RESUMO
The current project is part of the Spatial location of breast cancer local rECurRence aftEr masTectomy (SECRET) study (NCT06130111). Herein we compared the chest wall thickness after non-skin sparing mastectomy (non-SSM) with the chest wall thickness after SSM, as a surrogate for residual breast tissue after mastectomy. METHODS: The study was approved by the ethics committee of relevant institutions. Data of patients with a local recurrence (LR) after non-SSM was collected from the Netherlands Cancer Registry (NCR); data of patients undergoing SSM were collected from Sheba Medical Center. Student's t-test was used to evaluate the difference between the cohorts. Chest wall thickness was measured on postoperative images. RESULTS: Out of 4949 patients who underwent mastectomy from the NCR cohort, a total of 173 (3.5 %) had a LR at 5 years, of these a total of 153 patients included in the non-SSM cohort. The median age was 59 years (age 33-92), LR occurred at a median of 23.6 months (2.5-60 months). The SSM cohort included 84 patients, with a median age of 38.4 years (28-63.5), overall, 5 LRs occurred at a median of 15 months (5-46 months). The SSM cohort had significantly thicker chest walls compared to non-SSM (p < 0.001). Most LRs in both groups occurred in the subcutis. CONCLUSION: The chest wall thickness differed according to mastectomy procedures. Most of the LR occurred at the subcutis. The role of residual breast tissue and residual cancer in relation to type of mastectomy should be further investigated.
RESUMO
INTRODUCTION: Different types of mastectomies leave different amounts of residual breast tissue. The significance of the residual breast volume (RBV) is not clear. Therefore, we developed an MRI tool that allows to easily assess the RBV. In this study we evaluated factors associated with RBV after skin or nipple sparing mastectomy (SSM/NSM) in breast cancer BRCA pathogenic variant (PV) carriers who underwent both therapeutic and risk reducing SSM/NSM and its relation to breast cancer outcomes using an innovative MRI-based tool. METHODS: Data of breast cancer BRCA PV who were treated between 2006 and 2020 were retrieved from of the oncogenetics unit databases. Only patients who underwent SSM/NSM and had a postoperative breast MRI available for analysis were included. Data collected included demographics, clinicopathological features, and outcomes. The MRI tool was developed by a breast cancer imaging laboratory. A logistic regression test and 95% confidence interval (CI) were used to assess the associated risk of increased RBV. A forward stepwise linear regression was used to correlate tumour-patient specific factors and RBV, and a Kaplan-Meier curve to show the probability of locoregional relapse. RESULTS: A total of 84 patients undergoing 89 mastectomies were included. At a median follow-up of 98 months, 5 local, 2 regional, and 4 distant recurrences were observed. RBV was not significantly related with breast cancer outcomes (p value = NS). A higher body mass index (BMI) was associated with a higher RBV (p < 0.0001). A larger number of involved axillary nodes was associated with a smaller RBV (p = 0.025). The RBV on the risk-reducing mastectomy side was significantly higher compared to the breast cancer side (p value = 0.007). Local recurrences occurred in the vicinity of the primary tumour.
