Clinical Significance of Apoptosis-Related Factors p53, Mdm2, and Bcl-2 in Advanced Ovarian Cancer

Baekelandt, M.; Kristensen, Gunnar B.; Nesland, Jahn M.; Tropé, Claes G.; Holm, Ruth

doi:10.1200/jco.1999.17.7.2061

Cited by 80 publications

(71 citation statements)

References 31 publications

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“…In subgroups related to the TP53 status, BCL-2 and BAX demonstrated an influence on CR or DFS, which was not seen in all tumours. Among other studies evaluating predictive significance of BCL-2 (Herod et al, 1996;Mano et al, 1999;Schuyer et al, 2001), including two published by Baekelandt et al (1999Baekelandt et al ( , 2000 on a comparable number of ovarian carcinomas, only Mano et al (1999) noticed higher frequency of CR in patients with BCL-2 negative tumours.…”

Section: Discussionmentioning

confidence: 89%

“…The strong impact of clinical parameters on clinical end points in our analysis is in agreement with other studies (Makar et al, 1995;Partridge et al, 1996;Eisenhauer et al, 1999). Usually, immunohistochemical markers present lower associations with clinical end points than clinical parameters (Diebold et al, 1996;Herod et al, 1996;Baekelandt et al, 1999Baekelandt et al, , 2000Mano et al, 1999;Geisler et al, 2000;Reles et al, 2001;Schuyer et al, 2001). In our analysis, the only exception was the positive influence of high BAX expression on DFS in patients with TP53-positive ovarian carcinomas -it was stronger than that of the FIGO stage.…”

Section: Discussionmentioning

confidence: 99%

“…As far as TP53 is concerned, in the literature there are few studies on clinical significance of TP53 protein accumulation in large groups of advanced stage ovarian carcinomas (Hartmann et al, 1994;Eltabbakh et al, 1997;Baekelandt et al, 1999;Ferrandina et al, 1999;Shahin et al, 2000;Reles et al, 2001). Two of three of those research groups who related TP53 protein accumulation to tumour response to platinum-based chemotherapy have found better response in TP53-negative tumours (Ferrandina et al, 1999;Reles et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…in ovarian carcinomas (Kupryjańczyk et al, 1993;Casey et al, 1996;DiCioccio et al, 1998;Wen et al, 1999), studies on TP53 status and tumour response to cisplatin-based chemotherapy have not so far given equivocal results (Righetti et al, 1996;de Feudis et al, 1997;Baekelandt et al, 1999;Eisenhauer et al, 1999;Fallows et al, 2001;Reles et al, 2001).…”

mentioning

confidence: 99%

“…Analyses of TP53 and/or apoptosis proteins in large groups of ovarian carcinomas are rare (Hartmann et al, 1994;Eltabbakh et al, 1997;Marx et al, 1997;Baekelandt et al, 1999Baekelandt et al, , 2000Ferrandina et al, 1999). To our knowledge, MEK1 expression and its clinical significance have not been evaluated yet in ovarian carcinomas.…”

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confidence: 99%

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Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

et al. 2003

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In cell line studies, BCL-2, BAX, as well as novel MEK1 protein levels have strong influence on ovarian cancer response to cisplatinbased chemotherapy. However, such associations have not been demonstrated clinically. We evaluated prognostic/predictive significance of these proteins with regard to TP53 status. Immunohistochemical analysis was performed on 229 ovarian carcinomas FIGO stage IIB -IV treated with platinum-based chemotherapy; the results were analysed by the Cox and logistic regression models. Clinical parameters (residual tumour size, patient age, FIGO stage) were the only indicators of overall survival (OS) and the strongest predictors of complete remission (CR). On the other hand, BAX expression was the strongest (P ¼ 0.005) or the only (in FIGO IIIC, P ¼ 0.02) prognostic indicator of disease-free survival (DFS) in the TP53(+) group. TP53(+) and TP53(À) ovarian carcinomas differed in clinical and molecular prognostic and predictive factors. Another novel finding is that CR was negatively influenced by high BAX expression in all patients group (P ¼ 0.047) and by BCL2 expression in the TP53(À) group (P ¼ 0.05). High MEK1 expression was associated with endometrioid and clear cell carcinomas (P ¼ 0.049); its loss was found with advancing FIGO stage (P ¼ 0.002). Our results suggest that binomial TP53 status divides ovarian carcinomas into two biologically distinct groups. BAX expression is an important factor of DFS in the TP53(+) group. BCL-2 and BAX, but not MEK1 expressions have predictive value in ovarian cancer patients treated with platinum-based chemotherapy.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

et al. 2003

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The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

Shahin

Hughes

Sood

et al. 2000

Cancer

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The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

Shahin¹,

Hughes²,

Sood³

et al. 2000

Cancer

115

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BACKGROUND The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored. METHODS Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed. RESULTS Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild‐type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. CONCLUSIONS Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival. Cancer 2000;89:2006–17. © 2000 American Cancer Society.

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Clinical Significance of Apoptosis-Related Factors p53, Mdm2, and Bcl-2 in Advanced Ovarian Cancer

Cited by 80 publications

References 31 publications

Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

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