Clinical testing of patients for hereditary breast and ovarian cancer syndromes began in the mid-1990s with the identification of the BRCA1 and BRCA2 genes.Since then,mutations in dozens of other genes have been corre...Clinical testing of patients for hereditary breast and ovarian cancer syndromes began in the mid-1990s with the identification of the BRCA1 and BRCA2 genes.Since then,mutations in dozens of other genes have been correlated to increased breast,ovarian,and other cancer risk.The following decades of data collection and patient advocacy allowed for improvements in medical,legal,social,and ethical advances in genetic testing.Technological advances have made it possible to sequence multiple genes at once in a panel to give patients a more thorough evaluation of their personal cancer risk.Panel testing increases the detection of mutations that lead to increased risk of breast,ovarian,and other cancers and can better guide individualized screening measures compared to limited BRCA testing alone.At the same time,multi-gene panel testing is more time-and cost-efficient.While the clinical application of panel testing is in its infancy,many problems arise such as lack of guidelines for management of newly identified gene mutations,high rates of variants of uncertain significance,and limited ability to screen for some cancers.Through on-going concerted efforts of pooled data collection and analysis,it is likely that the benefits of multi-gene panel testing will outweigh the risks in the near future.展开更多
Background Circulating cell-free tumor DNA(ctDNA)provides a non-invasive approach for assessing somatic alterations.The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integr...Background Circulating cell-free tumor DNA(ctDNA)provides a non-invasive approach for assessing somatic alterations.The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice.In this context,ctDNA testing was included to understand the motivations of clinicians to initiate testing,to identify somatic alterations,and to assess the clinical impact of the results obtained.Methods Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting(PRAEGNANT study;NCT02338167).The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations.A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results.Results ctDNA from 49 patients was analyzed prospectively:37(76%)had at least one somatic alteration in the analyzed geneset;14 patients(29%)harbored alterations in TP53,12(24%)in PIK3CA,and 6(12%)in ESR1.Somatic mutations in BRCA1 or BRCA2 were detected in 3(6%)and 4(8%)patients,respectively,and 59%of patients had hormone receptor-positive,human epidermal growth factor receptor 2-negative breast cancer.Questionnaires regarding test intentions and clinical impact were completed for 48(98%)patients.These showed that ctDNA testing influenced treatment decisions for 35%of patients.Discussion The high prevalence of somatic alterations in TP53,PIK3CA,ESR1,and BRCA1/2 genes,identified by ctDNA genotyping,highlights their potential as biomarkers for targeted therapies.Detection of specific mutations affected treatment decisions,such as eligibility for alpelisib,and might further facilitate treatment with e.g.elacestrant or capiversatib in future treatment lines.展开更多
文摘Clinical testing of patients for hereditary breast and ovarian cancer syndromes began in the mid-1990s with the identification of the BRCA1 and BRCA2 genes.Since then,mutations in dozens of other genes have been correlated to increased breast,ovarian,and other cancer risk.The following decades of data collection and patient advocacy allowed for improvements in medical,legal,social,and ethical advances in genetic testing.Technological advances have made it possible to sequence multiple genes at once in a panel to give patients a more thorough evaluation of their personal cancer risk.Panel testing increases the detection of mutations that lead to increased risk of breast,ovarian,and other cancers and can better guide individualized screening measures compared to limited BRCA testing alone.At the same time,multi-gene panel testing is more time-and cost-efficient.While the clinical application of panel testing is in its infancy,many problems arise such as lack of guidelines for management of newly identified gene mutations,high rates of variants of uncertain significance,and limited ability to screen for some cancers.Through on-going concerted efforts of pooled data collection and analysis,it is likely that the benefits of multi-gene panel testing will outweigh the risks in the near future.
文摘Background Circulating cell-free tumor DNA(ctDNA)provides a non-invasive approach for assessing somatic alterations.The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice.In this context,ctDNA testing was included to understand the motivations of clinicians to initiate testing,to identify somatic alterations,and to assess the clinical impact of the results obtained.Methods Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting(PRAEGNANT study;NCT02338167).The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations.A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results.Results ctDNA from 49 patients was analyzed prospectively:37(76%)had at least one somatic alteration in the analyzed geneset;14 patients(29%)harbored alterations in TP53,12(24%)in PIK3CA,and 6(12%)in ESR1.Somatic mutations in BRCA1 or BRCA2 were detected in 3(6%)and 4(8%)patients,respectively,and 59%of patients had hormone receptor-positive,human epidermal growth factor receptor 2-negative breast cancer.Questionnaires regarding test intentions and clinical impact were completed for 48(98%)patients.These showed that ctDNA testing influenced treatment decisions for 35%of patients.Discussion The high prevalence of somatic alterations in TP53,PIK3CA,ESR1,and BRCA1/2 genes,identified by ctDNA genotyping,highlights their potential as biomarkers for targeted therapies.Detection of specific mutations affected treatment decisions,such as eligibility for alpelisib,and might further facilitate treatment with e.g.elacestrant or capiversatib in future treatment lines.
