title: p-53 gene mutations as a predictive marker in a population of advanced breast cancer patients randomly treated with doxorubicin or docetaxel in the context of a phase III clinical trial.
abstract: BACKGROUND
  Preclinical data indicate that p-53 gene mutations predict resistance to doxorubicin (A) but not to docetaxel (Taxotere) (T). In the TAX 303 trial, A and T have been compared with advanced breast cancer patients.
  
  
  METHODS
  Primary tumor samples from patients participating in the TAX 303 trial were collected. p-53 gene mutations were evaluated by denaturing high-performance liquid chromatography (DHPLC) and confirmed by sequencing. Topoisomerase II alpha (topo II alpha) protein levels were evaluated by immunohistochemistry. Clinical and biological data were correlated.
  
  
  RESULTS
  Tumor samples for DHPLC analysis were available for 108 of 326 patients from the clinical trial. p-53 gene mutations were observed in 20% of patients. In patients with a mutated p-53 gene, a trend for a lower percentage of responders was observed in the A arm (17%) compared with the T arm (50%). In the wild-type p-53 cohort, response rates to A and T were 27% and 36%, respectively. Of the 16 patients carrying wild-type p-53- and topo II protein-positive tumors, seven (44%) responded to anthracyclines, while response rate to the same drug was 13% in the remaining cohorts [odds ratio 5.06 (95% confidence interval 1.19-21.41), P = 0.03]. The combination of the two markers had no predictive value in patients treated with docetaxel.
  
  
  CONCLUSIONS
  (i) p-53 gene analysis indicates that gene mutations may compromise the efficacy of A while they do not interfere with the antitumor activity of T; and (ii) the evaluation of multiple molecular markers including p-53 and proliferation markers as topo II protein levels looks more promising in predicting response to anthracyclines.
authors: Medical Oncology, Sandro Pitigliani Hospital of Prato, Prato, Italy. adileo@usl4.toscana.it
authors: A
authors: A
authors: Di Leo
authors: M
authors: M
authors: Tanner
authors: C
authors: C
authors: Desmedt
authors: M
authors: M
authors: Paesmans
authors: F
authors: F
authors: Cardoso
authors: V
authors: V
authors: Durbecq
authors: S
authors: S
authors: Chan
authors: T
authors: T
authors: Perren
authors: M
authors: M
authors: Aapro
authors: C
authors: C
authors: Sotiriou
authors: M J
authors: MJ
authors: Piccart
authors: D
authors: D
authors: Larsimont
authors: J
authors: J
authors: Isola
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D000077143:Docetaxel; D004317:Doxorubicin / Q000627:therapeutic use*; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D011237:Predictive Value of Tests; D011336:Probability; D014176:Protein Biosynthesis; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D004273:DNA, Neoplasm; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin