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Titolo:
Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer
Autore:
Berns, EMJJ; Foekens, JA; Vossen, R; Look, MP; Devilee, P; Henzen-Logmans, SC; van Staveren, IL; van Putten, WLJ; Inganas, M; Meijer-van Gelder, ME; Cornelisse, C; Claassen, CJC; Portengen, H; Bakker, B; Klijn, JGM;
Indirizzi:
Univ Rotterdam Hosp, Daniel den Hoed Klin, Dept Med Oncol, Div Endocrine Oncol, NL-3008 AE Rotterdam, Netherlands Univ Rotterdam Hosp Rotterdam Netherlands NL-3008 AE terdam, Netherlands Univ Rotterdam Hosp, Daniel den Hoed Klin, Dept Stat, NL-3008 AE Rotterdam, Netherlands Univ Rotterdam Hosp Rotterdam Netherlands NL-3008 AE terdam, Netherlands Univ Rotterdam Hosp, Daniel den Hoed Klin, Rotterdam Canc Inst, NL-3008 AERotterdam, Netherlands Univ Rotterdam Hosp Rotterdam Netherlands NL-3008 AE terdam, Netherlands Amersham Pharmacia Biotech, Uppsala, Sweden Amersham Pharmacia Biotech Uppsala Sweden acia Biotech, Uppsala, Sweden Leiden Univ, Med Ctr, Dept Human & Clin Genet, NL-2300 Leiden, NetherlandsLeiden Univ Leiden Netherlands NL-2300 enet, NL-2300 Leiden, Netherlands Leiden Univ, Med Ctr, Dept Pathol, NL-2300 Leiden, Netherlands Leiden Univ Leiden Netherlands NL-2300 thol, NL-2300 Leiden, Netherlands
Titolo Testata:
CANCER RESEARCH
fascicolo: 8, volume: 60, anno: 2000,
pagine: 2155 - 2162
SICI:
0008-5472(20000415)60:8<2155:CSOTPP>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
P53 PROTEIN ACCUMULATION; PROGNOSTIC VALUE; ADJUVANT CHEMOTHERAPY; TAMOXIFEN THERAPY; GENE-MUTATIONS; EXPRESSION; C-ERBB-2; BCL-2; RADIOTHERAPY; RESISTANCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Berns, EMJJ Josephine Nefkens Inst, Dept Med Oncol, Room BE 424,POB 1738, NL-3000 DR Rotterdam, Netherlands Josephine Nefkens Inst Room BE 424,POB 1738 Rotterdam Netherlands NL-3000 DR
Citazione:
E.M.J.J. Berns et al., "Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer", CANCER RES, 60(8), 2000, pp. 2155-2162

Abstract

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primarytumors of the chemotherapy patients, TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014), TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype, Interestingly, the responseof patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant), The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumoris helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

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Documento generato il 25/01/21 alle ore 16:11:27