TY - JOUR
T1 - Mutation rates in cancer susceptibility genes in patients with breast cancer with multiple primary cancers
AU - Maxwell, Kara N.
AU - Wenz, Brandon M.
AU - Kulkarni, Abha
AU - Wubbenhorst, Bradley
AU - D’Andrea, Kurt
AU - Weathers, Benita
AU - Goodman, Noah
AU - Vijai, Joseph
AU - Lilyquist, Jenna
AU - Hart, Steven N.
AU - Slavin, Thomas P.
AU - Schrader, Kasmintan A.
AU - Ravichandran, Vignesh
AU - Thomas, Tinu
AU - Hu, Chunling
AU - Robson, Mark E.
AU - Peterlongo, Paolo
AU - Bonanni, Bernardo
AU - Ford, James M.
AU - Garber, Judy E.
AU - Neuhausen, Susan L.
AU - Shah, Payal D.
AU - Bradbury, Angela R.
AU - DeMichele, Angela M.
AU - Offit, Kenneth
AU - Weitzel, Jeffrey N.
AU - Couch, Fergus J.
AU - Domchek, Susan M.
AU - Nathanson, Katherine L.
N1 - Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2020
Y1 - 2020
N2 - PURPOSE Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non–breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION Mutation rates are at least 7% in all patients with BRCA1/2 mutation–negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age, 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.
AB - PURPOSE Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non–breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION Mutation rates are at least 7% in all patients with BRCA1/2 mutation–negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age, 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.
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U2 - 10.1200/PO.19.00301
DO - 10.1200/PO.19.00301
M3 - Article
AN - SCOPUS:85092714664
SN - 2473-4284
VL - 4
SP - 916
EP - 925
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -