scholarly journals Mutations in the genes of glutathione-S-transferase in patients with breast cancer and their close relatives living in chernivtsi region

2014 ◽  
Vol 18 (4 (72)) ◽  
Author(s):  
T. V. Kruk ◽  
O. P. Peresunko ◽  
R. A. Volkov
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Prognostic Factor ◽  
Blood Plasma ◽  
Genetic Marker ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Glutathione S Transferase ◽  
High Risk Disease ◽  
Close Relatives

Based on genotyping study of two variants (GSTP1 and GSTT1) of gene mutations glutathione-Stransferase (GST) in the blood plasma of patients with breast cancer, relatives of I degree of kinship and healthy women of Chernivtsi region, we made a conclusion as to the usefulness of this study as additional molecular genetic marker, determining high-risk disease as a prognostic factor for further observation and specifying diagnostics.

eMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS596-TPS596
Author(s):  
Sara M. Tolaney ◽  
Lesley Fallowfield ◽  
Peter A. Kaufman ◽  
Eva M. Ciruelos ◽  
Mary Corona Gainford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Endocrine Therapy ◽  
Early Breast Cancer ◽  
Primary Breast Tumor ◽  
Phase 3 ◽  
Free Survival ◽  
Node Positive ◽  
High Risk Disease ◽  
Definitive Surgery

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.

Breast cancer treatment and recurrence in octogenarians.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 94-94
Author(s):  
Adam Harris ◽  
Sarah A. McLaughlin ◽  
Cameron Adkisson ◽  
Sanjay Prakash Bagaria ◽  
Tammeza Gibson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Hormonal Therapy ◽  
Treatment Guidelines ◽  
Disease Risk ◽  
Low Risk ◽  
Patient Choice ◽  
High Risk Disease ◽  
Er Positive ◽  
Risk Patients

94 Background: Octogenarian breast cancer (BrCa) patients accept less aggressive BrCa treatment due to decreased life expectancy, increased comorbidities, and high likelihood of death from other causes. Unfortunately little data exist stratifying octogenarian outcomes by disease risk. We sought to characterize treatment and recurrence patterns in patients >80yo. Methods: Retrospective review identified 432 women >80yo treated surgically for stage 0-3 BrCa between 11/99-8/11. We gathered clinicopathologic data and classified patients by disease risk as DCIS only, low risk (<2cm and ER positive and node negative), or high risk (>2cm or ER negative or node positive). We compared recurrence rates and estimated survival by Kaplan-Meier curves. Results: Among the 432 women, disease was found by mammogram in 86%, treated with BCT in 64%, and predominantly ER-positive (87%). We classified patients as having DCIS only (N=61), low risk (N=205), or high risk (N=166) disease. We identified the following deviations from standard treatment guidelines: 68% DCIS BCT and 38% high risk BCT patients did not have radiation therapy, 25% low risk BCT patients had surgery only, 51% low risk patients did not take adjuvant hormonal therapy, and 40% high risk patients had no adjuvant chemo/hormonal therapy. At 5 and 10 years the overall estimated survival was 63% and 31%, respectively. Overall, 19/432 (5%) patients developed recurrence (table 1). Patients needing mastectomy for high risk disease had significantly higher risk of recurrence than high or low risk BCT patients (p=0.02). Of the 19 recurrence patients, 7/19 (37%; 1 DCIS, 1 low risk, 5 high risk) occurred despite standard multimodality treatment, while12 (63%; 3 low risk, 9 high risk) had the initial tumor treated less aggressively due to patient choice (n=9) or medical co-morbidities (n=3). Conclusions: Significant deviations from treatment guidelines occur in women >80yo. Those with high risk disease should be counseled accordingly and encouraged to receive adjuvant treatment as two thirds of women >80yo will live at least 5 years. [Table: see text]

scholarly journals Oncogenic Predictors of Outcome in Older AML Patients Treated Intensively. Analysis of the ALFA-1200 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 993-993 ◽  
Author(s):  
Raphael Itzykson ◽  
Elise Fournier ◽  
Thorsten Braun ◽  
Céline Berthon ◽  
Alice Marceau-Renaut ◽  
...  
Keyword(s):  
High Risk ◽  
Univariate Analysis ◽  
Gene Mutations ◽  
Penalized Regression ◽  
Low Risk ◽  
Tp53 Mutations ◽  
High Risk Disease ◽  
Clinical Covariates ◽  
Wbc Count

