1. Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer.
- Author
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Goetz MP, Kalari KR, Suman VJ, Moyer AM, Yu J, Visscher DW, Dockter TJ, Vedell PT, Sinnwell JP, Tang X, Thompson KJ, McLaughlin SA, Moreno-Aspitia A, Copland JA, Northfelt DW, Gray RJ, Hunt K, Conners A, Sicotte H, Eckel-Passow JE, Kocher JP, Ingle JN, Ellingson MS, McDonough M, Wieben ED, Weinshilboum R, Wang L, and Boughey JC
- Subjects
- Adult, Aged, Animals, 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 genetics, Triple Negative Breast Neoplasms metabolism, Tumor Suppressor Protein p53 genetics, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms drug therapy, Xenograft Model Antitumor Assays methods
- 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., (© The Author, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)
- Published
- 2017
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