Abstract
Abstract Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target. We sought to determine how tumor heterogeneity and biospecimen variables affect assessment of PI3K/Akt/mTOR pathway activation. Methods: Intraoperative image-guided core-needle biopsies (CNB) of primary breast tumors were prospectively collected in 53 patients with invasive breast cancer. After surgery, specimens were collected from the center and periphery of the excised tumor. CNB, central and peripheral surgical specimens were assessed with reverse phase proteomic arrays (RPPA), H&E and immunohistochemistry (IHC). Results: The expression of standard of care markers ER, PR, and HER2 by RPPA correlated well between biospecimen types. Overall, there was a significant correlation between the expression of 132 (86%) of 154 different markers in the center and periphery; the correlation was significantly higher for smaller tumors, and with shorter cold ischemia time. Expression of many investigational prognostic markers and druggable targets on CNB correlated with expression in the surgical specimen (average of center and periphery), while others, such as EGFR and c-MET, had a weak correlation. Of 154 RPPA markers, 132 (86%) were not statistically different between the center and periphery, and 97 (67%) were not different between the CNB and the surgical specimen. On analysis of the PI3K/AKT/mTOR pathway, pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimens. However, pAkt S473, pS6 S235/236 and pS6 240/244 levels were higher in CNB than the central specimens both by RPPA and by IHC. When patients were classified by RPPA PI3K pathway activation score, there was a moderate agreement between classification on the CNB and central specimens (Cohen's Kappa 0.539). However 9 of 20 tumors classified as having PI3K activation on CNB were classified as not having pathway activation on central specimens. Conclusions: There is remarkable homogeneity in expression of biomarkers within a tumor. However, proteomic markers are differentially expressed by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared to surgical samples. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-06.
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