scholarly journals Adrenocortical Carcinoma Is a Lynch Syndrome–Associated Cancer

2013 ◽  
Vol 31 (24) ◽  
pp. 3012-3018 ◽  
Author(s):  
Victoria M. Raymond ◽  
Jessica N. Everett ◽  
Larissa V. Furtado ◽  
Shanna L. Gustafson ◽  
Chelsy R. Jungbluth ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Genetic Counseling ◽  
Lynch Syndrome ◽  
Adrenocortical Carcinoma ◽  
Cancer Genetics ◽  
Gene Mutations ◽  
Clinical Genetics ◽  
Genetic Risk Assessment ◽  
Group 2 ◽  
Group 1

Purpose Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC. Patients and Methods One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency. Results Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene–positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status. Conclusion The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.

Association between germline DNA damage repair-related genes mutation and tumor mutational burden in lung cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21163-e21163
Author(s):  
Wei Nie ◽  
Hua Zhong ◽  
Ding Zhang ◽  
Shiqing Chen ◽  
Baohui Han
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Gene Mutations ◽  
Related Gene ◽  
Mutational Burden ◽  
Damage Repair ◽  
Tumor Mutational Burden ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P < 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.

scholarly journals Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

2013 ◽  
Vol 169 (3) ◽  
pp. 263-270 ◽  
Author(s):  
M Terzolo ◽  
A E Baudin ◽  
A Ardito ◽  
M Kroiss ◽  
S Leboulleux ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Plasma Concentrations ◽  
Multivariable Analysis ◽  
Radical Resection ◽  
Free Survival ◽  
Risk Of Death ◽  
Radical Removal ◽  
Group 2 ◽  
Group 1

ContextMitotane plasma concentrations ≥14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting.ObjectiveTo compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations ≥14 mg/l vs patients who did not.Design and settingRetrospective analysis at six referral European centers.PatientsPatients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14–20 mg/l.Main outcome measuresRFS (primary) and overall survival (secondary).ResultsOf the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22–0.79; P=0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26–1.34; P=0.20). Grades 3–4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity.ConclusionsMitotane concentrations ≥14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

scholarly journals Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Muhammad Usman Rashid ◽  
Humaira Naeemi ◽  
Noor Muhammad ◽  
Asif Loya ◽  
Jan Lubiński ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Research Centre ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
History Of ◽  
Group 2 ◽  
Colorectal Cancer Patients ◽  
Group 1

Abstract Background Pathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients. Methods Consecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2. Results Eight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected. Conclusion Pathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

scholarly journals Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population

2021 ◽  
Author(s):  
Kathleen F. Mittendorf ◽  
Chinedu Ukaegbu ◽  
Marian J. Gilmore ◽  
Nangel M. Lindberg ◽  
Tia L. Kauffman ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Lynch Syndrome ◽  
Prediction Model ◽  
Underserved Populations ◽  
Gene Mutations ◽  
Family Health ◽  
Family Health History ◽  
Assessment Model ◽  
Health History ◽  
Clinically Significant

AbstractLynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM5™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM5™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM5™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk.

scholarly journals DNA Methylation and Genetic Profiles in 320 Patients with Myelodysplastic Syndromes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1799-1799
Author(s):  
Suguru Morimoto ◽  
Hideki Makishima ◽  
Yasunobu Nagata ◽  
Niroshan Nadarajah ◽  
Constance Baer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Mutations ◽  
Epigenetic Alterations ◽  
Employment Equity ◽  
Group 3 ◽  
Equity Ownership ◽  
Epigenetic Regulators ◽  
Group 2 ◽  
Genetic Profiles ◽  
Group 1

