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- Title
Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer.
- Authors
Goetz, Matthew P.; Kalari, Krishna R.; Suman, Vera J.; Moyer, Ann M.; Jia Yu; Visscher, Daniel W.; Dockter, Travis J.; Vedell, Peter T.; Sinnwell, Jason P.; Xiaojia Tang; Thompson, Kevin J.; McLaughlin, Sarah A.; Moreno-Aspitia, Alvaro; Copland, John A.; Northfelt, Donald W.; Gray, Richard J.; Hunt, Katie; Conners, Amy; Weinshilboum, Richard; Liewei Wang
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
TUMOR antigens; CANCER chemotherapy; XENOGRAFTS; CANCER patients; CANCER clusters; ANTINEOPLASTIC agents; ANIMALS; BREAST tumors; COMBINED modality therapy; GENOMES; LONGITUDINAL method; MICE; GENETIC mutation; PROTEINS; RESEARCH funding; TREATMENT effectiveness; SEQUENCE analysis
- Publication
JNCI: Journal of the National Cancer Institute, 2017, Vol 109, Issue 7, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djw306