Abstract
Abstract Background: Lapatinib is a tyrosine kinase inhibitor targeting growth factor receptors 1 and 2 (HER1, HER2) used in the case of HER2 positive advanced breast cancer. Lapatinib effects may be impaired by disregulation of the PI3K/Akt pathway. However, there are conflicting reports on the impact of the pathway disregulation on treatment efficacy. This study focused on a catalytic subunit of phosphoinositide-3-kinase, alpha polypeptide (PIK3CA) mutation status as well as phosphatase and tensin homolog (PTEN), ribosomal protein S6 (RPS6), the pathway downstream target and its phosphorylated form (P-RPS6) expression in relation to lapatinib plus capecitabine (LC) treatment. Materials and Methods: Retrospective formalin-fixed, paraffin-embedded tumor samples from 28 LC treated patients (Pts) were used. PIK3CA mutations in exon 9 and 20 were investigated in DNA by polymerase chain reaction followed by high-resolution melting analysis. Exact mutation occurring in a sample was estimated by pyrosequencing. PTEN, RPS6 and P-RPS6 expressions were assessed by immunohistochemistry. The data were evaluated by standard statistical methods in correlation with Pts clinical and histopathological data. Results: The majority of tumors were invasive ductal carcinomas 82% (23/28); 43% (12/28) with hormonal receptor positivity. Pts were treated with LC for advanced disease for 1.2 - 15.6 months. LC treatment was ended mostly due to progression (20/28), only in 6 cases owing to toxicity. PIK3CA mutations were found in 21% (4/19), only in exon 20. The mutations were in all cases: c.3140A>G. PTEN, RPS6 and P-RPS6 cytoplasmic expressions were observed in 45 % (10/22), 81% (17/21) and 82% (18/22), respectively. P-RPS6 high expression (3+) was found in 73% (16/22). PTEN loss or PIK3CA mutation was found in 66.7% (16/24) but never in the same tumor. PIK3CA mutation tended to shorter disease free survival (DFS) (p = 0.062). PTEN and RPS6 expression showed a trend to longer LC treatment (p = 0.075 and p = 0.089, respectively). RPS6 expression correlated with longer trastuzumab treatment (p = 0.04). However, P-RPS6 3+ expression was associated with shorter DFS (p = 0.043), overall survival (p = 0.04) and tended to shorter survival after beginning LC treatment (p = 0.077). This parameter also correlated with progression on LC treatment whereas its negativity correlated with withdrawal of LC treatment because of toxicity (p = 0.009). Discussion: PTEN loss or PIK3CA mutation, suggesting PI3K/Akt pathway deregulation, was observed in 66.7 % of Pts. PTEN as well as non-phosphorylated RPS6 positivity tended to longer LC treatment duration which might be due to maintained PI3K/Akt regulation. On the other hand, high level RPS6 phosphorylation associated with poorer patient outcome, and its positivity correlated with progression on LC treatment. Together, these results suggest a negative influence of PI3K/Akt pathway disregulation on disease prognosis and LC treatment response. Supported by a grant of the Faculty of Medicine and Dentistry, Palacky University 91110301, MSM 6198959216, project Biomedreg CZ.1.05/2.1.00/01.0030 and partially IGA NS10286-3. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-30.
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