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.
Background: Bone is the most common site of metastasis of breast cancer, and bone metastasis is associated with a high rate of skeletal-related events, all of which contribute to decreased quality of life and poor outcomes. Biological mechanisms of metastasis to bone may be unique, and identification of distinct signaling pathways and somatic mutations may provide biological insight into or rational targets for treatment of and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone only versus non-bone as first metastatic site. Methods: Tumor samples were collected from 389 patients who had metastasis and untreated primary breast cancer. In each sample, 46 or 50 cancer-related genes were selectively amplified and analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. We used Fisher's exact test to identify somatic mutations associated with bone-only first metastasis and logistic regression models to identify differences in clinicopathologic characteristics, survival, and somatic mutations between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only (“other-only first metastasis”). Results: Among the 389 patients, the first metastasis was located in bone only in 72 patients (18.5%), non-bone sites only in 223 patients (57.3%), and both in 94 patients (24.2%). Of the cancer-related genes analyzed, the most commonly mutated were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and low nuclear grade (grade 1 or 2) (all 3 comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68; respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer. Citation Format: Kono M, Fujii T, Matsuda N, Harano K, Chen H, Wathoo C, Aron JY, Tripathy D, Meric-Bernstam F, Ueno NT. Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-04.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.