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Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer
Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this...
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| Published in: | JNCI : Journal of the National Cancer Institute 2017-07, Vol.109 (7) |
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| creator | Goetz, Matthew P Kalari, Krishna R Suman, Vera J Moyer, Ann M Yu, Jia Visscher, Daniel W Dockter, Travis J Vedell, Peter T Sinnwell, Jason P Tang, Xiaojia Thompson, Kevin J McLaughlin, Sarah A Moreno-Aspitia, Alvaro Copland, John A Northfelt, Donald W Gray, Richard J Hunt, Katie Conners, Amy Sicotte, Hugues Eckel-Passow, Jeanette E Kocher, Jean-Pierre Ingle, James N Ellingson, Marissa S McDonough, Michelle Wieben, Eric D Weinshilboum, Richard Wang, Liewei Boughey, Judy C |
| description | Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown.
We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery.
Recurrent "targetable" alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance ( p53, AKT, and IKBKE ). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs.
In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. "Targetable" alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development. |
| doi_str_mv | 10.1093/jnci/djw306 |
| format | article |
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We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery.
Recurrent "targetable" alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance ( p53, AKT, and IKBKE ). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs.
In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. "Targetable" alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development.</description><identifier>ISSN: 0027-8874</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djw306</identifier><identifier>PMID: 28376176</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Adult ; Aged ; Animals ; Antineoplastic Agents - therapeutic use ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Chemotherapy, Adjuvant ; Exome - genetics ; Female ; Humans ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Middle Aged ; Mutation ; Neoadjuvant Therapy ; Prospective Studies ; Sequence Analysis, DNA - methods ; Treatment Outcome ; Triple Negative Breast Neoplasms - drug therapy ; Triple Negative Breast Neoplasms - genetics ; Triple Negative Breast Neoplasms - metabolism ; Tumor Suppressor Protein p53 - genetics ; Xenograft Model Antitumor Assays - methods</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2017-07, Vol.109 (7)</ispartof><rights>The Author, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com</rights><rights>The Author, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-bf859545b210f25c8bb2d17a15f6ed5b7e21a76b1ce63ac8ffd207cd156a75463</citedby><cites>FETCH-LOGICAL-c489t-bf859545b210f25c8bb2d17a15f6ed5b7e21a76b1ce63ac8ffd207cd156a75463</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28376176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goetz, Matthew P</creatorcontrib><creatorcontrib>Kalari, Krishna R</creatorcontrib><creatorcontrib>Suman, Vera J</creatorcontrib><creatorcontrib>Moyer, Ann M</creatorcontrib><creatorcontrib>Yu, Jia</creatorcontrib><creatorcontrib>Visscher, Daniel W</creatorcontrib><creatorcontrib>Dockter, Travis J</creatorcontrib><creatorcontrib>Vedell, Peter T</creatorcontrib><creatorcontrib>Sinnwell, Jason P</creatorcontrib><creatorcontrib>Tang, Xiaojia</creatorcontrib><creatorcontrib>Thompson, Kevin J</creatorcontrib><creatorcontrib>McLaughlin, Sarah A</creatorcontrib><creatorcontrib>Moreno-Aspitia, Alvaro</creatorcontrib><creatorcontrib>Copland, John A</creatorcontrib><creatorcontrib>Northfelt, Donald W</creatorcontrib><creatorcontrib>Gray, Richard J</creatorcontrib><creatorcontrib>Hunt, Katie</creatorcontrib><creatorcontrib>Conners, Amy</creatorcontrib><creatorcontrib>Sicotte, Hugues</creatorcontrib><creatorcontrib>Eckel-Passow, Jeanette E</creatorcontrib><creatorcontrib>Kocher, Jean-Pierre</creatorcontrib><creatorcontrib>Ingle, James N</creatorcontrib><creatorcontrib>Ellingson, Marissa S</creatorcontrib><creatorcontrib>McDonough, Michelle</creatorcontrib><creatorcontrib>Wieben, Eric D</creatorcontrib><creatorcontrib>Weinshilboum, Richard</creatorcontrib><creatorcontrib>Wang, Liewei</creatorcontrib><creatorcontrib>Boughey, Judy C</creatorcontrib><title>Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>J Natl Cancer Inst</addtitle><description>Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown.
We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery.
Recurrent "targetable" alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance ( p53, AKT, and IKBKE ). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs.
