Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment.
OBJECTIVE
The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown.


OBJECTIVE
To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort.


METHODS
Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations.


METHODS
We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals.


METHODS
We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history.


RESULTS
Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients.


CONCLUSIONS
In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.
Massachusetts General Hospital Cancer Center, Boston.
Andrea
A
Desmond
Stanford University School of Medicine, Stanford, California.
Allison W
AW
Kurian
Massachusetts General Hospital Cancer Center, Boston.
Michele
M
Gabree
Stanford University School of Medicine, Stanford, California.
Meredith A
MA
Mills
Invitae Corporation, San Francisco, California.
Michael J
MJ
Anderson
Invitae Corporation, San Francisco, California.
Yuya
Y
Kobayashi
Massachusetts General Hospital Cancer Center, Boston.
Nora
N
Horick
Invitae Corporation, San Francisco, California.
Shan
S
Yang
Massachusetts General Hospital Cancer Center, Boston.
Kristen M
KM
Shannon
Beth Israel Deaconess Medical Center, Boston, Massachusetts5Harvard Medical School, Boston, Massachusetts.
Nadine
N
Tung
Stanford University School of Medicine, Stanford, California.
James M
JM
Ford
Invitae Corporation, San Francisco, California.
Stephen E
SE
Lincoln
Massachusetts General Hospital Cancer Center, Boston5Harvard Medical School, Boston, Massachusetts.
Leif W
LW
Ellisen
D000046:Academic Medical Centers; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D001900:Boston; D001943:Breast Neoplasms / Q000235:genetics*; D002140:California; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D040941:Heredity; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor