p53 mutations in epithelial ovarian cancers: possible role in predicting chemoresistance.
OBJECTIVE
The investigators undertook a retrospective study to determine (1) whether p53 mutations are predictors of survival in patients with advanced epithelial ovarian cancer, (2) whether p53 status by sequencing is associated with established prognostic indicators, and (3) the agreement of results between direct sequencing of p53 mutations and immunohistochemistry.


METHODS
This study was retrospective review of 43 patients with advanced epithelial ovarian cancer treated with surgery and by paclitaxel-based chemotherapy. Clinical data were extracted from the charts. By use of paraffin-embedded blocks, p53 analysis was carried out by (1) direct sequencing and (2) immunohistochemistry. Kaplan-Meier estimates were used for overall and disease-free survivals. To determine whether p53 mutation (sequencing) was related to prognosis and to determine the agreement between p53 abnormalities by sequencing and immunohistochemistry, risk ratios were calculated.


RESULTS
Mean age at diagnosis was 57.4 years. Surgical stages were as follows: 5% were stage IIC, 79% were stage III, and 16% were stage IV. Seventy-seven percent of tumors were serous, and 56% of tumors were grade 3. All patients received paclitaxel-based chemotherapy. Mean disease-free and overall survivals were 16.4 and 22.6 months, respectively. p53 abnormalities were detected by sequencing in 53% of cases and by immunohistochemistry in 70%. Agreement between both techniques was 68%. Patients with stages IIC/IV had a risk of 1.7 of having a p53 mutation by sequencing; grade, histology, disease-free survival and overall survival were not predictive of p53 mutation status.


CONCLUSIONS
The 54% mutation rate may be underestimated by limiting our analysis to exons 5 to 9. p53 mutation status was not predictive of survival (disease free and overall) or of chemoresistance; this suggests that paclitaxel-based apoptosis is independent of the p53 gene. The concomitant use of cisplatin, an inducer of apoptosis that is dependent on the normal function of p53, makes the interpretation of these results difficult. Histopathologic factors were not statistically associated with p53 status, but more advanced surgical stage and tumor grade were suggestive of higher rates of p53 mutations, implying more aggressive behavior. Finally, the lack of agreement between results obtained by sequencing and immunohistochemistry highlights the limitation of the latter technique and the possibility of underestimating abnormal p53 function. In conclusion, because discrepancies exist between the two techniques, we recommend direct sequencing of exons 4 through 10 to determine the true prevalence of p53 mutation. Furthermore, larger randomized studies are required to elucidate the role of p53 in predicting chemoresponse in advanced epithelial ovarian cancer.
Laframboise
S
S
Division of Gynecology Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada.
Chapman
W
W
McLaughlin
J
J
Andrulis
I L
IL
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003062:Codon; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005091:Exons; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D011379:Prognosis; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D003062:Codon; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D002945:Cisplatin