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Original Investigation
August 2018

Uptake, Results, and Outcomes of Germline Multiple-Gene Sequencing After Diagnosis of Breast Cancer

Author Affiliations
  • 1Departments of Medicine and Health Research and Policy, Stanford University, Stanford, California
  • 2Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
  • 3Department of Preventive Medicine in the Keck School of Medicine, Keck School of Medicine, University of Southern California, Los Angeles
  • 4Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor
  • 5Department of Internal Medicine, Division of General Medicine, Department of Health Management and Policy, School of Public Health, University of Michigan, Ann Arbor, and Veterans Administration Center for Clinical Management Research, Ann Arbor VA Health Care System, Ann Arbor
  • 6Memorial Sloan-Kettering Cancer Center, Department of Surgery, New York, New York
  • 7Center for Bioethics and Social Science in Medicine, Oncology, Department of Radiation, University of Michigan, Ann Arbor
  • 8Department of Health Management and Policy, School of Public Health, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
JAMA Oncol. 2018;4(8):1066-1072. doi:10.1001/jamaoncol.2018.0644
Key Points

Question  What are the results and outcomes of more comprehensive genetic sequencing after diagnosis of breast cancer?

Findings  In this population-based study, multiple-gene sequencing markedly replaced BRCA1- and BRCA2-only tests and enabled 2-fold higher detection of clinically relevant pathogenic variants without an associated increase in prophylactic mastectomy. Multiple-gene sequencing was more often delayed postsurgery and yielded much higher rates of variants of uncertain significance, particularly in racial/ethnic minorities.

Meaning  Multiple-gene sequencing rapidly replaced more limited testing and enabled 2-fold higher detection of clinically relevant findings, but important targets for improvement include postsurgical delay and racial/ethnic disparity in variants of uncertain significance.

Abstract

Importance  Low-cost sequencing of multiple genes is increasingly available for cancer risk assessment. Little is known about uptake or outcomes of multiple-gene sequencing after breast cancer diagnosis in community practice.

Objective  To examine the effect of multiple-gene sequencing on the experience and treatment outcomes for patients with breast cancer.

Design, Setting, and Participants  For this population-based retrospective cohort study, patients with breast cancer diagnosed from January 2013 to December 2015 and accrued from SEER registries across Georgia and in Los Angeles, California, were surveyed (n = 5080, response rate = 70%). Responses were merged with SEER data and results of clinical genetic tests, either BRCA1 and BRCA2 (BRCA1/2) sequencing only or including additional other genes (multiple-gene sequencing), provided by 4 laboratories.

Main Outcomes and Measures  Type of testing (multiple-gene sequencing vs BRCA1/2-only sequencing), test results (negative, variant of unknown significance, or pathogenic variant), patient experiences with testing (timing of testing, who discussed results), and treatment (strength of patient consideration of, and surgeon recommendation for, prophylactic mastectomy), and prophylactic mastectomy receipt. We defined a patient subgroup with higher pretest risk of carrying a pathogenic variant according to practice guidelines.

Results  Among 5026 patients (mean [SD] age, 59.9 [10.7] years), 1316 (26.2%) were linked to genetic results from any laboratory. Multiple-gene sequencing increasingly replaced BRCA1/2-only testing over time: in 2013, the rate of multiple-gene sequencing was 25.6% and BRCA1/2-only testing, 74.4%; in 2015 the rate of multiple-gene sequencing was 66.5% and BRCA1/2-only testing, 33.5%. Multiple-gene sequencing was more often ordered by genetic counselors (multiple-gene sequencing, 25.5% and BRCA1/2-only testing, 15.3%) and delayed until after surgery (multiple-gene sequencing, 32.5% and BRCA1/2-only testing, 19.9%). Multiple-gene sequencing substantially increased rate of detection of any pathogenic variant (multiple-gene sequencing: higher-risk patients, 12%; average-risk patients, 4.2% and BRCA1/2-only testing: higher-risk patients, 7.8%; average-risk patients, 2.2%) and variants of uncertain significance, especially in minorities (multiple-gene sequencing: white patients, 23.7%; black patients, 44.5%; and Asian patients, 50.9% and BRCA1/2-only testing: white patients, 2.2%; black patients, 5.6%; and Asian patients, 0%). Multiple-gene sequencing was not associated with an increase in the rate of prophylactic mastectomy use, which was highest with pathogenic variants in BRCA1/2 (BRCA1/2, 79.0%; other pathogenic variant, 37.6%; variant of uncertain significance, 30.2%; negative, 35.3%).

Conclusions and Relevance  Multiple-gene sequencing rapidly replaced BRCA1/2-only testing for patients with breast cancer in the community and enabled 2-fold higher detection of clinically relevant pathogenic variants without an associated increase in prophylactic mastectomy. However, important targets for improvement in the clinical utility of multiple-gene sequencing include postsurgical delay and racial/ethnic disparity in variants of uncertain significance.

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