Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers

Abstract

BackgroundIdentification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway.Methods1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated.ResultsA pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%.ConclusionsMutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3422-2) contains supplementary material, which is available to authorized users.

Mainstreamed genetic testing of breast cancer patients in two hospitals in South Eastern Norway

“…We have previously estimated that 39% of all BC patients in South Eastern Norway were tested in 2014 and 2015 [21]. In the current study we found that 36.8% of all BC patients (29.8% at IH and 42.6% at Ahus) were offered testing, and that 34.6% (27.8% at IH and 40.2% at Ahus) had been tested.…”

“…We have recently estimated that about 39% of all BC patients in the South-Eastern Norway Regional Health Authority (hereafter called South Eastern Norway) were tested in 2014 and 2015 [21]. However, we do not know how many of the patients who fulfilled the criteria that were offered testing.…”

Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

“…Grindedal et al . evaluated the results of BRCA1/2 testing in South‐Eastern Norway and found that 65% of the BRCA1/2 carriers would have been missed if using age of onset below 40 or triple negative breast cancer as criteria for testing . It is also conceivable that, due to an emphasis on disease family history in current guidelines, a smaller family size may compromise the identification of high risk individuals who would otherwise benefit from genetic testing .…”

“…Grindedal et al evaluated the results of BRCA1/2 testing in South-Eastern Norway and found that 65% of the BRCA1/2 carriers would have been missed if using age of onset below 40 or triple negative breast cancer as criteria for testing. 40 It is also conceivable that, due to an emphasis on disease family history in current guidelines, a smaller family size may compromise the identification of high risk individuals who would otherwise benefit from genetic testing. 41 In a Swedish retrospective study by Nilsson et al where all breast cancer patients were tested, it was found that while 65% of the BRCA1/2 carriers fulfilled Swedish criteria for testing, only 18% had been identified in regular clinical routine.…”

Knowledge and opinions regarding BRCA1 and BRCA2 genetic testing among primary care physicians

“…The prevalence among individuals with a personal and/or family history of breast and/or ovarian cancer is higher, and guidelines for BRCA1/2 testing exist (Moyer, ; National Comprehensive Cancer Network (NCCN), ), but these consensus guidelines are constantly changing based on evolving evidence. Furthermore, with increasing availability and accessibility to cancer genetic testing, it is becoming more evident that the currently commonly utilized testing guidelines might not be sufficiently sensitive for the identification of all individuals/families with a cancer predisposition (Beitsch et al, ; Grindedal et al, ; Li et al, ; Mandelker et al, ).…”