RESUMO
BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Mutação em Linhagem Germinativa , Receptor ErbB-2 , Humanos , Feminino , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Proteína BRCA1/genética , Proteína BRCA2/genética , Adulto Jovem , Intervalo Livre de Doença , PrognósticoRESUMO
PURPOSE: The contribution of clinical breast exam (CBE) to breast cancer diagnosis in average risk women undergoing regular screening mammography is minimal. To evaluate the role of CBE in high-risk women, we compared BC diagnosis by CBE in BRCA mutation carriers undergoing regular BC surveillance to average to intermediate risk women undergoing regular breast cancer screening. METHODS: A retrospective chart review of all consecutive screening visits of BRCA mutation carriers (January 2012-October 2022) and average to intermediate risk women (November 2016-December 2022) was completed. Women with histologically confirmed BC diagnosis were included. Additional CBE yield for BC diagnosis, defined as the percentage of all BC cases detected by CBE alone, was assessed in both groups. RESULTS: Overall, 12,997 CBEs were performed in 1,328 BRCA mutation carriers in whom 134 BCs were diagnosed. In 7,949 average to intermediate risk women who underwent 15,518 CBEs, 87 BCs were diagnosed. CBE contributed to BC diagnosis in 3 (2%) BRCA mutation carriers and 3 (4%) non-carriers. In both groups, over 4,000 CBEs were needed in order to diagnose one cancer. In all 3 BRCA mutation carriers BC was palpated during the surveillance round that did not include MRI. In the average to intermediate risk group, 2 of 3 cancers diagnosed following CBE findings were in a different location from the palpable finding. CONCLUSIONS: The contribution of CBE to BC diagnosis is marginal for all women including BRCA mutation carriers. In BRCA mutation carriers, CBE appears redundant during the MRI surveillance round.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Detecção Precoce de Câncer , Mamografia , Mutação , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/diagnóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Detecção Precoce de Câncer/métodos , Mamografia/métodos , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Idoso , Heterozigoto , Predisposição Genética para Doença , Fatores de RiscoRESUMO
OBJECTIVES: Women harboring germline BRCA1/BRCA2 pathogenic sequence variants (PSVs) are at an increased risk for breast cancer. There are no established guidelines for screening during pregnancy and lactation in BRCA carriers. The aim of this study was to evaluate the utility of whole-breast ultrasound (US) screening in pregnant and lactating BRCA PSV carriers. METHODS: Data were retrospectively collected from medical records of BRCA PSV carriers between 2014 and 2020, with follow-up until 2021. Associations between imaging intervals, number of examinations performed and pregnancy-associated breast cancers (PABCs) were examined. PABCs and cancers diagnosed at follow-up were evaluated and characteristics were compared between the two groups. RESULTS: Overall 212 BRCA PSV carriers were included. Mean age was 33.6 years (SD 3.93, range 25-43 years). During 274 screening periods at pregnancy and lactation, eight (2.9 %) PABCs were diagnosed. An additional eight cancers were diagnosed at follow-up. Three out of eight (37.5 %) PABCs were diagnosed by US, whereas clinical breast examination (n = 3), mammography (n = 1) and MRI (n = 1) accounted for the other PACB diagnoses. One PABC was missed by US. The interval from negative imaging to cancer diagnosis was significantly shorter for PABCs compared with cancers diagnosed at follow-up (3.96 ± 2.14 vs. 11.2 ± 4.46 months, P = 0.002). CONCLUSION: In conclusion, pregnant BRCA PSV carriers should not delay screening despite challenges like altered breast tissue and hesitancy towards mammography. If no alternatives exist, whole-breast ultrasound can be used. For lactating and postpartum women, a regular screening routine alternating between mammography and MRI is recommended.
Assuntos
Proteína BRCA1 , Neoplasias da Mama , Detecção Precoce de Câncer , Lactação , Ultrassonografia Mamária , Humanos , Feminino , Gravidez , Neoplasias da Mama/genética , Neoplasias da Mama/diagnóstico por imagem , Adulto , Estudos Retrospectivos , Detecção Precoce de Câncer/métodos , Ultrassonografia Mamária/métodos , Proteína BRCA1/genética , Proteína BRCA2/genética , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/diagnóstico por imagem , Mamografia/métodos , HeterozigotoRESUMO
PURPOSE: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years. METHODS: Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed. RESULTS: Of 2706 patients with BC (mean age at diagnosis, 54 years; range, 20-92 years) counseled, 515 patients of non-AJ (all four grandparents) descent, diagnosed ≥age 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) of non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants were found in 2.5% of genotyped TNBC and in 3.7% of patients with non-TNBC, including CHEK2 c.499G>A (n = 3), APC c.3920T > A (n = 4), and heterozygous MUTYH c.1187G>A (n = 5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n = 2, c.846+1G>C and c.592+3A>T), ATM c.103C>T (n = 2), and NBN c.966C>G (n = 1). CONCLUSIONS: The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.
