Presymptomatic Awareness of Germline Pathogenic <i>BRCA</i> Variants and Associated Outcomes in Women With Breast Cancer

Hadar, Tal; Mor, Pnina; Gefen, Amit; Lieberman, Sari; Gekhtman, David; Rabinovitch, Rachel; Levy‐Lahad, Ephrat

doi:10.1001/jamaoncol.2020.2059

Cited by 20 publications

(17 citation statements)

References 6 publications

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“…These results are clinically meaningful because variants in these genes confer a high risk of serious disease compared with the risk in the general population. Identifying this risk facilitates the application of precision preventive medical interventions, including appropriate screening protocols to either prevent disease or detect it early to reduce morbidity and mortality [6]. The clinical yield in the 59 ACMG genes increased from 3.1 to 5.2% when the APC p.Ile1307Lys increased risk allele and MUTYH heterozygotes were included.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence supports primary genetic screening for a few hereditary disorders, such as hereditary breast and ovarian cancer syndromes [6,7]. The Centers for Disease Control and Prevention (CDC) recognizes that hereditary breast and ovarian cancer, familial hypercholesterolemia, and Lynch syndrome have sufficient evidence for intervention that could positively impact public health [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

Haverfield

Aguilar

Hatchell

et al. 2021

BMC Med

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Background The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. Methods Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction. Results Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. Conclusions This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

Haverfield

Aguilar

Hatchell

et al. 2021

BMC Med

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“…A small hint of improved efficacy of high-risk screening was shown in a recent paper by Hadar et al. ( 29 ) The authors described a limited population (42 out of 105 BRCA1/2 carriers) who knew that they were BRCA carriers prior to cancer diagnosis, were under high-risk screening, and had better outcomes with a possible survival advantage. Our work shows an interesting improvement in survival in young women who underwent high-risk screening.…”

Section: Discussionmentioning

confidence: 99%

“High-Risk Breast Cancer Screening in BRCA1/2 Carriers Leads to Early Detection and Improved Survival After a Breast Cancer Diagnosis”

et al. 2021

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BackgroundGermline BRCA1/2 pathogenic variant (PV) carriers have high lifetime risk of developing breast cancer and therefore subjected to intense lifetime screening. However, solid data on the effectiveness of high-risk screening of the BRCA1/2 carrier population is limited.Patients and MethodsRetrospectively, we analyzed 346 women diagnosed with breast tumors. Patients were divided according to the timing of BRCA1/2 PVrecognition, before (BRCA-preDx awareness, N = 62) or after (BRCA-postDx awareness group, N = 284) cancer diagnosis.ResultsMedian follow-up times were 131.42 and 93.77 months in the BRCA-preDx awareness and BRCA-postDx awareness groups, respectively. In the BRCA-preDx awareness group, 78.7% of the patients had invasive tumors and 21.3% were diagnosed with pure ductal carcinoma in situ. In contrast, in the BRCA-postDx awareness group over 93% of women were diagnosed with invasive cancer and only 6.4% had in situ disease. The mode of tumor detection differed significantly between the groups: 71.9% in the BRCA-postDx awareness group and 26.2% in the BRCA-preDx awareness group were diagnosed after personally palpating a lump. Tumor size and nodal involvement were significantly more favorable in the BRCA-preDx awareness group. T stage was significantly lower in the BRCA-preDx awareness group: 54.84% at T1 and 20.96% at Tis. In the BRCA-postDx awareness group, only 37.54% were at T1 and 6.49% at Tis. The N stage was also significantly lower in the BRCA-preDx awareness group: 71% had no lymph node metastases, compared with 56.1% in the BRCA-postDx awareness group. Additionally, therapeutic procedures varied between the groups: BRCA-preDx awareness group patients underwent more breast conserving surgeries. Axillary lymph node dissection was done in 38% of women in the BRCA-postDx awareness group and in only 8.7% of the BRCA-preDx awareness group patients. Interestingly, improved survival was found among patients who underwent high-risk screening (hazard ratio=0.34).ConclusionsHigh-risk screening might facilitate downstaging of detected breast tumor among BRCA1/2 carrier population.

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“…In the combined UK MARIBS and NICE studies, in which 45 breast cancers were detected, only two women died of breast cancer (both BRCA1 mutation carriers) after a median follow-up of 12 years [ 17 ]. In a recent retrospective study of 42 BRCA mutation carriers who opted for annual breast screening with MRI and mammography and were subsequently diagnosed with breast cancer, the 5-year survival after breast cancer was 94% [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Mortality among Women with a BRCA1 or BRCA2 Mutation in a Magnetic Resonance Imaging Plus Mammography Screening Program

Zhu

Plewes

Hill

et al. 2020

Cancers

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Annual breast magnetic resonance imaging (MRI) plus mammography is the standard of care for screening women with inherited BRCA1/2 mutations. However, long-term breast cancer-related mortality with screening is unknown. Between 1997 and June 2011, 489 previously unaffected BRCA1/2 mutation carriers aged 25 to 65 years were screened with annual MRI plus mammography on our study. Thereafter, participants were eligible to continue MRI screening through the high-risk Ontario Breast Screening Program. In 2019, our data were linked to the Ontario Cancer Registry of Cancer Care Ontario to identify all incident cancers, vital status and causes of death. Observed breast cancer mortality was compared to expected mortality for age-matched women in the general population. There were 91 women diagnosed with breast cancer (72 invasive and 19 ductal carcinoma in situ (DCIS)) with median follow-up 7.4 (range: 0.1 to 19.2) years. Four deaths from breast cancer were observed, compared to 2.0 deaths expected (standardized mortality ratio (SMR) 2.0, p = 0.14). For the 489 women in the study, the probability of not dying of breast cancer at 20 years from the date of the first MRI was 98.2%. Annual screening with MRI plus mammography is a reasonable option for women who decline or defer risk-reducing mastectomy.

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Presymptomatic Awareness of Germline Pathogenic BRCA Variants and Associated Outcomes in Women With Breast Cancer

Cited by 20 publications

References 6 publications

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

“High-Risk Breast Cancer Screening in BRCA1/2 Carriers Leads to Early Detection and Improved Survival After a Breast Cancer Diagnosis”

Breast Cancer Mortality among Women with a BRCA1 or BRCA2 Mutation in a Magnetic Resonance Imaging Plus Mammography Screening Program

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