S3-3: Association of PTEN Loss and PIK3CA Mutations on Outcome in HER2+ Metastatic Breast Cancer Patients Treated with First-Line Lapatinib Plus Paclitaxel or Paclitaxel Alone.

Abstract

Background Identifying molecular determinants underpinning response and resistance to anti-cancer therapies is essential to selecting optimal treatment for patients (pts). The PI3K pathway is frequently deregulated in cancer. In preclinical models deregulated PI3K has been shown to enhance the survival of breast cancer cells and confer resistance to chemotherapy and HER2−directed agents. This exploratory study evaluated the impact PIK3CA mutations and PTEN loss had on the efficacy of paclitaxel alone (P) and in combination with lapatinib (L+P) in HER2−positive metastatic breast cancer (MBC) pts enrolled in study EGF104535, results of which demonstrated that pts treated with the combination of L+P derived an absolute improvement in median overall survival (OS) of 7.3.months (median OS=27.8 months in L+P compared with 20.5 months in P). Method Baseline tissue from primary breast tumor or metastatic site was obtained in the form of formalin-fixed, paraffin-embedded material. Of the total study population (n=444), 389 pts had tissue available for biomarker analyses, 277 of whom provided written informed consent for optional tumor genetics (i.e., PIK3CA analysis). PTEN was evaluated on whole sections by immunohistochemistry (rabbit monoclonal antibody); pathology review and image analysis were performed, producing an ordinal score and optical density (OD). Qiagen/DxS assay was used in assessing PIK3CA mutation status. Logistic regression and Cox-proportional hazard models were used in analyses of biomarkers with efficacy endpoints. Results Evaluable results for PTEN and PIK3CA were available for 91% (354/389) and 62% (171/274) of pts, respectively. In the overall population, 24% (65/274) had tumors harboring PIK3CA mutations (E542K, E545K/D, H1047R); 13% (49/389) had absence of PTEN expression. Survival outcome appeared to be independent of PTEN expression (P >0.2). PIK3CA mutations were significantly associated with worse OS (HR=1.88; 95% CI=1.26, 2.80; P=0.002). PFS was significantly improved in pts treated with L+P compared with P in both PTEN strata (loss/expression; P<0.001). In pts stratified by PIK3CA status, treatment with L+P reduced the risk of progression compared with P in the wildtype strata (N=106; HR=0.43; 95% CI=0.28, 0.65; P<0.0001); in the mutation strata, PFS was not significantly reduced with the addition of L (N=65; HR=0.70; 95% CI= 0.42, 1.17; P=0.179). Conclusions In this exploratory study, PTEN was not prognostic whereas PIK3CA mutations appear to be an adverse prognostic feature in HER2+ MBC. PTEN expression may not be predictive as both strata derived significant benefit with L+P treatment. PFS benefit from L+P was significant in pts with PIK3CA wildtype tumors whereas the PFS benefit was not significant in the PIK3CA mutation strata. Additional analyses are ongoing and will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-3.

Breast Cancer 2012 - New Aspects

“…Mutations in the gene PIK3-CA under treatment with paclitaxel ± lapatinib have been investigated. In 30.1 % of the cases a genetic change was found which was accompanied by a statistically poorer overall survival for the patients [56]. Similarly, the trend was apparent that just No.…”