471 A Novel Translational Design to Investigate The Role of TP53 in Predicting Carboplatin Response in Advanced Ovarian Carcinoma
- Abstract:
- TP53 has been investigated as a predictor of hemotherapy response. as cancer cell fate following carboplatin treatment is determined by a cascade of molecular events, the presence of non-mutated form of TP53 does not necessarily imply response. Moreover, gain as well as loss of function TP53 mutations have been described. We conducted a systematic review of 75 clinical studies, 8331 patients that evaluated the prognostic value of TP53 mutation in ovarian cancer. We found that it was impossible to draw conclusions on the role of TP53 due to methodological inconsistencies and, importantly, the use of simplistic classifications, mutated or not, of TP53 mutations. Novel designs are needed to study the prognostic role of TP53. We report the first prospective study to combine TP53 sequencing with global transcriptional monitoring within the first 48 hours following cycle 1 of neoadjuvant carboplatin in a 72 y female with G3, stage IIIC serous ovarian cancer. Surprisingly, expression profiling revealed lack of significant transcriptional activation of TP53 responsive genes in spite of expression of non-mutated TP53 and activation of ATM and CHEK2 which would be expected following DNA damage. Furthermore, independent component analysis revealed significant activation of immunological gene ontology modes. This was associated with initial partial carboplatin response. Samples obtained at sub-optimal debulking confirmed the absence of new TP53 mutation. The patient died three months after completion of 8 cycles of carboplatin of refractory disease. These results underscore the need for trial designs that seek to correlate in vivo functional insights with clinical outcome.
- Authors:
- AA Ahmed, M Riyad, A Teschendorff, L Jackson, A Naderi, R Crawford, JD Brenton
- Journal:
- International Journal of Gynecological Cancer
- Citation info:
- 14:132
- Publication date:
- 1st Sep 2004
- Full text
- DOI