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

Matthew P. Goetz, Krishna R. Kalari, Vera J. Suman, Ann M. 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. Copland, Donald W. Northfelt, Richard J. Gray, Katie Hunt, Amy Conners, Richard Weinshilboum, Liewei WangJudy C Boughey, Matthew P. Goetz, Krishna R. Kalari, Vera J. Suman, Ann M. Moyer, Jia Yu, Daniel W. Visscher, Travis J. Dockter, Peter T. Vedell, Jason P. Sinnwell, Xiaojia Tang, Kevin J. Thompson, Poulami Barman, Douglas W. Mahoney, Erin Carlson, Steven Hart, Ping Yin, Bo Qin, Sara J. Felten, Sarah A. McLaughlin, Alvaro Moreno-Aspitia, John A. Copland, Donald W. Northfelt, Richard J. Gray, Katie Hunt, Amy Conners, Hugues Sicotte, Jeanette E Eckel-Passow, Jean-Pierre Kocher, James N. Ingle, Marissa S. Ellingson, Michelle McDonough, Eric D. Wieben, Richard Weinshilboum, Liewei Wang, Judy C. Boughey

Research output: Contribution to journalArticle

23 Scopus citations

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)
JournalJournal of the National Cancer Institute
Volume109
Issue number7
DOIs
StatePublished - Jul 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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