title: Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissues sarcomas.
abstract: OBJECTIVE
  Neoadjuvant chemotherapy for locally advanced soft tissue sarcomas (LASTS), although not standard, represents a promising option for resectable tumours. Current lack of biological predictors of chemotherapy response led us to establish a relationship between Topoisomerase II-alpha (Topo2A), HER2, excision repair cross-complementing group 1 (ERCC1) protein expression, histological response and clinical outcomes of LASTS patients.
  
  
  METHODS
  A retrospective study based on clinical data and archival paraffin-embedded tumour tissue at diagnosis from 78 consecutive LASTS patients treated with neo-adjuvant chemotherapy in our institution enabled analysis of ERCC1, HER2 and Topo2A protein expression by immuno-histochemistry.
  
  
  RESULTS
  Disease free survival (DFS) and overall survival (OS) were 48% and 64%, respectively. The annual risk of relapse increased with a higher percentage of residual identifiable cells (RIC). A higher Topo2A protein was associated with an improved rate of good HR (r=0.416) and with a decreased risk of relapse. Median DFS decreased with low Topo2A (p⩽0.042). The ERCC1 status had no impact on histological response while ERCC1 positive tumours correlated with a favourable OS (p ≤ 0.058). Patients with LASTS co-expressing Topo2A and ERCC1 had a significant better outcome (p=0.018). Topo2A was the only independent variable linked to a good HR (p ≤ 0.017); histological grade 3 was the only independent adverse prognostic variable linked to both DFS (p ≤ 0.04) and OS (p ≤ 0.004).
  
  
  CONCLUSIONS
  While histological response predicts better DFS, Topo2A protein expression correlates with histological response and better DFS. The combination of an early predictive factor for chemosensitivity (Topo2A) and for survival (ERCC1) highlights the possibility to develop individualised therapeutic approaches (CONTICANET program).
authors: Medicine Department, Institut Gustave Roussy, Villejuif, France.
authors: Ruiz-Soto
authors: RS
authors: Rodrigo
authors: Auger
authors: A
authors: Nathalie
authors: Tournay
authors: T
authors: Elodie
authors: Gomez-Abuin
authors: GA
authors: Gonzalo
authors: Terrier
authors: T
authors: Philippe
authors: Drusch
authors: D
authors: Françoise
authors: Domont
authors: D
authors: Julien
authors: Cioffi
authors: C
authors: Angela
authors: Boulet
authors: B
authors: Bérénice
authors: Blay
authors: B
authors: Jean-Yves
authors: Coindre
authors: C
authors: Jean-Michel
authors: Bénard
authors: B
authors: Jean
authors: Bonvalot
authors: B
authors: Sylvie
authors: Le Cesne
authors: le C
authors: Axel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000494:pharmacology*; D004720:Endonucleases / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D012008:Recurrence; D012189:Retrospective Studies; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D004720:Endonucleases; D018719:Erb-b2 Receptor Tyrosine Kinases; C071447:ERCC1 protein, human