Abstract Context. The prognostic value of gene mutations in older AML patients (pts) treated intensively remains unclear. Only one study has explored the role of mutation patterns determined by NGS in older AML pts prospectively treated with various chemotherapies in years 2000-2010 (Eisfeld Leukemia 2018). Methods. Pts older than 60y enrolled in the ALFA-1200 trial (NCT01966497) between 09/2012 and 06/2016 were sequenced with a 37-gene myeloid panel. Pts received one 7+3 course followed by 2 intermediate-dose cytarabine courses. Pts with non-favorable risk were eligible for allogeneic stem cell transplantation (SCT). Variable selection for multivariate analyses was performed by lasso penalized regression including age, gender and log(WBC) as covariates. Results. Sequencing was done in 471 (93%) of the 509 enrolled pts. Median age and WBC count were 68y and 5.3x109/L, respectively (resp). CR (including CRp) was achieved in 341 (72%) pts and 90 underwent RIC-SCT in first CR. With a median follow-up of 25.4 months, median OS was 20.7 months. Pts had a median of 3 mutations (range 1-10). The 17 mostly frequently mutated genes (≥5% of pts, by decreasing frequency: DNMT3A, NPM1, TET2, ASXL1, FLT3, SRSF2, IDH2, RUNX1, NRAS, IDH1, STAG2, BCOR, TP53, PTPN11, U2AF1, EZH2 and KRAS) were retained for prognostic analyses. Genes belonging to a common pathway (eg. NRAS and KRAS) may have divergent prognostic values, preventing biology-informed grouping of mutations. Cytogenetic risk (derived from ELN 2017, Döhner Blood 2017, not considering gene mutations) was favorable (fav), intermediate (int), adverse (adv) and missing in 3%, 72%, 18% and 7% resp. Because of the few pts with fav cytogenetics in our cohort, pts were further grouped into non-adv and adv cytogenetics. CR rates and median OS were 75.6% vs 56.6% and 24.8 vs 9.5 months in pts with non-adv and adv cytogenetics, resp (both p<0.0001). Because of difference in mutational patterns and gene-gene interactions, the prognostic role of mutations was considered independently in these two non-adv and adv subgroups. In the 388 pts with non-adv cytogenetics, NPM1 mutations independently predicted improved CR rate (Odds Ratio [OR]=2.3, p=0.014), while mutations in ASXL1 (OR=0.46, p=0.012), RUNX1 (OR=0.46, p=0.013) and NRAS (OR=0.49, p=0.04) had independent adverse predictive value. In univariate analysis the shorter OS of FLT3-ITD pts was confined to allele ratios≥ 0.5 (FLT3-ITDhigh, p=0.02). In a multivariate analysis accounting for clinical covariates, mutations in NPM1 (Hazard Ratio [HR]=0.45, p<0.0001) and in SRSF2 (HR=0.64, p=0.03) predicted improved outcome, while FLT3-ITDhigh (HR=2.00, p=0.03), mutations in DNMT3A (HR=1.74, p=0.001), ASXL1 (HR=1.84, p=0.002) and NRAS (HR=1.70, p=0.009), but not RUNX1 or TP53, independently predicted worse OS. Significant interactions (eg. NPM1 - SRSF2, p=0.009, NPM1 - DNMT3A, p=0.03) precluded a simple NPM1-based stratification of pts with non-adv cytogenetics. This led to define a new prognostic hierarchy (Figure). The 49 NPM1mut pts with SRSF2 mutation and/or without adverse co-mutations (FLT3-ITDhighDNMT3A, ASXL1 and NRAS) had a median OS of 49.7 months, defining very low risk. NPM1wt pts without adverse co-mutations (n=114) had a median OS of 30.7 months and were considered at low risk. Among pts with ≥1 adverse co-mutation, NPM1 status had no significant prognostic influence (p=0.18). Regardless of NPM1 status, pts with a single (n=187) or ≥2 (n=38) adverse co-mutations (FLT3-ITDhighDNMT3A, ASXL1 or NRAS) had a median OS of 21.0 and 12.0 months, resp, and were considered at intermediate and high risk, resp. In the 83 pts with adv cytogenetics, TP53 mutations predicted shorter OS (p=0.004). Among pts with adv cytogenetics, those without TP53 mutation had a median OS of 12.6 months and were thus classified as high risk while the median OS of the 30 pts with adv cytogenetics and TP53 mutations was only 5.4 months, defining very high risk disease. This stratification resulted in improved OS prediction compared to the full molecular ELN 2017 (C-index 0.63 vs 0.58, resp). This stratification also predicted Relapse-Free Survival (RFS, Figure, p<0.0001). Censoring at SCT did not affect these results. Conclusion. In AML patients older than 60y treated intensively, mutations in 7 genes (NPM1, SRSF2, FLT3, DNMT3A, ASLX1, NRAS and TP53) can refine the prognosis of cytogenetic sub-groups. Figure Figure. Disclosures Cluzeau: MENARINI: Consultancy; CELGENE: Consultancy; JAZZ PHARMA: Consultancy.

