Evaluation of the Dutch BRCA1/2 clinical genetic center referral criteria in an unselected early breast cancer population

Abstract

In this study, we evaluated the diagnostic value of the Dutch Clinical Genetic Center (CGC) referral guidelines for BRCA1/2 mutation testing in 903 early breast cancer patients, unselected for family history, diagnosed in a cancer hospital before the age of 50 years in 1974-2002; most prevalent Dutch pathogenic BRCA1/2 mutations had been analyzed on coded DNA in a research setting. Forty-nine (5.4%) of the patients were proven to be BRCA1/2 mutation carriers. We found that 78% and 69% of BRCA1 and BRCA2 mutation carriers identified met the criteria for referral to the CGC based on age, family history and synchronous multiple tumors; reflected by a combined sensitivity of 75.5% and specificity of 63.2%. More than half of the BRCA1 mutation carriers, that is, 58% had a triple-negative tumor. The highest AUC was obtained by shifting the age at diagnosis threshold criterion from 40 to 35 years and by adding a 'triple-negative breast cancer' criterion with an age threshold of 45 years; the specificity increased to 71.2%, whereas the sensitivity remained the same; that is, a referral of fewer patients will lead to the identification of at least the same number of BRCA1/2 mutation carriers. Two-thirds of the BRCA1/2 mutation carriers identified in this research setting had been referred for counseling and testing. Our results indicate that, awaiting a possibly more extended mutation screening of all breast cancer patients, the triple-negative status of a breast cancer should be added to the CGC referral criteria.

Figure 1

Inclusion of patients in the study and in the analyses.

Figure 2

Overview of the women who proved to be BRCA1/2 mutation carriers and non-carriers in our research cohort and referral of these patients to the CGC of the Netherlands Cancer Institute (NCI) (N=1620), stratified for the calendar year of diagnosis (a–c). Bold represents the number of patients who are carriers of a BRCA1/2 mutation and were diagnosed after 1994, but who were not referred to the CGC of the NCI or the BRCA status was not known in the CGC of the NCI; BRCA−, BRCA mutation non-carrier as determined in our research cohort; BRCA+, BRCA1/2 mutation carrier as determined in our research cohort. For 166 (18%) patients in panel a family history data was missing; for 57 (8%) patients in panels b and c family history data was missing. (a) Patients diagnosed <1995: all patients referred to the CGC by April 2012 are indicated as referred. (b) Patients diagnosed >1994: only the patients referred to the CGC before breast cancer diagnosis (gray), or within 1 year after their breast cancer diagnosis are indicated as referred (patients with unknown referral date (n=17; of which two BRCA+) are included in the group ‘not referred'). (c) Patients diagnosed >1994: all patients referred to the CGC by April 2012 are indicated as referred.