Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer

Matthew Philip Goetz, Krishna R Kalari, Vera Jean Suman, Ann Moyer, Jia Yu, Daniel W Visscher, Travis J. Dockter, Peter T. Vedell, Jason P. Sinnwell, Xiaojia Tang, Kevin J. Thompson, Sarah A. McLaughlin, Alvaro Moreno Aspitia, John A III Copland, Donald W Northfelt, Richard J. Gray, Katie Hunt, Amy Conners, Richard M Weinshilboum, Liewei M WangEric D Wieben

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article numberdjw306
JournalJournal of the National Cancer Institute
Volume109
Issue number7
DOIs
StatePublished - Jul 1 2017

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Neoadjuvant Therapy
Heterografts
Breast Neoplasms
Drug Therapy
Neoplasms
Androgen Receptors
Triple Negative Breast Neoplasms
Pharmaceutical Preparations
Large-Core Needle Biopsy
Mutation
British Columbia
Atlases
Steroid Receptors
Feasibility Studies
Mutation Rate
Up-Regulation
Genome
Prospective Studies
Recurrence

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer. / Goetz, Matthew Philip; Kalari, Krishna R; Suman, Vera Jean; Moyer, Ann; 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 III; Northfelt, Donald W; Gray, Richard J.; Hunt, Katie; Conners, Amy; Weinshilboum, Richard M; Wang, Liewei M; Wieben, Eric D.

In: Journal of the National Cancer Institute, Vol. 109, No. 7, djw306, 01.07.2017.

Research output: Contribution to journalArticle

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abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: 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.",
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T1 - Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer

AU - Goetz, Matthew Philip

AU - Kalari, Krishna R

AU - Suman, Vera Jean

AU - Moyer, Ann

AU - Yu, Jia

AU - Visscher, Daniel W

AU - Dockter, Travis J.

AU - Vedell, Peter T.

AU - Sinnwell, Jason P.

AU - Tang, Xiaojia

AU - Thompson, Kevin J.

AU - McLaughlin, Sarah A.

AU - Moreno Aspitia, Alvaro

AU - Copland, John A III

AU - Northfelt, Donald W

AU - Gray, Richard J.

AU - Hunt, Katie

AU - Conners, Amy

AU - Weinshilboum, Richard M

AU - Wang, Liewei M

AU - Wieben, Eric D

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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