0000000000338995
AUTHOR
Aysegul A. Sahin
Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer
Abstract There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations…
An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer
Abstract Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy–based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike AKT1 mutations that were absent …
AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.
SummaryDysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PI…
Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics
Abstract Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor–positive cancers (34.5%; P = 0.32), 17 of 75 HER-2–positive samples (22.7%; P = 0.04), 20 of 240 basal-like c…
Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer
Abstract Purpose: We studied the expression levels of cyclins B1, D1, and E1 and the implications of cyclin overexpression for patient outcomes in distinct breast cancer subtypes defined by clinical variables and transcriptional profiling. Experimental Design: The expression levels of cyclins B1, D1, and E1 were quantified in 779 breast tumors and 53 cell lines using reverse phase protein arrays and/or transcriptional profiling. Results: Whereas cyclin E1 overexpression was a specific marker of triple-negative and basal-like tumors, cyclin B1 overexpression occurred in poor prognosis hormone receptor–positive, luminal B and basal-like breast cancers. Cyclin D1 overexpression occurred in lum…
The natural history of breast carcinoma in patients withor = 10 metastatic axillary lymph nodes before and after the advent of adjuvant therapy: a multiinstitutional retrospective study.
BACKGROUND The majority of patients with breast carcinoma with ≥ 10 metastatic axillary lymph nodes (ALNs) develop recurrent disease within 5 years from diagnosis. The purpose of the current study, performed retrospectively, was to characterize the natural history of this subset of patients, both before and after the advent of adjuvant anthracycline-based chemotherapy and tamoxifen. METHODS Retrospectively, patients with primary breast carcinoma (N = 882) with ≥ 10 metastatic ALNs, treated between 1954 and 1998, were selected from 3 institutions: The University of Texas M. D. Anderson Cancer Center (Houston, TX); the Institut Gustave Roussy (Villejuif, France); and Hospital Clinico Universi…