Identifying a number of cancer predisposition genes could help improve upon risk assessment and counseling for ductal carcinoma in situ and contralateral breast cancer.
Pathogenic gene variants in a number of cancer predisposition genes have been identified as carrying a moderate or high risk of developing ductal carcinoma in situ (DCIS) or invasive ductal breast cancer (IDBC) for women. The data were presented at the 2022 American Association for Cancer Research Special Conference, Rethinking DCIS: An Opportunity for Prevention?1
The study authors, led by Huaizhi (Gilbert) Huang, BS, a graduate student at Mayo Clinic in Rochester, Minnesota, aimed to estimate women’s risk for developing DCIS and breast cancer among germline mutation carriers, as even the association between DCIS and carriers of BRCA1/2 is not well established.
The researchers looked at 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) for any association between pathogenic gene variants and DCIS. They analyzed these using a case control group of 3876 women with DCIS and age-matched women who did not have DCIS from a population-based study; 9887 women with DCIS who received genetic testing at Ambry Genetics between March 15, 2012, and December 30, 2016; and an unaffected control group from the Genome Aggregation Database.
In the clinical testing cohort, pathogenic variants were observed in 7 of the cancer predisposition genes and associated with increased risks for DCIS, amounting to an odds ratio above 2. The CDH1 and BRCA2 genes, particularly, were associated with an odds ratio above 4.
Four cancer predisposition genes were highlighted in the population-based cohort: BRCA1, CHEK2, PALB2, and ATM.
“We found that pathogenic variants in 4 cancer predisposition genes BRCA1, CHEK2, PALB2, and ATM, were associated with significantly increased risk of DCIS in both the population-based cohort and the clinical testing cohort,” Huang said in a poster presentation at the conference.
In both cohorts, pathogenic variants in BRCA1, BRCA2, and PALB2 were associated with increased cases of DCIS over IDBC (P < .05). Among patients with DCIS who were carriers of pathogenic variants in these genes, the combined incidence of contralateral breast cancer was 11% in 5 years and 20% in 15 years.
Frequencies of cancer predisposition mutations in DCIS and IDBC cases from the clinical testing cohort are included in the TABLE. Frequencies were lower in the population-based cohort and odds ratios were higher.
In both cohorts, the frequencies of pathogenic variants in the ATM and CHEK2 genes were similar for women with DCIS and those with IDBC. Huang et al suggested that genetic testing for these genes could be used for women with DCIS.
There were fewer instances of pathogenic variants in the BRCA1, BRCA2, and PALB2 genes for women with DCIS than for those with IDBC but these variants are still associated with a higher risk of DCIS. As such, the study authors recommended that contralateral prophylactic mastectomy could be considered in women with DCIS who are carriers of pathogenic gene variants in BRCA1, BRCA2, and/or PALB2.
They noted that identifying these cancer predisposition genes could help improve upon risk assessment and counseling for DCIS and contralateral breast cancer.