Research ArticlesCharacterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast CancerGurda, Grzegorz T. MD, PhD*,†; Ambros, Tadeu MD‡; Nikiforova, Marina N. MD†; Nikiforov, Yuri E. MD, PhD†; Lucas, Peter C. MD, PhD†,§; Dabbs, David J. MD*,§; Lee, Adrian V. PhD§; Brufsky, Adam M. MD, PhD‡,§; Puhalla, Shannon L. MD‡,§; Bhargava, Rohit MD*,§Author Information Departments of *Pathology, Division of Breast & Gynecologic Pathology ‡Oncology, Magee-Womens Hospital †Pathology, Division of Molecular & Genomic Pathology §Magee-Womens Research Institute & Foundation, The University of Pittsburgh Medical Center, Pittsburgh, PA Supported by Fashion Footwear of New York (FFANY), Breast Cancer Research Foundation (BCRF), and Susan G. Komen for the Cure (A.V.L.). Additional support was provided by the Department of Pathology at University of Pittsburgh (PIRRT to G.T.G.). Presented in part at the 2015 annual American Society of Clinical Oncology (ASCO) meeting (Chicago, IL). The authors declare no conflict of interest. Reprints: Rohit Bhargava, MD, Department of Pathology Magee-Womens Hospital, The University of Pittsburgh Medical Center, Room 4423 300 Halket Street Pittsburgh, PA 15213 (e-mail: [email protected]). Applied Immunohistochemistry & Molecular Morphology: July 2017 - Volume 25 - Issue 6 - p 392-398 doi: 10.1097/PAI.0000000000000322 Buy SDC Metrics Abstract Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.