P53 Isoform A133p53a Triple Negative Breast Cancer And Increased Relapse With Neoadjuvant Taxanes

Background: Studies of TP53 mutation, protein expression and modifications of the p53 network in breast cancer yield a complexity which has so far hindered substantive clinical progress. The effects of p53 mutation and p53 protein expression in breast cancer is dependent on the breast cancer subtype and stressors involved. Since identifying differential expression of p53 isoform mRNAs in breast cancer a decade ago, we have demonstrated associations between individual p53 isoforms (p53â, p53a, A133p53a, A133p53â), breast cancer cell behaviour and clinical outcomes. Co-expressed combinations of isoforms may influence canonical p53 (p53a), whether mutant or wild type. Patterns of p53 isoform co-expression may hold the key to understanding p53 functionality, responses to therapy and disease behaviour in breast cancer. Methods: Expression of p53a, p53â, p53a, A133p53a, A133p53â, A133p53a by reverse-transcription PCR was analysed for the EORTC 10994 neoadjuvant breast cancer trial. In 469 available primary breast tumors, 223 patients had been randomised to a preoperative anthracycline regimen (fluorouracil, epirubicin, cyclophosphamide [FEC]) and 246 patients to receive a taxane based regimen (three cycles of docetaxel followed by three cycles of docetaxel + epirubicin [T-ET]). TP53 status was assessed by use of the yeast functional assay (FASAY) on biopsy samples that contained at least 20% tumour cells. Breast tumor subtypes: HER2 positive, triple-negative (TNBC), luminal-A, luminal-B (HER2 negative) and luminal-B (HER2 positive) were determined using the pathological markers recommended by the St Gallen breast cancer consensus guidelines. The primary endpoint was progression-free survival (PFS) with 9 years median follow up at the time of analysis. Results: All cancers expressed multiple p53 isoform mRNAs; none expressed canonical p53 mRNA (p53a) alone. There was a strong association between the p53 isoforms with 4 combinations of co-expressed p53 mRNAs predominated. Expression patterns included: (a) 285 tumours co-expressed p53a, p53â, p53a, A133p53a, and A133p53a; (b) 122 tumours co-expressed p53a, p53â, p53a, A133p53a, A133p53â and A133p53a (c) in 25 A133p53 negative tumors, p53a, p53â and p53a were co-expressed (d) 22 p53â negative tumors co-expressed p53a, p53a, A133p53a and A133p53a. While no individual p53 isoform expression was associated with PFS, among the 104 TNBC expressing all p53 isoforms (pattern (b), A133p53â positive tumors), patients had 11.31 times greater risk of relapse when treated with T-ET than when treated with FEC (95%CI 1.91-66.99, p Conclusions: Corroborating the experimental and animal model data that p53 isoform expression, p53 mutation and p53 protein expression influence the pluripotent nature of p53, patients bearing A133p53â positive TNBC may benefit more from treatment with FEC than T-ET in the neoadjuvant setting. Citation Format: Jean-Christophe Bourdon, Alexandra Diot, Valerie Meuray, Leen Slaets, Richard Iggo, Herve Bonnefoi, David Cameron, Alastair M. Thompson. p53 isoform A133p53â triple negative breast cancer and increased relapse with neoadjuvant taxanes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 855.