Dataset Information

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

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.

SUBMITTER: Goetz MP

PROVIDER: S-EPMC5408989 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Goetz Matthew P MP Kalari Krishna R KR Suman Vera J VJ Moyer Ann M AM Yu Jia J Visscher Daniel W DW Dockter Travis J TJ Vedell Peter T PT Sinnwell Jason P JP Tang Xiaojia X Thompson Kevin J KJ McLaughlin Sarah A SA Moreno-Aspitia Alvaro A Copland John A JA Northfelt Donald W DW Gray Richard J RJ Hunt Katie K Conners Amy A Sicotte Hugues H Eckel-Passow Jeanette E JE Kocher Jean-Pierre JP Ingle James N JN Ellingson Marissa S MS McDonough Michelle M Wieben Eric D ED Weinshilboum Richard R Wang Liewei L Boughey Judy C JC

Journal of the National Cancer Institute 20170701 7

<h4>Background</h4>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.<h4>Methods</h4>We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient ...[more]

PMID: 28376176

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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