Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of risk assessment, screening and prevention strategies in the clinic and propose future approaches. Between 1987–2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (≥30% lifetime risk), 37.7% at moderate risk (17–29%), and 17.7% at an average/population risk who were discharged. A total of 4168 (29.1%) women were eligible for genetic testing and 736 carried pathogenic variants, predominantly in BRCA1 and BRCA2 but also other genes (5.1% of direct referrals). All women at high or moderate risk were offered annual mammographic screening between ages 30 and 40 years old: 646 cancers were detected in women at high and moderate risk (5.5%) with a detection rate of 5 per 1000 screens. Incident breast cancers were largely of good prognosis and resulted in a predicted survival advantage. All high/moderate-risk women were offered lifestyle prevention advice and 14–27% entered various lifestyle studies. From 1992–2003, women were offered entry into IBIS-I (tamoxifen) and IBIS-II (anastrozole) trials (12.5% of invitees joined). The NICE guidelines ratified the use of tamoxifen and raloxifene (2013) and subsequently anastrozole (2017) for prevention; 10.8% women took up the offer of such treatment between 2013–2020. Since 1994, 7164 eligible women at ≥25% lifetime risk of breast cancer were offered a discussion of risk-reducing breast surgery and 451 (6.2%) had surgery. New approaches in all aspects of the service are needed to build on these results.

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Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in BRCA1, BRCA2, and TP53 Genes in Women with Very Early-Onset (<36 Years) Breast Cancer

Cancers ◽

10.3390/cancers12020378 ◽

2020 ◽

Vol 12 (2) ◽

pp. 378 ◽

Cited By ~ 2

Author(s):

Zerin Hyder ◽

Elaine F. Harkness ◽

Emma R. Woodward ◽

Naomi L. Bowers ◽

Marta Pereira ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Contralateral Breast Cancer ◽

Genomic Medicine ◽

Contralateral Breast ◽

Breast Cancers ◽

Brca1 And Brca2 ◽

North West ◽

Pathogenic Variants ◽

Brca1 Brca2

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed <36 years of age were obtained from three sources: (i) a population-based study of 283 women diagnosed sequentially from 1980–1997 in North-West England, (ii) referrals to the Genomic Medicine Department at St Mary’s Hospital from 1990–2018, and (iii) individuals from (i) and the Family History Clinic at Wythenshawe Hospital South Manchester who tested negative for pathogenic variants (PV) in all three genes. Sequencing of BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

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Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22226 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22226-e22226

Author(s):

A. Kwong ◽

L. Wong ◽

C. Wong ◽

F. Law ◽

E. Tang ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

High Risk ◽

Breast Cancers ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

Mutation Carriers ◽

History Of ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

e22226 Background: Breast cancers due to underlying germline BRCA1 and BRCA2 mutations are associated with particular pathological features that may differ from sporadic breast cancers. We report clinical and pathologic characteristics of breast cancer in a clinical cohort of high risk Chinese women with BRCA mutations and those without mutations. Methods: 202 high risk women based on their age and family history were recruited from March 2007 to November 2008. Medical information was prospectively collected from the patients and medical records. BRCA1 and BRCA2 mutations were detected using full gene sequencing and multiplex ligation-dependent probe amplification (MLPA). Results: Of the 202 female probands tested, 25 (12.3 %) were BRCA mutation carriers of which 11 (44%) were BRCA1 and 14 (56%) were BRCA2 mutations. Breast cancer risk factors, other than family history, did not differ between carriers and non-carriers. Mutation carriers were more likely to have a familial history of breast cancer (p=0.07) and personal and family history of ovarian cancer (p=0.005; p=0.007). Other cancers found in carriers families included pancreatic, gastric, colon, lung, liver, and nasopharyngeal. 23% of women diagnosed with DCIS had BRCA mutations compared with 11.4% of those with invasive cancers. BRCA related tumors were more likely to be ER, PR and Her-2 negative (Triple negative, TN) (p= 0.006). Overall 9.6% of non-BRCA cancers were TN whereas 25.9% of BRCA cancers were TN. Prevalence of TN in BRCA1 carriers is 71% compared with 13.4% in BRCA2 carriers. BRCA1 mutation related cancers were significantly more likely to be ER negative than BRCA2 and this is only significant in those who are under 40 years of age (p=0.070). Conclusions: We have a high BRCA2 mutation rate in our cohort. BRCA related breast cancer is associated with families with increasing number of first degree relatives with breast and/or ovarian cancers and were higher for DCIS cancers. Prevalence of TN breast cancers was high compared to Caucasian cohorts. BRCA mutations were associated with pathologically, poor prognostic features (TN and high grade) especially in younger women. No significant financial relationships to disclose.

