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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Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2017-07, Vol.109 (7)
Main Authors: 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
Format: Article
Language:English
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
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Summary: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.
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djw306