TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

Abstract

BackgroundTaxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.MethodsWe compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].ResultsThe advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.ConclusionOur results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.

Androgen, progesterone, and FSH receptor polymorphisms in ovarian cancer risk and outcome

“…Therefore, evaluation of clinical importance of the studied polymorphisms was performed in all patients treated with taxane-platinum, and in subgroups determined by TP53 immunohistochemical status (TP53(K) and TP53(C)), in which TP53(C) means TP53 dysfunction manifested by TP53 protein accumulation; the latter had been determined previously (Kupryjańczyk et al 2008).…”

“…Among cases, 69 patients were uniformly treated in gynecologic oncology units with standard taxaneplatinum regimens, as previously described (Kupryjańczyk et al 2008). Taxol, given in a 24 h (135 mg/m 2 ) or 3 h infusion (175 mg/m 2 ), or docetaxel (75 mg/m 2 ) was followed by cisplatin (75 mg/m 2 ) or carboplatin (AUC6).…”

“…The patients were carefully selected to meet several criteria, among them are an adequate staging procedure, no chemotherapy before staging laparotomy, International Federation of Gynecologists and Obstetricians stage IIB to IV disease, completed first-line chemotherapy, and tumor tissue from the first laparotomy available as previously described (Kupryjańczyk et al 2008).…”

The role of p53 as a surrogate marker for chemotherapeutical responsiveness in ovarian cancer

“…In OC, p53 has been investigated in various studies in which a mutation rate between 23 and 80% has been found (Hollstein et al 1991(Hollstein et al , 1994Levine et al 1991;Levine 1997;Galic et al 2007;Kupryjanczyk et al 2008;Salani et al 2008). P53 mutations in OC have been related to poor prognosis (Wen et al 1999;Ueno et al 2006) as well as to better survival (Ueno et al 2006) but still no large scale prospective studies have been conducted to determine whether the p53 status is of definitive predictive value for survival.…”

Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

“…Seminal studies revealed a significant correlation between p53 status and aneuploidy in advanced stage disease (6). Studies have revealed that p53 status (measured by p53 protein overexpression) correlated with favorable response to taxane-platinum based therapy (7). Therefore, loss of p53 function and ablation of the DNA-damage induced p53 -dependent apoptosis pathway is a strong predictor of taxane-platinum-based therapy.…”