PIK3CA Mutations Are Enriched in Special Type Invasive Mammary Carcinomas
Jennifer Giltnane, Justin Balko, Maria Gabriela Kuba, Nikhil Wagle, Eli Van Allen, Ingrid Mayer, Vandana Abramson, Levi Garraway, Ingrid Meszoely, Carlos Arteaga, Melinda Sanders. Vanderbilt University, Nashville, TN; Broad Institute of Harvard and MIT, Cambridge, MA
Background: Aberrant signaling through the phosphatidylinositol-3 kinase (PI3K) pathway is a common alteration in breast cancer (BC), with frequent activating mutations in the PIK3CA gene helical (exon 9) and catalytic (exon 20) domains of the PIK3CA (p110a catalytic subunit of PI3K) gene. PI3K pathway alterations are present in 40% of estrogen receptor positive (ER+) breast cancer (BC); however, the literature is divided as to whether these alterations are prognostic. Recent data from the Breast Cancer Genome Atlas Network (doi:1-.1038/nature11412) indicates that PIK3CA mutations are highly enriched in the luminal BC subtypes, especially luminal A (45%). Histologically, the luminal A subtype includes low grade no special type (NST) carcinomas and the special type (ST) carcinomas (low grade and >90% purity of pattern), including pure lobular, tubular, cribriform, and mucinous. We examined whether the prevalence of PIK3CA mutations among ST BC would differ from NST BC.
Design: Using H&E stained slides, we typed (NST vs. ST) and graded the first 98 stage I-II ER+ operable tumors from postmenopausal patients enrolled in a clinical trial of presurgical letrozole. Slides were reviewed by three expert breast pathologists with concordance. We correlated the histologic type with the pretreatment Ki67 index and PIK3CA mutation status as determined by RNA-Seq.
Results: Mutation data were available on 8 of 18 (44%) ST and 35 of 80 NST (44%) tumors in the study group, with an overall mutation rate of 42% (exon 20, n=11; exon 9, n=7), consistent with the enrichment of luminal tumors in this cohort. Mutations were more frequent in ST versus NST carcinomas (63% versus 37%). Baseline proliferation rates as measured by percent of Ki67+ tumor cells were higher in wild-type versus PIK3CA mutants (30.5% versus 19.4%, p=0.03). Although the cohort contained few high grade tumors (9%), exon 20 mutations were found exclusively in low-intermediate grade, low proliferative rate tumors. There were no other recurrent histologic features among NST carcinomas predictive of a PIK3CA mutation.
Conclusions: PIK3CA mutations are enriched in ST and NST carcinomas with low baseline proliferation rates. Pending analyses of RNA-Seq and whole exome DNA-Seq for the remaining tumors may increase power and provide further insight into these relationships and their role in resistance to antiestrogen therapy.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 38, Wednesday Morning