Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 109, Issue 7, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djw306
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Funding
- Mayo Clinic Center for Individualized Medicine
- Nadia's Gift Foundation
- John P. Guider
- Eveleigh Family
- Pharmacogenomics Research Network [U10GM 61388-15]
- National Institutes of Health [RO1 GM28157]
- Mayo Clinic Cancer Center [CA1508340A2]
- George M. Eisenberg Foundation for Charities
- Mayo Clinic Breast SPORE [P50CA 116201-9]
- Prospect Creek Foundation
- Randy Shaver Cancer Research and Community Fund
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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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