Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer
Background Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods Patients with mCRPC underwent c...
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| Veröffentlicht in: | Cancer 2019-05, Vol.125 (9), p.1459-1469 |
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| creator | Sonpavde, Guru Agarwal, Neeraj Pond, Gregory Russell Nagy, Rebecca J. Nussenzveig, Roberto H. Hahn, Andrew W. Sartor, Oliver Gourdin, Theodore Stewart Nandagopal, Lakshminarayanan Ledet, Elisa M. Naik, Gurudatta Armstrong, Andrew J. Wang, Jue Bilen, Mehmet Asim Gupta, Shilpa Grivas, Petros Pal, Sumanta K. Lanman, Richard B. Talasaz, AmirAli Lilly, Michael B. |
| description | Background
Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.
Methods
Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer‐associated genes. Clinical factors, therapy information, failure‐free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.
Results
Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta‐1 (CTNNB1), and AT‐rich interactive domain‐containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure‐free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.
Conclusions
ctDNA frequently was detected in this large cohort of “real‐world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.
Circulating tumor DNA frequently is detected in patients with advanced prostate cancer, and alterations are similar to those noted in tumor tissue. Androgen receptor alterations frequently evolve, and are associated with poor outcomes. |
| doi_str_mv | 10.1002/cncr.31959 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2165055351</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2165055351</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3939-2fa780e2667412e3ba40f99df3e2a66881c6bcade04398a6b9f574b254a7e5ed3</originalsourceid><addsrcrecordid>eNp9kMtKxTAURYMoen1M_AAJOBGhmkfTNkOpTxAFUXAW0vRUK216TVLEmZ_gN_ol5lp14MBRTnYWO8lCaJuSA0oIOzTWuANOpZBLaEaJzBNCU7aMZoSQIhEpv19D694_xW3OBF9Fa5xkjHBJZ6guW2fGTofWPuAw9oPDx1dHWHcBXAwH63Fr8TyOYIPHL214xD0E7UOMDDZxmLiPt3cHvo25DXjuhgUA8dwacJtopdGdh63vdQPdnZ7clufJ5fXZRXl0mRguuUxYo_OCAMuyPKUMeKVT0khZNxyYzrKioCarjK6BpFwWOqtkI_K0YiLVOQio-Qbam3rj_c8j-KD61hvoOm1hGL1iNBNECC5oRHf_oE_D6Gx8nWIsWqUiZQtqf6JM_JB30Ki5a3vtXhUlauFeLdyrL_cR3vmuHKse6l_0R3YE6AS8tB28_lOlyqvyZir9BMQukN0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2210015421</pqid></control><display><type>article</type><title>Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Sonpavde, Guru ; Agarwal, Neeraj ; Pond, Gregory Russell ; Nagy, Rebecca J. ; Nussenzveig, Roberto H. ; Hahn, Andrew W. ; Sartor, Oliver ; Gourdin, Theodore Stewart ; Nandagopal, Lakshminarayanan ; Ledet, Elisa M. ; Naik, Gurudatta ; Armstrong, Andrew J. ; Wang, Jue ; Bilen, Mehmet Asim ; Gupta, Shilpa ; Grivas, Petros ; Pal, Sumanta K. ; Lanman, Richard B. ; Talasaz, AmirAli ; Lilly, Michael B.</creator><creatorcontrib>Sonpavde, Guru ; Agarwal, Neeraj ; Pond, Gregory Russell ; Nagy, Rebecca J. ; Nussenzveig, Roberto H. ; Hahn, Andrew W. ; Sartor, Oliver ; Gourdin, Theodore Stewart ; Nandagopal, Lakshminarayanan ; Ledet, Elisa M. ; Naik, Gurudatta ; Armstrong, Andrew J. ; Wang, Jue ; Bilen, Mehmet Asim ; Gupta, Shilpa ; Grivas, Petros ; Pal, Sumanta K. ; Lanman, Richard B. ; Talasaz, AmirAli ; Lilly, Michael B.</creatorcontrib><description>Background
Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.
Methods
Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer‐associated genes. Clinical factors, therapy information, failure‐free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.
Results
Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta‐1 (CTNNB1), and AT‐rich interactive domain‐containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure‐free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.