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Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients

Diagnostics ◽

10.3390/diagnostics10050269 ◽

2020 ◽

Vol 10 (5) ◽

pp. 269

Author(s):

Gianluca Tedaldi ◽

Michela Tebaldi ◽

Valentina Zampiga ◽

Ilaria Cangini ◽

Francesca Pirini ◽

...

Keyword(s):

Breast Cancer ◽

Male Breast Cancer ◽

Case Series ◽

Brca2 Gene ◽

Brca1 Gene ◽

Cancer Predisposition ◽

Male Breast ◽

Breast Cancers ◽

Brca1 And Brca2 ◽

Pathogenic Variants

Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than BRCA1 and BRCA2. We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of BRCA1/2 genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the BRCA1 gene and six in the BRCA2 gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in PALB2, CHEK2, ATM, RAD51C, BAP1 and EGFR genes. From our study, BRCA1 and BRCA2 emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development.

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Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort

Journal of Hematology & Oncology ◽

10.1186/s13045-020-01010-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yun Liu ◽

Honglian Wang ◽

Xin Wang ◽

Jiaqi Liu ◽

Junjian Li ◽

...

Keyword(s):

Breast Cancer ◽

Risk Assessment ◽

Chinese Population ◽

Functional Assay ◽

Healthy Controls ◽

Brca1 And Brca2 ◽

Chinese Han ◽

Pathogenic Variants ◽

Breast Cancer Cohort ◽

Invasive Carcinomas

AbstractAccurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2–5 and 15–23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.

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Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study

JCO Global Oncology ◽

10.1200/go.21.00051 ◽

2021 ◽

pp. 849-861

Author(s):

Sudeep Gupta ◽

Senthil Rajappa ◽

Suresh Advani ◽

Amit Agarwal ◽

Shyam Aggarwal ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Family History ◽

Newly Diagnosed ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

Fallopian Tube Cancer ◽

Cross Sectional ◽

Brca2 Mutations ◽

Brca1 Brca2

PURPOSE There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 ( BRCA1/ BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features. METHODS This prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/ BRCA2 mutations, and the secondary objective was to correlate BRCA1/ BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay. RESULTS Between March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively. CONCLUSION There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.

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Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

Oncology Reviews ◽

10.4081/oncol.2021.544 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Hikmat Abdel-Razeq

Keyword(s):

Breast Cancer ◽

Brca1 And Brca2 ◽

Healthy Women ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

History Of ◽

Risk Reducing ◽

Current Guidelines ◽

Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

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Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

Cancer Research Communications ◽

10.1158/2767-9764.crc-21-0099 ◽

2021 ◽

Vol 1 (3) ◽

pp. 140-147

Author(s):

Cynthia Villarreal-Garza ◽

Ana S. Ferrigno ◽

Alejandro Aranda-Gutierrez ◽

Paul H. Frankel ◽

Nora H. Ruel ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Point Mutations ◽

Treatment Resistance ◽

Cancer Center ◽

Breast Cancers ◽

Entire Cohort ◽

Pathogenic Variants ◽

Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

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Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco

BMC Cancer ◽

10.1186/s12885-020-07352-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Joaira Bakkach ◽

Mohamed Mansouri ◽

Touria Derkaoui ◽

Ali Loudiyi ◽

ElMostafa El Fahime ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Early Onset ◽

Brca2 Gene ◽

Germline Mutations ◽

Genetic Alterations ◽

Early Onset Breast Cancer ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

History Of

Abstract Background To date, the contribution of BRCA1/2 mutations in Moroccan early onset breast cancer patients remains unknown. Here we assess these genetic alterations for the first time in a cohort from North of Morocco. Methods Thirty-three patients diagnosed with breast cancer at the age of ≤40 years were recruited irrespective of breast and/or ovarian cancer family history. Coding regions and intron-exon boundaries of BRCA1 and BRCA2 genes were sequenced from peripheral blood DNA using Ion Proton (Thermo Fisher Scientific) next generation sequencing platform. Results Overall, five BRCA germline mutations were identified (15.1%). The frequency of mutations among patients with family history of breast cancer was 16.7%. Three mutations were found in BRCA1 (9%) and two within the BRCA2 gene (6%). These are three frameshift mutations (c.798_799del, c.2125_2126insA, c.5116_5119delAATA), one missense (c.116G > A) and one nonsense mutation (c.289G > T). The mutation c.5116_5119delAATA has a founder effect in North Africa. Moreover, one variant of unknown significance was identified in BRCA2 (c.4090A > G). Most BRCA mutations carriers (80%) had no family history of breast cancer. Conclusion Our data do not support the hypothesis that BRCA mutations alone explain the higher frequency of breast cancer in Moroccan young women. The young age (≤40 years) for breast cancer diagnosis seems to be strongly predictive of BRCA mutation status in Moroccan patients. These results will help in decision making with regard to genetic counseling and testing in the national scale.

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