Risk management decisions in women with BRCA1 and BRCA2 mutations

Morgan, Rosemary E.; Brown, Audrey; Hamman, Kelly Jo; Sampson, Jone E.; Naik, Arpana; Massimino, Kristen P.

doi:10.1016/j.amjsurg.2018.02.010

Cited by 8 publications

(12 citation statements)

References 12 publications

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“…Table 1 provides the characteristics of the included studies. Of the included 22 papers,17 reported surgical outcomes, 10,15‐17,19‐21,23‐25,27‐30,32,34,35 including mastectomy, lumpectomy, and oophorectomy, and six reported cancer screening outcomes, 16,17,20,21,27,32 including mammography, breast MRI, TVUS, CA‐125 testing, and colonoscopy. Studies were published between 2011 and 2020 representing data collected between 1995 and 2019.…”

Section: Resultsmentioning

confidence: 99%

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Clinical management among individuals with variant of uncertain significance in hereditary cancer: A systematic review and meta‐analysis

et al. 2021

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Improper medical use of variant of uncertain significance (VUS) remains a concern in hereditary cancer genetic testing. The goal of this study was to assess the association between pathogenic and likely pathogenic (P/LP), VUS, and benign and likely benign (B/LB) genetic test results and cancer‐related surgical and screening management. Systematic searches of Medline, Embase, EBSCO CINAHL Plus, and PsycINFO were conducted from 1946 to August 26, 2020. Eligible studies included individuals with cancer genetic test result and surgical or screening management outcomes. We reviewed 885 abstracts and 22 studies that reported relevant surgical and screening outcomes were included. Meta‐analysis revealed significantly higher surgical rates among individuals with P/LP than among those with VUS for therapeutic mastectomy with contralateral prophylactic mastectomy (OR = 7.35, 95% CI, 4.14–13.64), prophylactic mastectomy (OR = 3.05, 95% CI, 1.5–6.19), and oophorectomy (OR = 6.46, 95% CI, 3.64–11.44). There were no significant differences in therapeutic mastectomy, or breast conservation or lumpectomy rates between individuals with P/LP and VUS, or in any outcomes between patients with VUS and B/LB. Studies evaluating screening outcomes were limited, and results were conflicting. Comprehensive analysis do not indicate that a significant number of individuals with VUS results undergo inappropriate clinical management.

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Section: Resultsmentioning

confidence: 99%

“…Five studies 16,23,28,30,34 reported therapeutic mastectomy rates among breast cancer patients with VUS vs P/LP (Figure 3) and VUS vs B/LB genetic test results (Figure 4). Pooled data from three studies 16,23,28 showed no difference in mastectomy rates between patients with VUS vs P/LP results or among patients with VUS vs B/LB results.…”

Section: Resultsmentioning

confidence: 99%

Clinical management among individuals with variant of uncertain significance in hereditary cancer: A systematic review and meta‐analysis

et al. 2021

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“…Though bilateral salpingo-oophorectomy can be potentially indicated in women for therapeutic indications, as in the case for premenopausal women with hormone receptor positive breast cancer, this distinction was not adequately captured in the documentation and thus was not included in this study. Recently, Morgan et al [25] studied the risk management decisions of women in regards to risk reducing mastectomy for women with VUS, and found no difference in the rates of surgery when comparing pathologic BRCA mutations to VUS mutations.…”

Section: Discussionmentioning

confidence: 99%

The influence of BRCA variants of unknown significance on cancer risk management decision-making

Chern

Lee

Frey³

et al. 2019

J Gynecol Oncol

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Objective To compare gynecological cancer risk management between women with BRCA variants of unknown significance (VUS) to women with negative genetic testing. Methods Ninety-nine patients whose BRCA genetic testing yielded VUS were matched with 99 control patients with definitive negative BRCA results at a single institution. Demographics and risk management decisions were obtained through chart review. Primary outcome was the rate of risk-reducing bilateral salpingo-oophorectomy (RRBSO). Chi square tests, t-tests, and logistic regression were performed, with significance of p<0.05. Results VUS patients were more likely to be non-Caucasian (p=0.000) and of Ashkenazi-Jewish descent (p=0.000). There was no difference in gynecologic oncology referrals or recommendations to screen or undergo risk-reducing surgery for VUS vs. negative patients. Ultimately, 44 patients (22%) underwent RRBSO, with no significant difference in surgical rate based on the presence of VUS. Ashkenazi-Jewish descent was associated with a 4.5 times increased risk of RRBSO (OR=4.489; 95% CI=1.484–13.579) and family history of ovarian cancer was associated with a 2.6 times risk of RRBSO (OR=2.641; 95% CI=1.107–6.299). Conclusion In our institution, patients with VUS were surgically managed similarly to those with negative BRCA testing. The numbers of patients with VUS are likely to increase with the implementation of multi-gene panel testing. Our findings underscore the importance of genetic counseling and individualized screening and prevention strategies in the management of genetic testing results.

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“…Such variants are typically reported as variants of uncertain significance (VUS). The BRCA VUS rate of test providers is extremely variable but can be as high as 20% (17–19,21). It is recommended individuals with a BRCA VUS are managed in the same way as individuals with a benign variant, because the available evidence strongly indicates the vast majority do not confer increased risks of cancer (15).…”

Section: Discussionmentioning

confidence: 99%

“…Only a small minority of nontruncating BRCA variants are pathogenic, and these are typically restricted to the ring finger and BRCT domains of BRCA1 and the DNA binding-domain of BRCA2 (15). Despite this large body of evidence, multiple studies have shown that up to 30% of rare, nontruncating BRCA variants are managed inappropriately as pathogenic mutations (17–19,21). This leads to inappropriate interventions in cancer patients and healthy individuals, and unnecessary costs to health services (15).…”

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confidence: 99%

Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers

Yost

Ruark

Alexandrov

et al. 2019

JNCI Cancer Spectrum

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Background It is often assumed any cancer in a germline BRCA1 or BRCA2 (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals. Methods We compared the frequency of BRCA mutations, allele loss, and Signature 3 in 7632 individuals with 28 cancers and 1000 population controls. Because only increased frequency was the focus of the study, all statistical tests were one-sided. Results Individuals with breast or ovarian cancer had increased germline BRCA pathogenic mutation frequencies compared to controls (P = 1.0x10−10 and P = 1.4x10−34, respectively). There was no increase in other cancer types. Wild-type allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers with BRCA mutations compared with other cancers with BRCA mutations (P = 5.1x10−10 and P = 3.7x10−9) and cancers without BRCA mutations (P = 2.8x10−53 and P = 1.0x10−134). There was no difference between non-breast and non-ovarian cancers with BRCA mutations and cancers without BRCA mutations. Allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers in individuals with BRCA pathogenic mutations compared to those with VUS (P = 3.8x10−17 and P = 1.6x10−8) or benign variants (P = 1.2x10−28 and P = 2.2x10−10). There was no difference between individuals with BRCA VUS and those with benign variants. Conclusions These data show that non-breast and non-ovarian cancers in individuals with germline BRCA pathogenic mutations are often not causally related to the mutation and that BRCA VUS are highly unlikely to be pathogenic. These results should reduce inappropriate management of germline BRCA information.

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Risk management decisions in women with BRCA1 and BRCA2 mutations

Cited by 8 publications

References 12 publications

Clinical management among individuals with variant of uncertain significance in hereditary cancer: A systematic review and meta‐analysis

Clinical management among individuals with variant of uncertain significance in hereditary cancer: A systematic review and meta‐analysis

The influence of BRCA variants of unknown significance on cancer risk management decision-making

Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers

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