scholarly journals Algorithm of molecular genetic investigation to identify hereditary BRCA-associated breast cancer

2019 ◽  
Vol 47 (1) ◽  
pp. 54-65 ◽  
Author(s):  
G. P. Snigireva ◽  
V. A. Rumyantseva ◽  
E. I. Novikova ◽  
N. N. Novitskaya ◽  
E. N. Telysheva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Real Time ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Hereditary Disease ◽  
Russian Population ◽  
Molecular Genetic Testing ◽  
Second Stage ◽  
Hereditary Nature

Background: About 30%  of cases of hereditary breast cancer (BC) are associated with the BRCA1 and BRCA2 gene mutations. The absence of the programs of mandatory genetic screening for hereditary BRCA-associated BC in Russia, as well as of an algorithm for molecular genetic testing does not allow fully accomplishing the necessary preventive, diagnostic and medical measures.Aim: To elaborate an algorithm for molecular genetic testing of BC patients in order to improve the efficacy of identification of the hereditary nature of the disease.Materials and methods: The study is based on the analysis of the results of molecular genetic testing of 3826 BC patients aged from 22 to 90 years, who were examined and treated in the Russian Research Center of Roentgenoradiology (Moscow) from 2010 to 2016. At the first stage of the study, germinal mutation in the BRCA1 and BRCA2 genes prevalent in the Russian population were identified by the real-time polymerase chain reaction (PCR). At the second stage, we searched for rare genetic variants of these genes by the ‘next generation sequencing’ (NGS) method.Results: The real-time PCR (the first stage) showed that the prevalence of the most typical for the Russian population mutations in the BRCA1 gene, associated with BC risk, was 3.5% (132/3826 BC patients). No carriers of the BRCA2 mutations were identified. Based on the analysis of a  questionnaire survey and primary medical documentation, a group of 717 patients was selected from the total cohort, who had clinical features of the hereditary disease (CFHD). In this group, the BRCA1 and BRCA2 gene mutations were found in 126 patients (17.6%). At the second stage, a group of 193 patients with CFHD and no BRCA1 and BRCA2 mutations prevalent in the Russian population was investigated by NGS. Rare pathogenic mutations of these genes were found in 27  patients (14%). In total, it may be concluded that at least 30% of the BC patients with CFHD have germinal mutations in the BRCA1 and BRCA2 genes. Based on the data obtained, we have developed the algorithm of molecular genetic testing of BC patients aimed at identification of the hereditary nature of the disease.Conclusion: The high frequency of mutations in the BRCA1 and BRCA2 genes found in this study in BC patients with CFHD confirms the necessity of genetic testing for this hereditary disease. The information on its hereditary nature allows for the introduction of essential therapy modification with a personalized approach. Regular follow-up of patients with hereditary BC and prevention of new BC cases and other cancers (ovarian, gastric, pancreatic and prostate cancer, as well as melanoma) in their relatives with BRCA1 and BRCA2 mutations have to be implemented by a multidisciplinary team (specialists in mammology, gynecology, oncology, medical genetics, chemotherapy and psychotherapy). 

