Abstract P4-06-07: PI3K Mutations Are More Common in Low Grade DCIS

Abstract

Abstract Background: DCIS is a non-obligate precursor to invasive breast cancer yet it remains difficult to predict which lesions will progress or over what time interval. Factors associated with a higher risk of progression include high histologic grade and HER2 amplification. HER2 signaling via the PI3K pathway is associated with accelerated invasiveness in laboratory models and mutations in the helical domain of PI3K have been associated with a worse prognosis in invasive cancer. We hypothesized that PI3K pathway mutations are associated with higher risk of progression in DCIS and therefore would be more common in high grade DCIS. Methods: 195 cases of pure DCIS were identified from the MSKCC breast service database (1999-2003). All cases were reviewed by a single pathologist to assign histologic grade. Sections were obtained from archived formalin-fixed paraffin embedded (FFPE) blocks for manual microdissection to isolate pure DCIS lesions for DNA extraction. Multiplex array (Sequenom®) genotyping for PIK3CA was performed on prePCR amplified DNA. Comparisons were made between high and low grade DCIS using Fisher's exact test. Results: Among 195 pure DCIS cases, 89 were classified as high grade and 106 as low grade. Sequenom® analysis was informative in all cases. PIK3CA mutations were identified in 4/89 (4%) cases of high grade DCIS and in 24/106 (23%) cases of low grade DCIS (p=0.000). All 4 mutations in high grade DCIS were located in the kinase domain, whereas in low grade DCIS, 9/24 (37%) mutations were in the kinase domain (H1047R) and 15/24 (67%) mutations were in the helical domain (E542K, E545K, N345K). Conclusion: PI3K mutations were relatively uncommon in pure high grade DCIS as compared to low grade DCIS. PI3K mutations in low grade DCIS were observed in both the kinase and helical domain. These findings support the hypothesis that breast tumorigenesis differs by grade and PI3K mutations may be more prominent in low grade carcinogenesis. The significance of helical domain mutations in low grade lesions requires further investigation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-07.