Cancer risk management among female BRCA1/2, PALB2, CHEK2, and ATM carriers

Cragun, Deborah; Weidner, Anne; Tezak, Ann; Clouse, Kate; Pal, Tuya

doi:10.1007/s10549-020-05699-y

Cited by 29 publications

(21 citation statements)

References 24 publications

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“…Therefore, the exact reasons for the uptake of these procedures have not been elucidated. These findings indicate the overuse of prophylactic mastectomy, based on the calculated cumulative breast cancer risks for females with CHEK2 pathogenic variants, in line with other studies [ 31 , 32 ].…”

Section: Discussionsupporting

confidence: 90%

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Apostolou

Dellatola

Papadimitriou

et al. 2021

Cancers

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CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen.

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Section: Discussionsupporting

confidence: 90%

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Apostolou

Dellatola

Papadimitriou

et al. 2021

Cancers

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“…Furthermore, multigene panel–based testing of older patients increases the chance of detecting clonal hematopoiesis of indeterminate potential, a somatic alteration that can be confused with an inherited PV, and this may require an evaluation for conditions such as myelodysplastic syndrome 16 . The lack of a clinical workforce adequately trained in cancer genetics also increases the potential for misinterpretation of genetic variants and inappropriate management recommendations, such as bilateral mastectomy for patients with a VUS in BRCA1/2 and prophylactic bilateral salpingo‐oophorectomy for patients with ATM and CHEK2 PVs 17‐19 . When the prevalence of PVs in high‐penetrance genes in a population is low, the cost‐effectiveness of genetic testing is diminished, and there is increased potential for harm from mismanagement of VUSs or PVs in genes with uncertain clinical validity 20 …”

Section: Age ≤ 65 Y (N = 2817) Age > 65 Y (N = 1090) Frequency Of Patmentioning

confidence: 99%

Germline genetic testing in breast cancer: Rationale for the testing of all women diagnosed by the age of 60 years and for risk‐based testing of those older than 60 years

Desai

Yadav

Batalini

et al. 2020

Cancer

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Approximately 5% to 10% of women diagnosed with breast cancer will have a pathogenic variant (PV) in a hereditary cancer susceptibility gene, and this has significant implications for the management of these patients and their relatives. Despite the benefits of genetic testing, many eligible patients with breast cancer never undergo testing because of various barriers, including complicated testing criteria such as those from the National Comprehensive Cancer Network (NCCN). In 2019, the American Society of Breast Surgeons (ASBrS) proposed germline genetic testing for all patients with breast cancer to increase the identification of PV carriers. In 2020, a Mayo Clinic study highlighted the limitations of these 2 genetic testing guidelines (NCCN and ASBrS) and proposed a hybrid approach of testing all women diagnosed with breast cancer by the age of 65 years and using NCCN criteria for older patients. This commentary presents an updated analysis of the Mayo Clinic data and discusses the rationale for using the age of 60 years rather than 65 years as the cutoff for this hybrid approach. Using an age at diagnosis of ≤60 or ≤65 years for the universal testing of patients with breast cancer detected more PVs (11.9% [16 of 134] and 15.7% [21 of 134], respectively) in comparison with using the NCCN criteria. Lowering the age for universal testing from 65 to 60 years maintained the sensitivity of detecting a PV at >90% while sparing testing for an additional 10% of women. Compared with the testing of all patients, the hybrid approach would allow 31% of all women with breast cancer to forgo testing and result in fewer variants of uncertain significance identified and, therefore, would decrease the chance of harm from misinterpretation of these variants.

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“…Similarly, studies from us and others have reported on risk-reducing oophorectomies conducted among those with BRCA1/2 carriers have reported lower rates among Black women compared to non-Hispanic whites [36]. Furthermore, we and others have also recently reported on potential overtreatment with oophorectomy among women with P/LP variants in inherited breast cancer genes in which oophorectomy is not generally recommended for risk reduction based on current ovarian cancer risk estimates [35,37]. These findings highlight the importance of promoting guideline-adherent care and avoiding overtreatment [38].…”

Section: Updated Guidelines To Address Low Genetic Testing Ratesmentioning

confidence: 56%

“…Yet, there is increasing evidence that suggests non-guideline adherent care among women with breast cancer who receive genetic testing. These studies include data to suggest high rates of bilateral mastectomy reported among breast cancer patients with a BRCA1/2 variant of uncertain significance [33], as well as those with non-BRCA1/2 moderate penetrance genes [34,35], suggesting potential overtreatment. Additionally, a recently published cancer registry-based study suggested that those with P/LP BRCA1/2 and other breast cancer-associated genes may have patterns of breast cancer treatment which are less concordant with practice guidelines; including being more likely to receive bilateral mastectomy for a unilateral tumor, less likely to receive post-lumpectomy radiotherapy, and more likely to receive chemotherapy for early-stage, ER/PR-positive disease [34].…”

Section: Updated Guidelines To Address Low Genetic Testing Ratesmentioning

confidence: 99%