title: Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.
abstract: BACKGROUND
  Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset.
  
  
  METHODS
  The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
  
  
  RESULTS
  Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (P(interaction): DDFS P = .14; OS P = .24).
  
  
  CONCLUSIONS
  In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. sherene.loi@petermac.org
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.forename: Bart
authors.initials: B
authors.lastname: Claes
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.forename: Petri
authors.initials: P
authors.lastname: Bono
authors.forename: Vesa
authors.initials: V
authors.lastname: Kataja
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D055088:Early Detection of Cancer; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005387:Finland / Q000453:epidemiology; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005472:Fluorouracil; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human