Abstract MDS is a heterogeneous group of myeloid neoplasms caused by genetic and epigenetic alterations. During the past decade, the major driver mutations in MDS have been fully investigated. However, the role of epigenetic alterations, particularly those of DNA methylation, has less intensively been studied, even though abnormal DNA methylation has long been implicated in the pathogenesis of MDS. In this study, we analyzed DNA methylation status of bone marrow mononuclear cells from 320 cases with MDS-SLD (n = 7), MDS-RS (n = 63), MDS-MLD (n = 51), MDS-EB (n = 186), MDS-U (n = 1), and MDS with isolated del(5q) (n = 12), using Illumina 450K methylation array. Mutations in major driver genes (51 genes) and abnormal genomic copy numbers were also interrogated using targeted-capture sequencing. Using unsupervised consensus clustering, we identified 3 subgroups showing unique DNA methylation profiles. Subsequently, we assessed differentially methylated positions (DMPs) associated with each subgroup. Differentially hypermethylated positions (hyper-DMPs) were significantly more enriched in Group 3 (n = 82) (P < 0.001), while differentially hypomethylated positions (hypo-DMPs) were more prominent in Group 1 (n = 125). Group 1 was significantly enriched for SF3B1 (46%) mutations (q < 0.01), while Group 2 (n = 131) was characterized by the enrichment of ASXL1 (38%), RUNX1 (30%), TP53 (26%), STAG2 (15%), and SETBP1 (6.7%) mutations (q < 0.01). In contrast, Group 3 (n = 64) was significantly enriched for TET2 (67%) and IDH1/2 (12% and 15%, respectively) mutations (q < 0.01), suggesting a strong association between DNA methylation and gene mutations. To further elucidate mutation-specific DNA methylation patterns, supervised analysis was performed for each mutation. As expected from their enrichment in Group 3 (q < 0.01), TET2 and IDH1/2 mutations were significantly associated with hyper-DMPs (P < 0.001) involving 1891 and 8330 promotor sites, respectively. Conspicuously, among these hypermethylated promoter sites, >1616 were commonly hypermethylated, strongly supporting the common impact of TET2 and IDH1/2 mutations on deregulated DNA methylation. To clarify prognostic impact of abnormal DNA methylation, we first interrogated the correlation between unique methylation subgroups and revised IPSS. Patients with very low or low risk were significantly dominant (74%) in Group 1 (q < 0.01), and very high or high risk cases were significantly enriched (68%) in Group 2 (q < 0.01). In accordance with this finding, patients in Group 3 showed significantly shorter overall survival (OS) compared to Group 1 (HR: 1.94, 95%CI: 1.11-3.4, P < 0.05) and OS was even worse in Group 2 patients (vs. Group 1: HR: 5.18, 95%CI: 3.21-8.36, P < 0.001). Strong correlations between epigenetic and genetic profiles were further interrogated using a Bayesian statistical model; on the basis of DNA methylation and gene mutations, the original 3 clusters were re-classified into 5 discrete clusters, clusters A, B, C, D, and E (n = 124, 17, 74, 46, and 59, respectively); patients in Group 1 and 3 largely clustered into Cluster A and E, respectively, while Group 2 was further subclassified into clusters B, C, and D. Clusters B and D were characterized by a conspicuos enrichment of DNMT3A (88%) and TP53 (69%) mutations (q < 0.001), while Cluster C was characterized by higher frequency of ASXL1 (71%), RUNX1 (54%), STAG2 (27%), and EZH2 (21%) mutations (q < 0.001). In contrast to significant associations between epigenetic regulators and unique methylation clusters, splice factor mutations tended to be clustered into multiple clusters, depending on type of co-occurring mutations. For example, combined SF3B1 and TET2 mutations (n = 20) were enriched in Cluster A, where highly associated with MDS-RS, while patients with SF3B1 and RUNX1 mutations (n = 9) were more grouped in Cluster C, mostly showing MDS-EB phenotype (89%). Similarly SRSF2 mutations with RUNX1 and/or ASXL1 mutations (n = 36) were enriched in Cluster C, largely associated with MDS-EB phenotype (80%), while those with TET2 or IDH1/2 (n = 39) were mainly grouped into Cluster C, many of which showed MDS-EB phenotype (74%). These findings highlight differential roles of mutated epigenetic regulators and splicing factors in abnormal DNA methylation. In conclusion, we elucidated the collaborative impact of DNA methylation profiles and mutation status on heterogeneous pathogenesis and prognosis in MDS. Figure. Figure. Disclosures Nadarajah: MLL Munich Leukemia Laboratory: Employment. Baer:MLL Munich Leukemia Laboratory: Employment. Nakagawa:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Inagaki:Sumitomo Dainippon Pharma Co., Ltd.: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals A Randomized Trial to Maximize Identification and Genetic Counseling Referral of Women at Risk for Hereditary Breast and Ovarian Cancer

2021 ◽  
pp. 1-8
Author(s):  
Cecelia Bellcross ◽  
Cecelia Bellcross ◽  
April Hermstad ◽  
Christine Tallo ◽  
Chelsea Leonard ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Randomized Trial ◽  
Direct Contact ◽  
Cancer Genetics ◽  
Effective Means ◽  
Screening Mammography ◽  
Screening Tools ◽  
Genetics Referral ◽  
Group 1

Purpose: The Breast Cancer Genetics Referral Screening Tool (B-RST™) has been endorsed as one of several validated screening tools to identify women appropriate for cancer genetics referral. We conducted a randomized trial to determine the most effective means of follow-up for women who screened positive on B-RST™ 3.0. Methods: Women undergoing screening mammography at one of four Emory clinics were approached to complete the B-RST™. Participants who screened positive were randomized to one of three follow-up groups: self-referral (Group 1), electronic health record (EHR) clinician messaging (Group 2), or direct contact (Group 3). We compared genetic counseling appointment scheduling and completion rates by group. Results: Of 2,422 participants, 658 (27.2%) screened positive. Genetic counseling appointments were scheduled by 9.2%, 20.1% and 9.7% of Group 1, 2 and 3 participants respectively (p=0.001). Challenges to scheduling included lack of physician response to EHR messages and unsuccessful direct contact. Among those scheduled (n=78) 70.5% completed the appointment, with no difference between the three groups. Conclusion: B-RST™ can be used effectively in mammography settings to identify high-risk women for cancer genetics referral. Follow-up via EHR appears an acceptable and efficient approach, but additional strategies are needed to facilitate completion of the genetic counseling process.

Coalescence of the German-Austrian and IMRAW Cytogenetic MDS Databases: Modification of Patient Risk Groups.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2468-2468 ◽  
Author(s):  
Christian Steidl ◽  
Julie Schanz ◽  
Michelle M. Le Beau ◽  
John M. Bennett ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Risk Stratification ◽  
Risk Group ◽  
Intermediate Risk ◽  
Risk Patients ◽  
Group 3 ◽  
Group 2 ◽  
Stratification System ◽  
Risk Stratification System ◽  
Group 1

Abstract Introduction The International Prognostic Scoring System (IPSS) for evaluating prognosis in myelodysplastic syndromes (MDS) has been the standard for risk assessment in this disease for the past ten years. Based on a patient cohort comprising 816 primary MDS patients from the IMRAW, a refined bone marrow cytogenetic classification system was introduced. Recently, the GACMSG published cytogenetic data including 1155 primary MDS patients treated with supportive care only. Coalescence of these two large databases offered the opportunity to analyze the cytogenetic data jointly and to propose a modified cytogenetic risk stratification system. Patients and Methods 1971 patients with karyotype and survival data originating from the IMRAW and the GACMSG cohorts were included in this study. The collectives comprised patients with primary MDS treated with supportive care, only allowing short courses of low dose oral chemotherapy or hemopoietic growth factors. By reviewing the ISCN karyotypes, the patients were grouped into cytogenetic categories defined by median survival (MS) (Haase et al, Blood in press). The categories comprised karyotypes with the respective abnormality alone or in combination with one additional anomaly. Karyotypes with 3, or more than 3 abnormalities were considered separate categories. Results We found 15 cytogenetic categories each comprising 10 or more patients. These categories could be combined into 4 prognostic groups according to the MS: Group 1 (MS&gt;3 years): normal karyotype, del(5q), del(12p), del(20q), +21, −Y, −X; Group 2 (1.5–3 years): +1/+1q/t(1q), add(3q)/inv(3q)/del(3q)/t(3q), +8, del(11q); Group 3 (1–1.5 years): 3 anomalies, −7, del(7q); Group 4 (MS&lt;1 year): &gt;3 anomalies. Further stratification of these categories led to a system with 4 distinct risk strata (number of patients): good (1374), int-1 (160), int-2 (99), and poor (166). Only 172 patients (9% of all patients) could not be classified according to this system. Survival analysis of these 4 groups showed distinct MS (Log-rank test: p&lt;0.0001): good, 50 months; int-1, 24 months; int-2, 15 months; poor, 6 months. When combining the non-classified patients into one group MS was 31 months. When comparing this new classification system with the original system defined by the IPSS, 66 formerly intermediate risk patients shifted into the good risk group and 114 poor risk patients into the intermediate risk group. Discussion Combined examination of the two databases introduces 7 new cytogenetic categories with distinct survival times as compared to the IPSS; Group 1: del(12p), +21, −X; Group 2: +1/+1q/t(1q), add(3q)/inv(3q)/del(3q)/t(3q), del(11q); Group 3: 3 anomalies. Based on previously published data, the proposed system combines non-complex karyotypes in one category and distinguishes karyotypes with 3 or more than 3 abnormalities. With respect to future refined integrative scoring in MDS we present an approach that distinguishes groups of intermediate risk and a heterogeneous group of as yet unclassified rare cases harboring uncertain prognoses. In the latter cases, risk assessment should be based on other prognostic parameters rather than assigning an intermediate risk to this group. This new cytogenetic risk stratification system needs to be validated and tested using multivariate approaches.

scholarly journals Sternum Dehiscence: A Preventable Complication of Median Sternotomy

2020 ◽  
Vol 23 (5) ◽  
pp. E599-E605
Author(s):  
Emin Can Ata ◽  
Metin Onur Beyaz
Keyword(s):  
Risk Assessment ◽  
Hospital Costs ◽  
Median Sternotomy ◽  
Sternal Dehiscence ◽  
Patient Dissatisfaction ◽  
Risk Patients ◽  
Group 2 ◽  
Preventable Complication ◽  
Related Mortality ◽  
Group 1

Background: The incidence of sternal dehiscence following cardiothoracic surgery via sternotomy is rare. It causes serious patient dissatisfaction and leads to higher hospital costs. For years, each clinic has made efforts to reduce this complication. Here, we aimed to summarize our techniques to prevent dehiscence. Material: This retrospective study included two groups operated via median sternotomy from March 2009 to May 2019. The first group included 1,105 consecutive patients who only received sternum wire for sternum closure from March 2009 to October 2013. The second group included 1,559 consecutive patients operated from January 2014 to May 2019; preventive closure techniques were performed for predefined high-risk patients in this group. These closure techniques included polyglyconate (Maxon) or simple longitudinal reinforced sutures, sternal cable or sternoband, sternal plate, and Robiscek technique. Results: All patients in Group 1, and 63.8% (995/1559) patients in Group 2 received sternal wire only (P < .001). In Group 2, we applied preventive closure techniques to 564 (36.2%) patients. There was no sternal dehiscence in Group 2, whereas 29 (2.6%) patients postoperatively suffered sternal dehiscence in Group 1; this was statistically significant (P = .001, OR:85.5, 95%CI:5.22-1400.4). The overall incidence of mediastinitis was 0.94%. The incidence significantly was lower in Group 2 (P = .004, OR:3.6, 95%CI:1.52-8.82). Sternum-related mortality in Group 2 also was lower (0.54% versus 0.06%, P = .048, OR:8.5, 95% CI: 1.02-70.75). Conclusion: Sternal dehiscence can be avoided by careful perioperative risk assessment and enhanced closure techniques. The same special consideration may significantly reduce mediastinitis and sternal-related mortality.

scholarly journals Anthracycline-induced cardiotoxicity: molecular and genetic predictors for risk assessment

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Grakova ◽  
S.N Shilov ◽  
E.N Berezikova ◽  
A.A Popova ◽  
M.N Neupokoeva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Assessment ◽  
Protein Gene ◽  
P53 Protein ◽  
Serum Levels ◽  
Polymorphic Marker ◽  
Anthracycline Antibiotics ◽  
Group 2 ◽  
6 Minute Walk Test ◽  
Group 1

Abstract Objective The objective of this study was to evaluate the role of molecular and genetic biomarkers in the development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy. Methods A total of 176 women, median age of 45,0 [42,0; 50,0] years with breast cancer without cardiovascular diseases who received anthracycline antibiotics as part of polychemotherapeutic treatment were enrolled in the study. Two-dimensional transthoracic echocardiography and 6-minute walk test were performed at baseline and at the 12 months after polychemotherapy. Serum levels of NT-proBNP, sFas-L were measured using an enzyme immunoassay after polychemotherapeutic treatment. Evaluation of gene polymorphisms of p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522) and nitric oxide synthase (NOS3, Glu298Asp, rs1799983) were carried out by polymerase chain reaction at baseline. Results After the 12 months of polychemotherapy all patients had breast cancer remission and were divided into 2 groups: group 1 (n=52) comprised patients with anthracycline-induced cardiotoxicity, group 2 (n=124) comprised those without it. After polychemotherapeutic treatment the median value of NT-proBNP in group 1 was higher (p&lt;0,00001) by 52,4% than in group 2 (113 [101,8; 126,15] pg/mL and 53,8 [43,4; 63,0] pg/mL, respectively). The median value of sFas-L in group 1 was higher (p&lt;0,00001) by 44,3% than in group 2 (125,3 [111,85; 133,95] pg/mL and 69,8 [59,8; 77,6] pg/mL, respectively). Based on ROC-analysis, sFas-L concentration of 95.8 pg/mL (sensitivity of 92.2%, specificity of 92.1%, and AUC=0,951; p=0,0001) and NT-proBNP concentration of 71.5 pg/mL (sensitivity of 99.9%, specificity of 91.9%, and AUC=0,951; p=0,0001) were identified as a cut-off values predicting the development of anthracycline-induced cardiotoxicity. The development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy significantly was related to the presence of T/T genotype of NOS3 gene (OR = 3,059; p=0,018) and with Arg/Arg genotype of p53 protein gene (OR = 2,972; p=0,001). While, the presence of Pro/Pro the Pro53 gene genotype of p53 protein gene was related to the absence of anthracycline-induced cardiotoxicity. Conclusion Our data suggest that evaluation of polymorphisms gene of p53 (rs1042522) and NOS3 (rs1799983) can be recommended before polychemotherapy in women with breast cancer for the risk assessment of anthracycline-induced cardiotoxicity. The serum levels of NT-proBNP and sFas-L after polychemotherapy may be considered as non-invasive biomarkers for prediction of the development of anthracycline-induced cardiotoxicity in women with breast cancer during the 12 months after polychemotherapy. Funding Acknowledgement Type of funding source: None

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