In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. "Targetable" alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development.</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Chemotherapy, Adjuvant</subject><subject>Exome - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Mice, Inbred NOD</subject><subject>Mice, Knockout</subject><subject>Mice, SCID</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Neoadjuvant Therapy</subject><subject>Prospective Studies</subject><subject>Sequence Analysis, DNA - methods</subject><subject>Treatment Outcome</subject><subject>Triple Negative Breast Neoplasms - drug therapy</subject><subject>Triple Negative Breast Neoplasms - genetics</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Xenograft Model Antitumor Assays - methods</subject><issn>0027-8874</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpVkc2LFDEQxYMo7rh68i45CtJuks5XXwQdP2FRwRG8SEgnldkeppPdJD3if2-GWRetS1HU49Wjfgg9peQlJUN_sYtuuvC7Xz2R99CKckk6Rom4j1aEMNVprfgZelTKjrQaGH-IzpjulaRKrtDPzTKnjL_BzQLNJ26xjR5_tXWCWLu3kKcDePwDYtpmG2rBU8T1CvBnSNbvloONFW8y2Do3PU4Bv2lDqXhto4P8GD0Idl_gyW0_R9_fv9usP3aXXz58Wr--7BzXQ-3GoMUguBhb7sCE0-PIPFWWiiDBi1EBo1bJkTqQvXU6BM-Icp4KaZXgsj9Hr06-18s4g3ctS7Z7c52n2ebfJtnJ_L-J05XZpoMRnOhBD83g-a1BTu0TpZp5Kg72exshLcVQrTmXjPXHWy9OUpdTKRnC3RlKzBGIOQIxJyBN_ezfZHfavwT6P_J0ikI</recordid><startdate>20170701</startdate><enddate>20170701</enddate><creator>Goetz, Matthew P</creator><creator>Kalari, Krishna R</creator><creator>Suman, Vera J</creator><creator>Moyer, Ann M</creator><creator>Yu, Jia</creator><creator>Visscher, Daniel W</creator><creator>Dockter, Travis J</creator><creator>Vedell, Peter T</creator><creator>Sinnwell, Jason P</creator><creator>Tang, Xiaojia</creator><creator>Thompson, Kevin J</creator><creator>McLaughlin, Sarah A</creator><creator>Moreno-Aspitia, Alvaro</creator><creator>Copland, John A</creator><creator>Northfelt, Donald W</creator><creator>Gray, Richard J</creator><creator>Hunt, Katie</creator><creator>Conners, Amy</creator><creator>Sicotte, Hugues</creator><creator>Eckel-Passow, Jeanette E</creator><creator>Kocher, Jean-Pierre</creator><creator>Ingle, James N</creator><creator>Ellingson, Marissa S</creator><creator>McDonough, Michelle</creator><creator>Wieben, Eric D</creator><creator>Weinshilboum, Richard</creator><creator>Wang, Liewei</creator><creator>Boughey, Judy C</creator><general>Oxford University Press</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170701</creationdate><title>Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer</title><author>Goetz, Matthew P ; Kalari, Krishna R ; Suman, Vera J ; Moyer, Ann M ; Yu, Jia ; Visscher, Daniel W ; Dockter, Travis J ; Vedell, Peter T ; Sinnwell, Jason P ; Tang, Xiaojia ; Thompson, Kevin J ; McLaughlin, Sarah A ; Moreno-Aspitia, Alvaro ; Copland, John A ; Northfelt, Donald W ; Gray, Richard J ; Hunt, Katie ; Conners, Amy ; Sicotte, Hugues ; Eckel-Passow, Jeanette E ; Kocher, Jean-Pierre ; Ingle, James N ; Ellingson, Marissa S ; McDonough, Michelle ; Wieben, Eric D ; Weinshilboum, Richard ; Wang, Liewei ; Boughey, Judy C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-bf859545b210f25c8bb2d17a15f6ed5b7e21a76b1ce63ac8ffd207cd156a75463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Antineoplastic Agents - 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Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown.
We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery.
Recurrent "targetable" alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance ( p53, AKT, and IKBKE ). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs.
In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. "Targetable" alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>28376176</pmid><doi>10.1093/jnci/djw306</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8874 |
| ispartof | JNCI : Journal of the National Cancer Institute, 2017-07, Vol.109 (7) |
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| language | eng |
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| source | Oxford Academic Journals (OUP) |
| subjects | Adult Aged Animals Antineoplastic Agents - therapeutic use Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Chemotherapy, Adjuvant Exome - genetics Female Humans Mice, Inbred NOD Mice, Knockout Mice, SCID Middle Aged Mutation Neoadjuvant Therapy Prospective Studies Sequence Analysis, DNA - methods Treatment Outcome Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Tumor Suppressor Protein p53 - genetics Xenograft Model Antitumor Assays - methods |
| title | Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer |
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