title: Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer.
abstract: 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.
authors.affiliation: Medical Oncology, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Moyer
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Dockter
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Vedell
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Sinnwell
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Thompson
authors.affiliation: Department of Surgery, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: McLaughlin
authors.affiliation: Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Moreno-Aspitia
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.affiliation: Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.affiliation: Department of Surgery, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gray
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Hunt
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Conners
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kocher
authors.affiliation: Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marissa S
authors.initials: MS
authors.lastname: Ellingson
authors.affiliation: Department of Surgery, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: McDonough
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors.forename: Judy C
authors.initials: JC
authors.lastname: Boughey
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D011446:Prospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53