Assuntos
Proteína BRCA2 , Neoplasias da Mama , Quinase do Ponto de Checagem 2 , Predisposição Genética para Doença , Judeus , Humanos , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Quinase do Ponto de Checagem 2/genética , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/etnologia , Judeus/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Israel/epidemiologia , Genótipo , Adulto Jovem , Proteínas Mutadas de Ataxia Telangiectasia/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína da Polipose Adenomatosa do Colo/genética , DNA Glicosilases/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/etnologia , Testes Genéticos/métodosRESUMO
BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteína BRCA1/genética , Estudos de Coortes , Proteína BRCA2/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Células Germinativas , Predisposição Genética para DoençaRESUMO
Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.
Assuntos
Neoplasias da Mama , Genes BRCA1 , Genes BRCA2 , Complicações Neoplásicas na Gravidez , Resultado da Gravidez , Adulto , Feminino , Humanos , Gravidez , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Mutação em Linhagem Germinativa , Estudos Retrospectivos , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/mortalidade , InternacionalidadeRESUMO
INTRODUCTION: Hereditary breast and ovarian cancer (HBOC) is predominantly accounted for by pathogenic variants (PVs) in BRCA1/BRCA2 genes. Population screening for recurring PVs in Ashkenazi Jews (AJ) was incorporated into the Israeli health basket in 2020, increasing the identification of BRCA carriers. Information on cancer risks for each PV in Israel is limited. AIMS: To assess genotype phenotype correlations of recurring BRCA PVs in Israeli carriers. METHODS: A retrospective cohort of 3,478 BRCA carriers followed-up in 12 medical centers, comprising the HBOC Consortium, formed the basis of the study. Data were collected using the electronic database, and analyzed by Chi square, t-tests and Kaplan-Meier survival analysis. RESULTS: Overall, 2145 BRCA1, 1131 BRCA2, and 22 double heterozygote PV carriers were analyzed. BRCA1 carriers had more cases of cancer (53.1% vs. 44.8%, p<0.001), ovarian cancer (OC) (17.1% vs. 10.6%, p<0.001), younger age at breast cancer (BC) (45.4 ±11.6SD years vs. 49.1 ±11.1SD years, p<0.001) and OC diagnosis (52.8 ±10.1SD yrs. vs. 61±10.6SD yrs. p<0.001), and more family history of BC (64.5% vs. 59.0%, p<0.001) and OC (36.7% vs. 27.3%, p<0.001) compared with BRCA2 carriers. Carriers of BRCA15382insC had more BC and less OC than BRCA1185delAG: 46.4% vs. 38.6% and 12.9% vs. 17.6% (p<0.04), respectively. CONCLUSIONS: In our population, similar to others, BRCA1 carriers have higher cancer rates and earlier age at diagnosis compared with BRCA2 carriers. The two recurring BRCA1 PVs have different risks: 5382insC carriers had more BC; 185delAG carriers had more OC. Risk-reducing measures should be based on variant-specific cancer risk.
Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Israel/epidemiologia , Estudos Retrospectivos , Genes BRCA1 , Recidiva Local de Neoplasia , Proteína BRCA2/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteína BRCA1/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Associação Genética , Judeus/genética , Mutação , Predisposição Genética para DoençaRESUMO
PURPOSE: 68 Ga-fibroblast activation protein inhibitor (FAPI), a new PET/CT radiotracer targeting cancer-associated fibroblasts in tumor microenvironment, can detect many types of cancer. We aimed to assess whether it can also be used for response assessment and follow-up. METHODS: We followed up patients with FAPI-avid invasive lobular breast cancer (ILC) before and after treatment changes and correlated qualitative maximal intensity projection images and quantitative tumor volume with CT results and blood tumor biomarkers. RESULTS: Six consenting ILC breast cancer patients (53 ± 8 years old) underwent a total of 24 scans (baseline for each patient and 2-4 follow-up scans). We found a strong correlation between 68 Ga-FAPI tumor volume and blood biomarkers ( r = 0.7, P < 0.01), but weak correlation between CT and 68 Ga-FAPI maximal intensity projection-based qualitative response assessment. CONCLUSIONS: We found a strong correlation between ILC progression and regression (as assessed by blood biomarkers) and 68 Ga-FAPI tumor volume. 68 Ga-FAPI PET/CT could possibly be used for disease response assessment and follow-up.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Seguimentos , Biomarcadores Tumorais/sangue , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Breast cancer diagnosis had been linked to an increased risk of melanoma in several reports. The aim of the current study was to assess the role of genetics, increased surveillance, and radiation treatment in patients with a dual diagnosis of breast cancer and melanoma (DBM). MATERIALS AND METHODS: All patients treated at Sheba Medical Center between 2007 and 2021 with DBM were included in the cohort. Data on family history, genetic tests, characteristics, and treatment of both cancers were collected. The proportion of patients with a pathogenic variant (PV) in BRCA1 and BRCA2 genes was compared to a control group of patients with breast cancer. The proportion of patients presenting with in-situ disease was compared to the national registry data. RESULTS: The cohort included 222 DBM patients of whom 114 had documentation of genetic testing. Twenty patients tested positive for PVs of which 13 (11%) were in BRCA genes. This was comparable to the proportion in patients with a diagnosis of breast cancer (736; 19%). The proportion of melanoma diagnosed at stage 0 was comparable to the national proportion ( N = 40; 30% vs. 28%, respectively). In comparison to the national registry, a larger proportion of breast cancers were ductal carcinoma in situ or lobular carcinoma in situ [10% in the registry vs. 19% (22) in the cohort; P < 0.003]. CONCLUSIONS: In patients with DBM we did not find an increased proportion of PVs in BRCA genes. Our findings suggest that the increased standardized incidence ratio of the dual diagnosis may be partially explained by increased surveillance and detection of earlier-stage cancers.
Assuntos
Neoplasias da Mama , Melanoma , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteína BRCA1/genética , Testes Genéticos , Genes BRCA2 , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/genética , Proteína BRCA2/genética , MutaçãoRESUMO
PURPOSE: Invasive lobular breast cancer (ILC) may be hard to detect using conventional imaging modalities and usually shows less avidity to 18 F-FDG PET/CT. 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/CT has shown promising results in detecting non- 18 F-FDG-avid cancers. We aimed to assess the feasibility of detecting metastatic disease in patients with non- 18 F-FDG-avid ILC. METHODS: This prospective study included patients with metastatic ILC, infiltrative to soft tissues, which was not 18 F-FDG avid. The patients underwent 68 Ga-FAPI PET/CT for evaluation, which was correlated with the fully diagnostic CT performed at the same time. RESULTS: Seven women (aged 57 ± 10 years) were included. Among the 30 organs and structures found to be involved by tumor, the number of findings observed by FAPI PET/CT was significantly higher than that observed by CT alone ( P = 0.022), especially in infiltrative soft tissue and serosal locations. CONCLUSIONS: This small pilot trial suggests a role for 68 Ga-FAPI PET/CT in ILC, which needs to be confirmed by subsequent trials.
