Abstract 3139: Can PI3K/AKT pathway mutations predict for type of recurrence after conservative treatment for DCIS
Authors: Sakr Rita A. , Andrade Victor P. , Muhsen Shirin , Chandarlapaty Sarat , Giri Dilip , Olvera Narciso , Paik Wooyul , Goldberg Jessica I. , Van Zee Kimberly J. , Rosen Neal , Morrow Monica , King Tari A. 
Published: June 2012

Abstract
INTRODUCTION: Although the overall mortality from ductal carcinoma in situ (DCIS) treated with conservative therapy is very low, local recurrence (LR), either as DCIS or invasive carcinoma, remains a significant problem occurring in up to 30% of cases. Young age, positive margins and omission of radiation therapy predict for a higher rate of LR after conservative treatment (BCT) yet cannot predict type of recurrence, DCIS versus invasive breast cancer. Emerging evidence suggests that alterations in the PI3K/AKT pathway may be prognostic in invasive breast cancer; therefore, we examined cases of DCIS that recurred after BCT to determine the relationship between PI3K/AKT mutations and type of recurrence.
METHODS: From a prospectively maintained database of 1873 patients with DCIS undergoing BCT (1991-2006), we identified 190 (10%) patients who recurred. Original DCIS archival blocks were available for 108 (57%) cases. Freshly cut sections were obtained for manual microdissection of pure DCIS lesions and DNA extraction. Genotyping for PIK3CA and AKT1 mutations was performed by Sequenom® MassARRAY® system on prePCR amplified DNA. Fisher's exact test was used to compare cases that recurred as DCIS versus those that recurred as invasive breast cancer.
RESULTS: Among 108 cases, 66 (61%) recurred as DCIS and 42 (39%) recurred as invasive cancer (p=0.002). Type of recurrence in the entire population of 190 patients demonstrated the same pattern. Among studied cases, median time to recurrence was 40 months (range 7-156 mo) and did not differ by type of recurrence. Similarly, patient age, use of radiation and/or tamoxifen therapy or grade of DCIS (low vs high) did not differ by type of recurrence. Sequenom® analysis identified a higher frequency of PIK3CA (n=17) and AKT1 (n=3) mutations among cases that recurred as DCIS compared to those that recurred as invasive cancer, combined mutation rate 16/66 (24%) vs 4/42 (9%), with a trend towards significance (p=0.07). Among the 17 PI3K mutations identified, kinase domain mutations (n=13) were more common than helical domain mutations (n=4). All 4 helical domain mutations were present in cases recurring as DCIS.
CONCLUSIONS: In our population, patients with DCIS who recurred after BCT were more likely recur with DCIS. Standard clinical and pathologic factors did not predict for type of recurrence. PI3K/AKT pathway mutations were more common among cases recurring as DCIS, with a predominance of kinase domain mutations. Further exploration of the significance of PI3K pathway aberrations, in combination with other biomarkers, are warranted to identify predictors for type of recurrence after conservative treatment for DCIS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3139. doi:10.1158/1538-7445.AM2011-3139