The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients — 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients — 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation Rates and Age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutation rates in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer Prevention and Screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.