine the TA. Patients (pts) were stratified (luminal, LUM; HER2-positive, HER2; triple negative, TN). Results 26.8% of MBC pts had PIK3CA mutation. PIK3CA mutation in LUM tumors was more frequent than non-LUM (40% vs.15 %, p = 0.047) ( table 1 ). The mean PIK3CA mA (p = 0.029) and the mean TA (p = 0.014) differed among MBC phenotypes. There was a linear relation between mA and TA for the LUM tumors (r =0.71), but when HER2 and TN tumors were also considered, this relation was less substantial (r = 0.53). Conclusion We could assess the intratumoral heterogeneity through the PIK3CA mA/TA ratio in the analyzed tumor samples. In the case of a homogeneous cellular distribution of heterozygous PIK3CA mutations within the tumor mass, the mA/TA ratio should be around 0.5. Interestingly, the mA/TA ratio of PIK3CA in LUM tumors was close to 0.5 while in the HER2 and TN tumors the ratio was lower. This suggests that LUM tumors might be more homogeneous regarding PIK3CA mutation than HER2 and TN. Therefore, PIK3CA oncogenic activation could be an early hit for tumor initiation or progression in LUM tumors and the use of PI3K inhibitors with endocrine therapy could have a greater clinical impact. Table 1 . PIK3CA mutant frequencies in MBC pts. LUM HER2 TN TOTAL PIK3CA mutant 14/35 (40%) 2/11 (18.2%) 2/16 (12.5%) 18/62 (29%) PIK3CA wild-type 21/35 (60%) 9/11 (81.8%) 14/16 (87.5%) 44/62 (71.9%) Total pts 39* 11 17* 67* * PIK3CA determination not available in 5 pts. Disclosure All authors have declared no conflicts of interest.