scholarly journals The Importance of Extended Analysis Using Current Molecular Genetic Methods Based on the Example of a Cohort of 228 Patients with Hereditary Breast and Ovarian Cancer Syndrome

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1483
Author(s):  
Luise D. Resch ◽  
Alrun Hotz ◽  
Andreas D. Zimmer ◽  
Katalin Komlosi ◽  
Nina Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
High Risk ◽  
Molecular Genetic ◽  
Pathogenic Variant ◽  
Molecular Diagnostic ◽  
Cancer Syndrome ◽  
Breast And Ovarian Cancer ◽  
Extended Analysis ◽  
Pathogenic Gene

In about 20–30% of all women with breast cancer, an increased number of cases of breast cancer can be observed in their family history. However, currently, only 5–10% of all breast cancer cases can be attributed to a pathogenic gene alteration. Molecular genetic diagnostics underwent enormous development within the last 10 years. Next-generation sequencing approaches allow increasingly extensive analyses resulting in the identification of additional candidate genes. In the present work, the germline molecular diagnostic analysis of a cohort of 228 patients with suspected hereditary breast and ovarian cancer syndrome (HBOC) was evaluated. The 27 pathogenic gene variants initially detected are listed, and their distribution in the high-risk BRCA1 and BRCA2 genes is presented in this study. In ten high-risk patients, in whom, to date, no pathogenic variant could be detected, an extended genetic analysis of previously not considered risk genes was performed. Three variants of uncertain significance and one pathogenic variant could be described. This proves the importance of extended analysis using current molecular genetic methods.

Identifying Ultra-High Risk Myeloma By Integrated Molecular Genetic and Gene Expression Profiling

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4407-4407 ◽  
Author(s):  
Amy L Sherborne ◽  
Dil B Begum ◽  
Amy Price ◽  
David C Johnson ◽  
Sidra Ellis ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Research Funding ◽  
Molecular Genetic ◽  
High Risk Group ◽  
Risk Status ◽  
Risk Profiling ◽  
High Risk Disease ◽  
Ultra High Risk ◽  
Support Research

