Clinical exome sequencing vs. usual care for hereditary colorectal cancer diagnosis: A pilot comparative effectiveness study.

Niu X1, Amendola LM2, Hart R2, Bennette CS3, Heagerty P4, Horike-Pyne M2, Trinidad SB5, Rosenthal EA2, Comstock B4, Nefcy C4, Hisama FM2, Bennett RL2, Grady WM6, Gallego CJ7, Tarczy-Hornoch P8, Fullerton SM5, Burke W5, Regier DA9, Dorschner MO10, Shirts BH11, Robertson PD12, Nickerson DA12, Patrick DL13, Jarvik GP14, Veenstra DL15.

Author information

1: Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
2: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
3: Flatiron Health, New York, NY 10010, USA.
4: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
5: Department of Bioethics and Humanities, University of Washington, Seattle, WA 98195, USA.
6: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98101, USA.
7: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Comparative Health Outcomes, Economics and Policy Institute (CHOICE), University of Washington, Seattle, WA 98195, USA.
8: Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA.
9: Canadian Centre for Applied Research in Cancer Control, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
10: Department of Pathology, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
11: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
12: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
13: Department of Health Services, University of Washington, Seattle, WA 98195, USA.
14: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
15: Comparative Health Outcomes, Economics and Policy Institute (CHOICE), University of Washington, Seattle, WA 98195, USA. Electronic address: veenstra@uw.edu.

Abstract

BACKGROUND:

Clinical exome sequencing (CES) provides the advantage of assessing genetic variation across the human exome compared to a traditional stepwise diagnostic approach or multi-gene panels. Comparative effectiveness research methods offer an approach to better understand the patient-centered and economic outcomes of CES.

PURPOSE:

To evaluate CES compared to usual care (UC) in the diagnostic work-up of inherited colorectal cancer/polyposis (CRCP) in a randomized controlled trial (RCT).

METHODS:

The primary outcome was clinical sensitivity for the diagnosis of inherited CRCP; secondary outcomes included psychosocial outcomes, family communication, and healthcare resource utilization. Participants were surveyed 2 and 4 weeks after results return and at 3-month intervals up to 1 year.

RESULTS:

Evolving outcome measures and standard of care presented critical challenges. The majority of participants in the UC arm received multi-gene panels [94.73%]. Rates of genetic findings supporting the diagnosis of hereditary CRCP were 7.5% [7/93] vs. 5.4% [5/93] in the CES and UC arms, respectively (P = 0.28). Differences in privacy concerns after receiving CRCP results were identified (0.88 in UC vs 0.38 in CES, P = 0.05); however, healthcare resource utilization, family communication and psychosocial outcomes were similar between the two arms. More participants with positive results (17.7%) intended to change their life insurance 1  month after the first return visit compared to participants returned a variant of uncertain significance (9.1%) or negative result (4.8%) (P = 0.09).