Assuntos
Neoplasias da Mama , Carcinoma Lobular , Humanos , Feminino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Mama/diagnóstico por imagem , Fluordesoxiglucose F18 , Estudos Prospectivos , Carcinoma Lobular/diagnóstico por imagem , Radioisótopos de GálioRESUMO
BACKGROUND: Population screening for the BRCA mutations in Ashkenazi Jewish women was recently implemented in Israel and is expected to lead to a 10-fold increase in the diagnosis of asymptomatic carriers. Performing the screening follow-up within multidisciplinary dedicated clinics for carriers is recommended for early detection and risk reduction. OBJECTIVES: : To determine the availability, capacity, and practices of dedicated screening clinic for BRCA carriers in Israel. METHODS: A telephone-based survey of all public hospitals in Israel was conducted October 2020 to August 2021 to determine whether they had a dedicated clinic. Dedicated clinics were defined as multidisciplinary screening clinics offering at least breast and gynecological screening and risk reducing services on site. The clinic director or nurse navigator answered a questionnaire about screening practices followed by a semi-structured interview. RESULTS: Of the ten dedicated BRCA clinics found in Israel, nine participated. Approximately 4500 BRCA carriers are currently being followed. No specialized clinics are available in the southern district or in the northernmost half of the northern district of Israel, leading to a disparity between periphery and center. Screening recommendations, although asserted as adhering to international guidelines, vary among clinics including age at initiating of clinical exam, use of adjunct imaging modalities, and follow-up during lactation and after risk reducing surgery. CONCLUSIONS: There is a suboptimal distribution of dedicated clinics for BRCA carriers in Israel. Nationally centralized attempt to create guidelines that will unify screening practices is warranted, especially considering the expected increase in demand.
Assuntos
Neoplasias da Mama , Ginecologia , Neoplasias Ovarianas , Humanos , Feminino , Mutação , Israel/epidemiologia , Heterozigoto , Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Proteína BRCA1/genética , Proteína BRCA2/genéticaRESUMO
Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene - CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype-phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94-96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype-phenotype correlations.
Assuntos
Adenoma , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasia Endócrina Múltipla , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Neoplasia Endócrina Múltipla/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Mutação em Linhagem Germinativa , Fenótipo , Neoplasias Hipofisárias/genética , Adenoma/genética , Tumores Neuroendócrinos/patologia , Neoplasia Endócrina Múltipla Tipo 1/genéticaRESUMO
Females harboring germline BRCA1/BRCA2 (BRCA) P/LPV are offered a tight surveillance scheme from the age of 25−30 years, aimed at early detection of specific cancer types, in addition to risk-reducing strategies. Multiple national and international surveillance guidelines have been published and updated over the last two decades from geographically diverse countries. We searched for guidelines published between 1 January 2015 and 1 May 2022. Differences between guidelines on issues such as primary prevention, mammography screening in young (<30 years) carriers, MRI screening in carriers above age 65 years, breast imaging (if any) after risk-reducing bilateral mastectomy, during pregnancy, and breastfeeding, and hormone-replacement therapy, are just a few notable examples. Beyond formal guidelines, BRCA carriers' concerns also focus on the timing of risk-reducing surgeries, fertility preservation, management of menopausal symptoms in cancer survivors, and pancreatic cancer surveillance, issues that, for some, there are no data to support evidence-based recommendations. This review discusses these unsettled issues, emphasizing the importance of future studies to enable global guideline harmonization for optimal surveillance strategies. Moreover, it raises the unmet need for personalized risk stratification and surveillance in BRCA P/LPV carriers.
RESUMO
PURPOSE: Cancer risks conferred by germline, heterozygous, ATM pathogenic/likely pathogenic variants (PSVs) are yet to be consistently determined. The current study assessed these risks by analysis of a large dataset of ATM heterozygote loss of function (LOF) and missense PSV carriers tested with a multigene panel (MGP). METHODS: De-identified data of all individuals who underwent ATM sequencing as part of MGP between October 2015 and February 2020 were reviewed. In cancer cases, rates for the six most prevalent variants and for all LOF and missense PSV combined were compared with rates of the same PSV in ethnically matched, healthy population controls. Statistical analysis included Chi-square tests and odds ratios calculations. RESULTS: For female breast cancer cases, LOF )1794/219,269) and missense (301/219,269) ATM PSVs were seen at higher rates compared to gnomAD non-cancer controls (n = 157/56,001 and n = 27/61,208; p < 0.00001, respectively). Notably, the rate of the c.103C > T variant was higher in controls than in breast cancer cases [p = 0.001; OR 0.31 (95% CI 0.1-0.6)]. For all cancer cases combined, compared with non-cancer population controls, LOF (n = 143) and missense (n = 15) PSVs reported in both datasets were significantly more prevalent in cancer cases [ORLOF 1.7 (95% 1.5-1.9) ORmissense 3.0 (95% CI 2.3-4); p = 0.0001]. CONCLUSION: Both LOF and missense heterozygous ATM PSVs are more frequently detected in cases of several cancer types (breast, ovarian, prostate, lung, pancreatic) compared with healthy population controls. However, not all ATM PSVs confer an increased cancer risk (e.g., breast).
Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Feminino , Humanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Mutação de Sentido Incorreto , Perda de Heterozigosidade , Heterozigoto , Proteínas Mutadas de Ataxia Telangiectasia/genéticaRESUMO
A missense variant (p.Ser428Phe [S428F]) in the CHEK2 gene is reportedly associated with a 2-3 fold increase in breast cancer risk in Ashkenazi Jews. This study aimed to re-evaluate cancer risks conferred by the CHEK2 S428F variant in Ashkenazi Jews. De-identified data from CHEK2 S428F variant carriers sequenced with multigene panels were analyzed. Overall, 486/341,531 (0.14%) cases of all ethnicities diagnosed with any cancer type were CHEK2 S428F carriers, of whom 243/9980 self-identified as Ashkenazi Jews and carried this risk variant only. Compared with ethnically matched non-cancer controls, across all cancer cases, this variant was not more prevalent (p = 0.271). Specifically, variant prevalence was not different in breast cancer cases compared with controls. Though the variant was shown to be enriched in pancreatic cancer cases (p = 0.008), sample size was small. The CHEK2 S428F variant was not overrepresented in Ashkenazi Jews with breast cancer and most other cancer types analyzed, except for pancreatic cancer, compared with ethnically matched non- cancer controls. These findings should prompt reevaluating ethnic-specific CHEK2 S428F cancer attributable risk.
Assuntos
Neoplasias da Mama , Quinase do Ponto de Checagem 2 , Neoplasias Pancreáticas , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Feminino , Efeito Fundador , Predisposição Genética para Doença/etnologia , Humanos , Judeus/genética , Neoplasias Pancreáticas/etnologia , Neoplasias Pancreáticas/genéticaRESUMO
PURPOSE OF REVIEW: In recent years there has been a dramatic evolution in the clinical utility of genetic testing with expanding therapeutic implications for individuals with breast cancer who harbor a germline mutation in BRCA1/2. As these therapeutic opportunities expand and evolve, this requires the clinical and research community to rethink the approach to genetic testing for individuals with breast cancer. RECENT FINDINGS: Genetic testing is evolving from traditional testing models based on pretest counseling with the aim of identifying hereditary and individual risk for purposes of screening and risk reduction to contemporary models that utilize technology to improve accessibility and oncology led mainstreaming of testing where the oncologist refers for genetic testing, discloses the results and formal counseling occurs later in the process than in traditional models. The cost and accessibility to multigene panel testing have resulted in broad uptake despite the fact that clinical utility and appropriate interpretation of results are not yet well established. Furthermore, somatic testing for genomic alterations may also yield results beyond the disease with detection of germline mutations impacting the individual and their family more broadly than anticipated. SUMMARY: With the establishment of poly (adenosine diphosphate-ribose) polymerase inhibitors as part of the treatment armamentarium for early and advanced breast cancer, paradigms, algorithms, and resources for genetic testing need to rapidly change in order to adapt to the evolution of germline mutations from hereditary and individual risk predictors to predictive therapeutic biomarkers.
Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/genética , Feminino , Testes Genéticos/métodos , HumanosRESUMO
BACKGROUND: Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. METHODS: Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. RESULTS: Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. CONCLUSIONS: The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.