There is still considerable debate on the value of multigene panel testing for inherited cancer in patients with breast cancer, based on both the prevalence of pathogenic/likely pathogenic (P/LP) variants and any therapeutic implications from genetic test results. Recent studies demonstrate that the prevalence of P/LP variants is similar in patients with breast cancer whether or not they meet critera for testing by the National Comprehensive Cancer Network (NCCN) guidelines.1,2 However, most participants in these studies were patients with early stage breast cancer and many low-risk variants were identified, raising the question of clinical actionability. The recent US Food and Drug Administration (FDA) approval of polyadenosine diphosphate–ribose polymerase (PARP) inhibitors for patients with metastatic human epidermal growth factor receptor 2 (HER2/ERBB2)-negative breast cancer with germline BRCA1 and BRCA2 (BRCA) pathogenic variants,3,4 suggests germline testing of patients with metastatic breast cancer could have therapeutic implications. Indeed, a recent study found 11.8% of otherwise unselected patients with metastatic prostate cancer harbored a P/LP germline variant,5 leading to a change in NCCN guidelines recommending germline testing for all patients with metastatic prostate cancer. However, to our knowledge, analogous studies to quantify the prevalence of P/LP variants among patients with metastatic breast cancer have not been performed.
In a Johns Hopkins institutional review board approved study, we prospectively enrolled 100 patients diagnosed with metastatic breast cancer and performed germline testing using a panel of 30 genes (Color Genomics) associated with hereditary cancer without consideration for NCCN guidelines. All patients provided written informed consent. Eligible patients could have either a recurrent or de novo diagnosis of metastatic disease and prior germline testing was allowed if testing contained 10 or fewer genes and results were negative for P/LP variants. Demographics of our cohort are shown in Table 1. The median (SD) age at time of consent for the study was 59 (12.0) years. Of 100 participants, 76 reported their race as white, and 66 patients had hormone receptor positive/HER2/ERBB2-negative disease, including 2 male patients with breast cancer.
Of the 100 patients, 14 were found to have a P/LP variant, and 21 were found to have a variant of unknown significance (VUS) (Table 2). Among patients with P/LP variants, 6 of 14 (43%) did not meet NCCN guidelines for genetic testing, though none were BRCA gene variants. Of the 6 patients with P/LP BRCA variants, 2 had never received genetic testing prior to our study despite meeting NCCN criteria, underscoring the need for improved implementation of recommended guidelines.
Limitations of our study include the relatively small sample size and the fact that the gene panel (Color Genomics) does not analyze the complete coding sequence of all tested genes. In addition, we excluded patients with prior germline testing unless the results were negative for 10 or fewer genes. Thus, our study may underestimate the true prevalence of germline variants in patients with metastatic breast cancer.
Our results provide additional support for testing patients with metastatic breast cancer based on their relatively high prevalence of P/LP variants, including a 6% frequency of P/LP variants in BRCA. Furthermore, given that many of the genes included on the multigene panel are involved in DNA repair, there is scientific rationale that some of these P/LP variants (ATM, BRIP1, CHEK2) may also be predictive for response to PARP inhibitors, a hypothesis currently being tested in clinical trials (NCT03344965). Consequently, our results provide evidence to support genetic testing for inherited cancer predisposition among all patients with metastatic breast cancer because this group represents a population with a high prevalence of P/LP variants that could have therapeutic implications.
Corresponding Author: Ben Ho Park, MD, PhD, Division of Hematology, Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center, 2220 Pierce Ave, PRB 777, Nashville, TN 37232 (firstname.lastname@example.org).
Accepted for Publication: June 7, 2019.
Published Online: August 29, 2019. doi:10.1001/jamaoncol.2019.3116
Author Contributions: Dr Park had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Stuttgen, Park.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Croessmann, Park.
Obtained funding: Fetting, Park.
Administrative, technical, or material support: Stuttgen, Croessmann, Stearns, Connolly, Park.
Study supervision: Park.
Conflict of Interest Disclosures: Dr Fetting reports grants from The Fetting Fund during the conduct of the study. Dr Stearns reported grants from Abbvie, Biocept, Pfizer, Novartis, Medimmune, and Puma Biotechnology; personal fees from Iridium Therapeutics, Inc, and Immunomedics, Inc, outside the submitted work. Dr Connolly reported grants from Genentech, Novartis, Puma biotechnology, Merck, and Macrogenics outside the submitted work. Dr Park reported grants from the Fetting Fund for Breast Cancer Prevention during the conduct of the study; personal fees from Horizon Discovery, and Loxo Oncology; grants and personal fees from Foundation Medicine, Inc, personal fees from Jackson Laboratories, H3 Biomedicine, Casdin Capital, Roche, Eli Lilly, and Astra Zeneca; grants from Abbvie and Pfizer outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank the patients for contributing to the study. Other significant contributors to this study include Evanthia T. Roussos Torres, MD, PhD; Cesar A Santa-Maria, MD, MSCI; Karen L. Smith, MD, MPH; Danijela Jelovac, MD; Antonio C. Wolff, MD; Deborah K Armstrong, MD; Kala Visvanathan, MD, MHS; Tatiana Prowell, MD; Dana Petry, ScM; and Jeffrey B. Reynolds, MS, all from Johns Hopkins University School of Medicine; and Tuya Pal, MD,Vanderbilt Ingram Cancer Center. We acknowledge The Fetting Fund for Breast Cancer Prevention for supporting these studies and Johns Hopkins University School of Medicine, Baltimore, MD; Vanderbilt Ingram Cancer Center, Division of Hematology, Oncology, Department of Medicine.