title: High-Throughput Mutation Profiling Changes before and 3 Weeks after Chemotherapy in Newly Diagnosed Breast Cancer Patients.
abstract: BACKGROUND
  Changes in tumor DNA mutation status during chemotherapy can provide insights into tumor biology and drug resistance. The purpose of this study is to analyse the presence or absence of mutations in cancer-related genes using baseline breast tumor samples and those obtained after exposure to one cycle of chemotherapy to determine if any differences exist, and to correlate these differences with clinical and pathological features.
  
  
  METHODS
  Paired breast tumor core biopsies obtained pre- and post-first cycle doxorubicin (n = 18) or docetaxel (n = 22) in treatment-naïve breast cancer patients were analysed for 238 mutations in 19 cancer-related genes by the Sequenom Oncocarta assay.
  
  
  RESULTS
  Median age of patients was 48 years (range 32-64); 55% had estrogen receptor-positive tumors, and 60% had tumor reduction ≥25% after cycle 1. Mutations were detected in 10/40 (25%) pre-treatment and 11/40 (28%) post-treatment samples. Four mutation pattern categories were identified based on tumor mutation status pre- → post-treatment: wildtype (WT)→WT, n = 24; mutant (MT)→MT, n = 5; MT→WT, n = 5; WT→MT, n = 6. Overall, the majority of tumors were WT at baseline (30/40, 75%), of which 6/30 (20%) acquired new mutations after chemotherapy. Pre-treatment mutations were predominantly in PIK3CA (8/10, 80%), while post-treatment mutations were distributed in PIK3CA, EGFR, PDGFRA, ABL1 and MET. All 6 WT→MT cases were treated with docetaxel. Higher mutant allele frequency in baseline MT tumors (n = 10; PIK3CA mutations n = 8) correlated with less tumor reduction after cycle 1 chemotherapy (R = -0.667, p = 0.035). No other associations were observed between mutation pattern category with treatment, clinicopathological features, and tumor response or survival.
  
  
  CONCLUSIONS
  Tumor mutational profiles can change as quickly as after one cycle of chemotherapy in breast cancer. Understanding of these changes can provide insights on potential therapeutic options in residual resistant tumors.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00212082.
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.
authors.forename: Sing-Huang
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Nur Sabrina
authors.initials: NS
authors.lastname: Sapari
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.affiliation: Department of Surgery, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.
authors.forename: Mikael
authors.initials: M
authors.lastname: Hartman
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Marie
authors.initials: M
authors.lastname: Loh
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Department of Surgery, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.
authors.forename: Philip
authors.initials: P
authors.lastname: Iau
authors.affiliation: Department of Surgery, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.
authors.forename: Shaik Ahmad
authors.initials: SA
authors.lastname: Buhari
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Pathology, National University of Singapore, Singapore, Singapore.
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D000077143:Docetaxel; D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids