JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada. Published online ahead of print at www.jco.org on January 19, 2016. This work was supported by the Victorian Breast Cancer Research Consortium, the National Breast Cancer Foundation, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Ian G. Campbell, PhD, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, 3002, Australia; e-mail: ian.campbell@petermac. org. © 2016 by American Society of Clinical Oncology 0732-183X/15/3499-1/$20.00 DOI: 10.1200/JCO.2015.63.7454 Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Michelle W. Wong-Brown, Alison H. Trainer, Gillian Mitchell, Rodney J. Scott, Paul A. James, and Ian G. Campbell A B S T R A C T Purpose Gene panel sequencing is revolutionizing germline risk assessment for hereditary breast cancer. Despite scant evidence supporting the role of many of these genes in breast cancer predisposition, results are often reported to families as the definitive explanation for their family history. We assessed the frequency of mutations in 18 genes included in hereditary breast cancer panels among index cases from families with breast cancer and matched population controls. Patients and Methods Cases (n = 2,000) were predominantly breast cancer-affected women referred to specialized Familial Cancer Centers on the basis of a strong family history of breast cancer and BRCA1 and BRCA2 wild type. Controls (n = 1,997) were cancer-free women from the LifePool study. Sequencing data were filtered for known pathogenic or novel loss-of-function mutations. Results Excluding 19 mutations identified in BRCA1 and BRCA2 among the cases and controls, a total of 78 cases (3.9%) and 33 controls (1.6%) were found to carry potentially actionable mutations. A sig- nificant excess of mutations was only observed for PALB2 (26 cases, four controls) and TP53 (five cases, zero controls), whereas no mutations were identified in STK11. Among the remaining genes, loss-of-function mutations were rare, with similar frequency between cases and controls. Conclusion The frequency of mutations in most breast cancer panel genes among individuals selected for possible hereditary breast cancer is low and, in many cases, similar or even lower than that observed among cancer-free population controls. Although multigene panels can significantly aid in cancer risk management and expedite clinical translation of new genes, they equally have the potential to provide clinical misinformation and harm at the individual level if the data are not interpreted cautiously. J Clin Oncol 34. © 2016 by American Society of Clinical Oncology INTRODUCTION Clinical genetic testing for hereditary cancer syndromes has been transformed by the advent of massively parallel sequencing, which allows simultaneous screening of a large number of genes at a fraction of the cost previously required to sequence just one gene (such as BRCA1). 1 Although the technical efficiency afforded by panel gene tests in providing more comprehensive genomic interrogation is attractive, the tempta- tion to include more speculative genes for which there are limited data relating to cancer risk is of concern. 2 This trend has led to the development of commercial breast cancer multigene panels that are being used in the clinical diagnostic setting but provide sequence data relating to genes of unknown clinical significance, more in keeping with a research study. Ironically, the high cost and other disad- vantages of single-gene testing previously ensured that only those genes with confident penetrance estimates and clear clinical utility were sequenced and the results reported back to patients. Of particular concern with the increasing use of these panel tests for hereditary breast and ovarian cancer predisposition in the diagnostic setting is the absence of data for matched population con- trols to inform the interpretation of the resulting data. Exome sequencing of BRCAX families for new breast cancer predisposition genes demon- strates that loss-of-function (LoF) mutations in genes that are plausibly involved in cancer © 2016 by American Society of Clinical Oncology 1 http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.63.7454 The latest version is at Published Ahead of Print on January 19, 2016 as 10.1200/JCO.2015.63.7454 Copyright 2016 by American Society of Clinical Oncology 134.148.10.12 Information downloaded from jco.ascopubs.org and provided by at Uni of Newcastle on February 17, 2016 from Copyright © 2016 American Society of Clinical Oncology. All rights reserved.