Abstract LB-138: TP53 mutation is a biomarker for prognosis in triple-negative breast cancer patients treated with post-neoadjuvant cisplatin
Authors: Hancock Bradley , Chen Yu-Hsiang , Solzak Jeffrey , Miller Kathy , Radovich Milan 
Published: July 2016

Introduction: Patients with Triple-Negative Breast Cancer (TNBC) who have residual disease (RD) after neoadjuvant chemotherapy (NAC) are at an increased risk of relapse and death. These patients display a marked diversity in outcome, thus markers that can predict prognosis would be of benefit. BRE09-146 was a Phase II post-neoadjuvant clinical trial testing Cisplatin + Rucaparib versus Cisplatin alone in TNBC patients with RD post-NAC. TP53 is mutated in 70-80% of TNBCs, but its prognostic potential has yet to be elucidated. Herein, we seek to comprehensively determine the prognostic capability of mutated TP53 to determine outcome with post-neoadjuvant Cisplatin in BRE09-146.

Methods: We performed sequence and copy number analysis of 134 genes in 76 tumors from BRE09-146 using the Oncomine Research Panel along with Ion Proton Next Generation Sequencing. All patients included had RD. Somatic mutations were called by identifying mutations that were present in the tumor that were not present in the germ line DNA from a normal blood sample. Mutations were annotated using the IARC TP53 somatic mutation database. Gene copy numbers in tumors were identified using the Ion Reporter System and called as copy number loss, normal, or gain based upon a comparison to a reference range established from the normal blood samples. Survival analyses were generated using Log-Rank and Kaplan-Meier statistics.

Results: TP53 was highly mutated in this patient cohort (92% incidence). TP53 copy loss was independently associated with disease-free survival (DFS) and overall survival (OS); DFS events = 50% vs. 34%; median = 19.09 mos. vs. NR (Not Reached); p = 0.03; HR = 2.27 (95% C.I.: 1.13-7.28); OS events = 40% vs. 37%; median = 24.02 mos. vs. NR; p = 0.02; HR = 2.64 (95% C.I.: 1.28-11.35). Cancers without a TP53 mutation or subclonal TP53 mutation (present in a fraction of cells) demonstrated superior OS; events = 40% vs. 10%; median = 29.14 mos. vs. NR; p = 0.005; HR = 6.00 (95% C.I.: 1.46-7.96). Likewise, cancers bearing compound mutations (point mutation plus loss-of-heterozygosity/copy loss) were correlated with inferior DFS and OS; DFS events = 50% vs. 26%; median = 19.09 mos. vs. NR; p = 0.009; HR = 2.64 (95% C.I.: 1.30-5.67); OS events = 45% vs. 16%; median = 24.02 mos. vs. NR; p = 0.0007; HR = 4.26 (95% C.I.: 1.89-10.01).

Conclusions: It is well-known that TP53 is heavily mutated in TNBC, yet to-date, realizing the prognostic potential for this marker has not been accomplished. We have demonstrated the prognostic signficance of TP53 mutations for TNBC patients with residual disease after NAC. Additionally, we have uncovered p53 dysfunction as a continuum in this patient population in which cancers with higher degrees of dysfunction are correlated with a poorer prognosis and cancers with less dysfunction a superior prognosis.

Citation Format: Bradley Hancock, Yu-Hsiang Chen, Jeffrey Solzak, Kathy Miller, Milan Radovich. TP53 mutation is a biomarker for prognosis in triple-negative breast cancer patients treated with post-neoadjuvant cisplatin. [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 LB-138.