Conclusions
ctDNA frequently was detected in this large cohort of “real‐world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.
Circulating tumor DNA frequently is detected in patients with advanced prostate cancer, and alterations are similar to those noted in tumor tissue. Androgen receptor alterations frequently evolve, and are associated with poor outcomes.</description><identifier>ISSN: 0008-543X</identifier><identifier>ISSN: 1097-0142</identifier><identifier>EISSN: 1097-0142</identifier><identifier>DOI: 10.1002/cncr.31959</identifier><identifier>PMID: 30620391</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Adenomatous polyposis coli ; Aged ; Aged, 80 and over ; Amplification ; Androgen receptors ; Biological evolution ; Biomarkers, Tumor - analysis ; Biomarkers, Tumor - blood ; Biomarkers, Tumor - genetics ; BRCA1 protein ; BRCA2 protein ; Breast cancer ; Cancer ; Castration ; castration resistant ; Catalysis ; circulating tumor DNA (ctDNA) ; Circulating Tumor DNA - analysis ; Circulating Tumor DNA - blood ; Circulating Tumor DNA - genetics ; Clinical outcomes ; Colorectal cancer ; Deoxyribonucleic acid ; DNA ; DNA Copy Number Variations ; Epidermal growth factor ; Epidermal growth factor receptors ; Evolutionary genetics ; Failure analysis ; failure‐free survival ; Genes ; Genetic disorders ; genomic profiling ; Growth factors ; Humans ; Immune checkpoint inhibitors ; Inhibitors ; Kinases ; Male ; Metastases ; Metastasis ; metastatic ; Middle Aged ; Mutation ; Myc protein ; Neoplasm Metastasis ; Neurofibromin 1 ; Oncology ; p53 Protein ; Patients ; Phosphatidylinositol ; Polyposis coli ; Polyps ; Prognosis ; Prostate cancer ; Prostatic Neoplasms, Castration-Resistant - genetics ; Prostatic Neoplasms, Castration-Resistant - mortality ; Prostatic Neoplasms, Castration-Resistant - pathology ; Prostatic Neoplasms, Castration-Resistant - therapy ; Proteins ; Retrospective Studies ; Survival ; Survival Analysis ; Therapy ; Tumors</subject><ispartof>Cancer, 2019-05, Vol.125 (9), p.1459-1469</ispartof><rights>2019 American Cancer Society</rights><rights>2019 American Cancer Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3939-2fa780e2667412e3ba40f99df3e2a66881c6bcade04398a6b9f574b254a7e5ed3</citedby><cites>FETCH-LOGICAL-c3939-2fa780e2667412e3ba40f99df3e2a66881c6bcade04398a6b9f574b254a7e5ed3</cites><orcidid>0000-0001-7012-1754 ; 0000-0001-7265-6605 ; 0000-0002-1712-0848 ; 0000-0003-2612-1348 ; 0000-0002-4153-205X ; 0000-0003-4003-1103 ; 0000-0001-8122-4329</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcncr.31959$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcncr.31959$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27903,27904,45553,45554,46387,46811</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30620391$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sonpavde, Guru</creatorcontrib><creatorcontrib>Agarwal, Neeraj</creatorcontrib><creatorcontrib>Pond, Gregory Russell</creatorcontrib><creatorcontrib>Nagy, Rebecca J.</creatorcontrib><creatorcontrib>Nussenzveig, Roberto H.</creatorcontrib><creatorcontrib>Hahn, Andrew W.</creatorcontrib><creatorcontrib>Sartor, Oliver</creatorcontrib><creatorcontrib>Gourdin, Theodore Stewart</creatorcontrib><creatorcontrib>Nandagopal, Lakshminarayanan</creatorcontrib><creatorcontrib>Ledet, Elisa M.</creatorcontrib><creatorcontrib>Naik, Gurudatta</creatorcontrib><creatorcontrib>Armstrong, Andrew J.</creatorcontrib><creatorcontrib>Wang, Jue</creatorcontrib><creatorcontrib>Bilen, Mehmet Asim</creatorcontrib><creatorcontrib>Gupta, Shilpa</creatorcontrib><creatorcontrib>Grivas, Petros</creatorcontrib><creatorcontrib>Pal, Sumanta K.</creatorcontrib><creatorcontrib>Lanman, Richard B.</creatorcontrib><creatorcontrib>Talasaz, AmirAli</creatorcontrib><creatorcontrib>Lilly, Michael B.</creatorcontrib><title>Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer</title><title>Cancer</title><addtitle>Cancer</addtitle><description>Background
Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.
Methods
Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer‐associated genes. Clinical factors, therapy information, failure‐free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.
Results
Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta‐1 (CTNNB1), and AT‐rich interactive domain‐containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure‐free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.
Conclusions
ctDNA frequently was detected in this large cohort of “real‐world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.
Circulating tumor DNA frequently is detected in patients with advanced prostate cancer, and alterations are similar to those noted in tumor tissue. Androgen receptor alterations frequently evolve, and are associated with poor outcomes.</description><subject>Adenomatous polyposis coli</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Amplification</subject><subject>Androgen receptors</subject><subject>Biological evolution</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Biomarkers, Tumor - blood</subject><subject>Biomarkers, Tumor - genetics</subject><subject>BRCA1 protein</subject><subject>BRCA2 protein</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Castration</subject><subject>castration resistant</subject><subject>Catalysis</subject><subject>circulating tumor DNA (ctDNA)</subject><subject>Circulating Tumor DNA - analysis</subject><subject>Circulating Tumor DNA - blood</subject><subject>Circulating Tumor DNA - genetics</subject><subject>Clinical outcomes</subject><subject>Colorectal cancer</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Copy Number Variations</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Evolutionary genetics</subject><subject>Failure analysis</subject><subject>failure‐free survival</subject><subject>Genes</subject><subject>Genetic disorders</subject><subject>genomic profiling</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Immune checkpoint inhibitors</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>metastatic</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Myc protein</subject><subject>Neoplasm Metastasis</subject><subject>Neurofibromin 1</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Phosphatidylinositol</subject><subject>Polyposis coli</subject><subject>Polyps</subject><subject>Prognosis</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms, Castration-Resistant - genetics</subject><subject>Prostatic Neoplasms, Castration-Resistant - mortality</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Prostatic Neoplasms, Castration-Resistant - therapy</subject><subject>Proteins</subject><subject>Retrospective Studies</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Therapy</subject><subject>Tumors</subject><issn>0008-543X</issn><issn>1097-0142</issn><issn>1097-0142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtKxTAURYMoen1M_AAJOBGhmkfTNkOpTxAFUXAW0vRUK216TVLEmZ_gN_ol5lp14MBRTnYWO8lCaJuSA0oIOzTWuANOpZBLaEaJzBNCU7aMZoSQIhEpv19D694_xW3OBF9Fa5xkjHBJZ6guW2fGTofWPuAw9oPDx1dHWHcBXAwH63Fr8TyOYIPHL214xD0E7UOMDDZxmLiPt3cHvo25DXjuhgUA8dwacJtopdGdh63vdQPdnZ7clufJ5fXZRXl0mRguuUxYo_OCAMuyPKUMeKVT0khZNxyYzrKioCarjK6BpFwWOqtkI_K0YiLVOQio-Qbam3rj_c8j-KD61hvoOm1hGL1iNBNECC5oRHf_oE_D6Gx8nWIsWqUiZQtqf6JM_JB30Ki5a3vtXhUlauFeLdyrL_cR3vmuHKse6l_0R3YE6AS8tB28_lOlyqvyZir9BMQukN0</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Sonpavde, Guru</creator><creator>Agarwal, Neeraj</creator><creator>Pond, Gregory Russell</creator><creator>Nagy, Rebecca J.</creator><creator>Nussenzveig, Roberto H.</creator><creator>Hahn, Andrew W.</creator><creator>Sartor, Oliver</creator><creator>Gourdin, Theodore Stewart</creator><creator>Nandagopal, Lakshminarayanan</creator><creator>Ledet, Elisa M.</creator><creator>Naik, Gurudatta</creator><creator>Armstrong, Andrew J.</creator><creator>Wang, Jue</creator><creator>Bilen, Mehmet Asim</creator><creator>Gupta, Shilpa</creator><creator>Grivas, Petros</creator><creator>Pal, Sumanta K.</creator><creator>Lanman, Richard B.</creator><creator>Talasaz, AmirAli</creator><creator>Lilly, Michael B.