Abstract Introduction A significant proportion of myeloma patients relapse early and show short survival with current therapies. Molecular diagnostic tools are needed to identify these high risk patients at diagnosis to stratify treatment and offer the prospect of improving outcomes. Two validated molecular approaches for risk prediction are widely used: 1) molecular genetic risk profiling [e.g. del(17p), t(4;14)] 2) gene expression (GEP) risk profiling, [e.g. EMC92 (Kuiper et al., Leukemia 2012)]. We profiled patients from a large multicentric UK National trial using both approaches for integrated risk stratification. Methods A representative group of 221 newly diagnosed, transplant eligible patients (median age 64 years) treated on the UK NCRI Myeloma XI trial were molecularly profiled. DNA and RNA were extracted from immunomagnetically CD138-sorted bone marrow plasma cells. Molecular genetic profiles, including t(4;14), t(14;16), Del(17p), Gain(1q) were generated using MLPA (MRC Holland) and a TC-classification based qRT-PCR assay (Boyle EM, et al., Gen Chrom Canc 2015, Kaiser MF, et al., Leukemia 2013). GEP risk status as per EMC92 was profiled on a diagnostic Affymetrix platform using the U133plus2.0-based, CE-marked MMprofiler (SkylineDx) which generates a standardised EMC92 risk score, called 'SKY92'. Progression-free (PFS) and overall survival (OS) were measured from initial randomization and median follow-up for the analysed group was 36 months. Statistical analyses were performed using R 3.3.0 and the 'survival' package. Results were confirmed in an independent dataset, MRC Myeloma IX, for which median follow-up was 82.7 months. Results Of the 221 analysed patients, 116 were found to carry an established genetic high risk lesion [t(4;14), t(14;16), del(17p) or gain(1q)]. We and others have recently demonstrated that adverse lesions have an additive effect and that co-occurrence of ≥2 high risk lesions is specifically associated with adverse outcome (Boyd KD et al, Leukemia 2011). 39/221 patients (17.6%) were identified as genetic high risk with ≥2 risk lesions (termed HR2). By GEP, 53/221 patients (24.0%) were identified as SKY92 high risk. Genetic and GEP high risk co-occurred in 22 patients (10.0%), 31 patients (14.0%) were high risk only by GEP and 17 patients (7.7%) by genetics only. SKY92 high risk status was associated with significantly shorter PFS (median 17.1 vs. 34.3 months; P<0.0001; Hazard ratio [HR] 3.2 [95%CI: 2.2-4.7]) and OS (median 36.0 vs. not reached; P<0.0001; HR 3.9 [2.3-6.9]). Genetic risk by HR2 was similarly associated with adverse outcome: median PFS 17.0 vs. 33.6 months; P<0.0001; HR 2.9 [1.9-4.4]), median OS 33.5 vs. not reached; P<0.0001; HR 4.1 [2.3-7.2]). Importantly, by multivariate analysis GEP and genetic high risk status were independently associated with shorter PFS (P<0.001) and OS (P<0.005). We next investigated interactions between genetic and gene expression high risk status. Three groups were defined: 1) Patients with both SKY92 and genetic (HR2) high risk status (n=22), 2) either GEP or genetic high risk (n=48) or 3) absence of GEP or genetic (HR2) high risk status (n=151). Co-occurring GEP and genetic high risk status was associated with very short PFS (median 12.5 vs. 20.0 vs. 38.3 months; P<0.0001) and OS (median 25.6 vs. 47.3 vs. not reached; P<0.0001) [Figure]. When comparing this ultra-high risk group against the remainder of cases (n=199), their risk of progressing and dying early was significantly elevated (PFS HR 4.4 [2.5-6.7]; OS HR 5.9 [3.1-11.0]). We confirmed this finding in 116 transplant-eligible patients from the MRC Myeloma IX trial. Patients carrying both EMC92 and genetic high risk status had a median PFS of 7.8 vs. 25.5 months and median OS of 9.5 vs. 62.1 months (both P<0.0001). Moreover, all patients in this ultra-high risk group progressed within 24 months and died within 48 months. Conclusion We demonstrate, for the first time, that combined genetic and gene expression risk profiling identifies a group of patients with ultra-high risk disease behaviour with high fidelity, using molecular features of the disease. Our results indicate that GEP and genetic high risk profiling identify independently relevant, but inter-related features of high risk disease biology. Integrated genetic and gene expression risk profiling could serve as a valuable tool for risk stratified, innovative treatment approaches in myeloma. Figure Figure. Disclosures Jones: Celgene: Honoraria, Research Funding. Pawlyn:Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding. Cook:Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Davies:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Morgan:Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Jackson:Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Kaiser:Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; BMS: Consultancy, Other: Travel Support; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy.

scholarly journals Prevalence of BRCA1 and BRCA2 gene mutations in Chinese patients with high‐risk breast cancer

2019 ◽  
Vol 7 (6) ◽  
Author(s):  
Xiaozhen Wang ◽  
Haimeng Liu ◽  
Amina Maimaitiaili ◽  
Gang Zhao ◽  
Sijie Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Gene Mutations ◽  
Brca2 Gene ◽  
Chinese Patients ◽  
Brca1 And Brca2 ◽  
High Risk Breast Cancer ◽  
High Risk Breast ◽  
Risk Breast Cancer
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