Presence of Lobular Features Predicts Enrichment for PI3K Pathway Mutations among No Special Type Breast Cancers
Maria G Kuba, Giltnane M Jennifer, Justin M Balko, Ingrid A Mayer, Vandana Abramson, Ingrid Meszoely, William Pao, Zengliu Su, Darson Lai, Delecia R LaFrance, Cindy L Vnencak-Jones, Carlos L Arteaga, Melinda E Sanders. Vanderbilt University, Nashville, TN
Background: The PI3K pathway is the most frequently mutated pathway in breast cancer (BC). Recent data from The Breast Cancer Genome Atlas Network (doi:1-.1038/nature11412) indicates these mutations occur across all BC subtypes (36%), with the highest frequency (∼45%) in luminal A/ER+ BC. Other studies found increased mutation frequency among special type (ST) breast cancers and metaplastic carcinomas. Histologic features among no special type (NST) BC correlating with mutation status have not been described.
Design: We characterized the histopathologic features of 169 primary or recurrent BC previously screened for 18 hotspot mutations in the PIK3CA (14), PTEN(3) and AKT(1) genes utilizing a SNaPshot multiplex platform developed at our institution. Tumors were typed and graded according to WHO and AJCC criteria. ST carcinomas are low grade with >90% purity of pattern with invasive lobular carcinoma (ILC) variant tumors separately recognized based on intermediate combined histologic grade. Relationship of mutation status to the presence of ST features (<70% of tumor), growth pattern (pushing vs. infiltrative), nuclear pleomorphism, mitotic index, density of lymphocytic response and stromal type (sclerotic vs. desmoplastic) were examined. Slides were reviewed by three breast pathologists for concordance.
Results: There were 15 ST/ILC variant tumors (1 tubular, 1 mucinous, 2 invasive cribriform, 1 ILC, 4 ILC variants), 1 metaplastic and 154 NST carcinomas. 27% of tumors carried mutations: 88% PIK3CA, 8% AKT and 4% PTEN. Five (36%) ST/ILC variant (all ILC) and 42 (27%) NST carcinomas carried PI3K mutations. Among 137 NST carcinomas, a higher mutation rate was observed in BC with lobular features (13/28 or 46%) versus BC without lobular features (25/109 or 23%; p=0.01). The frequency of mutations was inversely correlated with histologic grade (52% low vs. 9% high; p<0.0001) and proliferative rate (low 41% vs. high 12%; p=0.002). 94% of mutations were present in ER+ tumors and less frequent in HER2+ (10%) and triple negative (0%) BC in this cohort. There were no other recurrent histologic features predictive of a PI3K pathway mutation.
Conclusions: Mutations in the PI3K pathway were more frequent in ST carcinomas. NST tumors with lobular features were enriched for PIK3CA mutations. Following ER positivity, lobular histology was most predictive of a mutation. These findings suggest PIK3CA mutations are a pathogenic driver in the low grade breast neoplasia pathway consistent with previous studies portending an improved prognosis in this setting.
Tuesday, March 5, 2013 8:45 AM
Proffered Papers: Section B, Tuesday Morning