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7012-1754</orcidid><orcidid>https://orcid.org/0000-0001-7265-6605</orcidid><orcidid>https://orcid.org/0000-0002-1712-0848</orcidid><orcidid>https://orcid.org/0000-0003-2612-1348</orcidid><orcidid>https://orcid.org/0000-0002-4153-205X</orcidid><orcidid>https://orcid.org/0000-0003-4003-1103</orcidid><orcidid>https://orcid.org/0000-0001-8122-4329</orcidid></search><sort><creationdate>20190501</creationdate><title>Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer</title><author>Sonpavde, Guru ; Agarwal, Neeraj ; Pond, Gregory Russell ; Nagy, Rebecca J. ; Nussenzveig, Roberto H. ; Hahn, Andrew W. ; Sartor, Oliver ; Gourdin, Theodore Stewart ; Nandagopal, Lakshminarayanan ; Ledet, Elisa M. ; Naik, Gurudatta ; Armstrong, Andrew J. ; Wang, Jue ; Bilen, Mehmet Asim ; Gupta, Shilpa ; Grivas, Petros ; Pal, Sumanta K. ; Lanman, Richard B. ; Talasaz, AmirAli ; Lilly, Michael B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3939-2fa780e2667412e3ba40f99df3e2a66881c6bcade04398a6b9f574b254a7e5ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenomatous polyposis coli</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Amplification</topic><topic>Androgen receptors</topic><topic>Biological evolution</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Biomarkers, Tumor - blood</topic><topic>Biomarkers, Tumor - genetics</topic><topic>BRCA1 protein</topic><topic>BRCA2 protein</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Castration</topic><topic>castration resistant</topic><topic>Catalysis</topic><topic>circulating tumor DNA (ctDNA)</topic><topic>Circulating Tumor DNA - analysis</topic><topic>Circulating Tumor DNA - blood</topic><topic>Circulating Tumor DNA - genetics</topic><topic>Clinical outcomes</topic><topic>Colorectal cancer</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Copy Number Variations</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>Evolutionary genetics</topic><topic>Failure analysis</topic><topic>failure‐free survival</topic><topic>Genes</topic><topic>Genetic disorders</topic><topic>genomic profiling</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Immune checkpoint inhibitors</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Male</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>metastatic</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Myc protein</topic><topic>Neoplasm Metastasis</topic><topic>Neurofibromin 1</topic><topic>Oncology</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Phosphatidylinositol</topic><topic>Polyposis coli</topic><topic>Polyps</topic><topic>Prognosis</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms, Castration-Resistant - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - mortality</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Prostatic Neoplasms, Castration-Resistant - therapy</topic><topic>Proteins</topic><topic>Retrospective Studies</topic><topic>Survival</topic><topic>Survival Analysis</topic><topic>Therapy</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sonpavde, Guru</creatorcontrib><creatorcontrib>Agarwal, Neeraj</creatorcontrib><creatorcontrib>Pond, Gregory Russell</creatorcontrib><creatorcontrib>Nagy, Rebecca J.</creatorcontrib><creatorcontrib>Nussenzveig, Roberto H.</creatorcontrib><creatorcontrib>Hahn, Andrew W.</creatorcontrib><creatorcontrib>Sartor, Oliver</creatorcontrib><creatorcontrib>Gourdin, Theodore Stewart</creatorcontrib><creatorcontrib>Nandagopal, Lakshminarayanan</creatorcontrib><creatorcontrib>Ledet, Elisa M.</creatorcontrib><creatorcontrib>Naik, Gurudatta</creatorcontrib><creatorcontrib>Armstrong, Andrew J.</creatorcontrib><creatorcontrib>Wang, Jue</creatorcontrib><creatorcontrib>Bilen, Mehmet Asim</creatorcontrib><creatorcontrib>Gupta, Shilpa</creatorcontrib><creatorcontrib>Grivas, Petros</creatorcontrib><creatorcontrib>Pal, Sumanta K.</creatorcontrib><creatorcontrib>Lanman, Richard B.</creatorcontrib><creatorcontrib>Talasaz, AmirAli</creatorcontrib><creatorcontrib>Lilly, Michael B.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sonpavde, Guru</au><au>Agarwal, Neeraj</au><au>Pond, Gregory Russell</au><au>Nagy, Rebecca J.</au><au>Nussenzveig, Roberto H.</au><au>Hahn, Andrew W.</au><au>Sartor, Oliver</au><au>Gourdin, Theodore Stewart</au><au>Nandagopal, Lakshminarayanan</au><au>Ledet, Elisa M.</au><au>Naik, Gurudatta</au><au>Armstrong, Andrew J.</au><au>Wang, Jue</au><au>Bilen, Mehmet Asim</au><au>Gupta, Shilpa</au><au>Grivas, Petros</au><au>Pal, Sumanta K.</au><au>Lanman, Richard B.</au><au>Talasaz, AmirAli</au><au>Lilly, Michael B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer</atitle><jtitle>Cancer</jtitle><addtitle>Cancer</addtitle><date>2019-05-01</date><risdate>2019</risdate><volume>125</volume><issue>9</issue><spage>1459</spage><epage>1469</epage><pages>1459-1469</pages><issn>0008-543X</issn><issn>1097-0142</issn><eissn>1097-0142</eissn><abstract>Background
Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.
Methods
Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer‐associated genes. Clinical factors, therapy information, failure‐free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.
Results
Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta‐1 (CTNNB1), and AT‐rich interactive domain‐containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure‐free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.
Conclusions
ctDNA frequently was detected in this large cohort of “real‐world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.
Circulating tumor DNA frequently is detected in patients with advanced prostate cancer, and alterations are similar to those noted in tumor tissue. Androgen receptor alterations frequently evolve, and are associated with poor outcomes.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30620391</pmid><doi>10.1002/cncr.31959</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-7012-1754</orcidid><orcidid>https://orcid.org/0000-0001-7265-6605</orcidid><orcidid>https://orcid.org/0000-0002-1712-0848</orcidid><orcidid>https://orcid.org/0000-0003-2612-1348</orcidid><orcidid>https://orcid.org/0000-0002-4153-205X</orcidid><orcidid>https://orcid.org/0000-0003-4003-1103</orcidid><orcidid>https://orcid.org/0000-0001-8122-4329</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-543X |
| ispartof | Cancer, 2019-05, Vol.125 (9), p.1459-1469 |
| issn | 0008-543X 1097-0142 1097-0142 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2165055351 |
| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adenomatous polyposis coli Aged Aged, 80 and over Amplification Androgen receptors Biological evolution Biomarkers, Tumor - analysis Biomarkers, Tumor - blood Biomarkers, Tumor - genetics BRCA1 protein BRCA2 protein Breast cancer Cancer Castration castration resistant Catalysis circulating tumor DNA (ctDNA) Circulating Tumor DNA - analysis Circulating Tumor DNA - blood Circulating Tumor DNA - genetics Clinical outcomes Colorectal cancer Deoxyribonucleic acid DNA DNA Copy Number Variations Epidermal growth factor Epidermal growth factor receptors Evolutionary genetics Failure analysis failure‐free survival Genes Genetic disorders genomic profiling Growth factors Humans Immune checkpoint inhibitors Inhibitors Kinases Male Metastases Metastasis metastatic Middle Aged Mutation Myc protein Neoplasm Metastasis Neurofibromin 1 Oncology p53 Protein Patients Phosphatidylinositol Polyposis coli Polyps Prognosis Prostate cancer Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - mortality Prostatic Neoplasms, Castration-Resistant - pathology Prostatic Neoplasms, Castration-Resistant - therapy Proteins Retrospective Studies Survival Survival Analysis Therapy Tumors |
| title | Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T01%3A44%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Circulating%20tumor%20DNA%20alterations%20in%20patients%20with%20metastatic%20castration%E2%80%90resistant%20prostate%20cancer&rft.jtitle=Cancer&rft.au=Sonpavde,%20Guru&rft.date=2019-05-01&rft.volume=125&rft.issue=9&rft.spage=1459&rft.epage=1469&rft.pages=1459-1469&rft.issn=0008-543X&rft.eissn=1097-0142&rft_id=info:doi/10.1002/cncr.31959&rft_dat=%3Cproquest_cross%3E2165055351%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2210015421&rft_id=info:pmid/30620391&rfr_iscdi=true |