Abstract P2-08-23: TP53 mutation is a biomarker for prognosis in triple-negative breast cancer patients treated with post-neoadjuvant cisplatin
Authors: Hancock BA , Chen Y-H , Solzak JP , Miller KD , Radovich M 
Published: May 2016

Abstract
Introduction: Patients with Triple-Negative Breast Cancer (TNBC) who have residual disease (RD) after neoadjuvant chemotherapy are at an increased risk of relapse and have a poor prognosis. No adjuvant therapies are currently indicated for this group. BRE09-146 was a Phase II post-neoadjuvant clinical trial testing Cisplatin or Cisplatin + Rucaparib in TNBC patients with RD after neoadjuvant chemotherapy. As TP53 is mutated in 70-80% of TNBCs, and is well known to play a role in the DNA damage response, we sought to determine the prognostic capability of mutated TP53 in BRE09-146.
Methods: We performed full 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 from Thermo-Fisher Scientific 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 the Log-Rank and Kaplan-Meier methods.
Results: 84% (64/76) of our TNBC tumors harbored a somatic mutation in the TP53 gene. The majority were missense mutations (particularly in the DNA binding and tetramerization domains) followed by frameshift insertions/deletions, and copy number loss. Patients whose tumors harbored somatic TP53 mutations were observed to have a significantly inferior disease free survival (DFS) compared to non-mutated tumors (events = 29/64 vs. 1/12; median = 25.9 mos vs. NR (Not Reached); p=0.021, HR=7.28 (95% C.I.: 2.98-17.79). The same was observed for overall survival (OS) (events = 23/64 vs. 0/12, median = 33.78 vs. NR; p=0.017, HR = Not evaluable). There was no difference in DFS or OS when comparing the nature of the mutation (point mutation vs. indel vs. copy loss) at a p=0.88 and p=0.91, respectively. We then sought to determine if clonal status of TP53 mutations was also associated with survival. Cases were divided into non-mutated, subclonal (mutations present in a fraction of cells), or truncal (mutation present in most or all cells). Interestingly, tumors that harbored subclonal TP53 mutations had a superior OS compared to truncal mutations (events = 1/9 vs. 22/55; median = NR vs. 29.1, p=0.036, HR =0.16 (95% C.I.:0.06-0.42). OS for subclonal mutations was highly similar to non-mutated tumors (p=0.25).
Conclusions: While RD after neoadjuvant chemotherapy in TNBC is a well-known risk factor for poor prognosis, in our study, we observed a subset of RD patients defined by a lack of TP53 mutation or presence of a subclonal mutation that portended a superior survival outcome after post-neoadjuvant Cisplatin. If validated, these results reveal that the presence and clonal status of TP53 mutations is important to accurate prognostication and should be considered in decision-making algorithms for this patient population.
Citation Format: Hancock BA, Chen Y-H, Solzak JP, Miller KD, Radovich M. TP53 mutation is a biomarker for prognosis in triple-negative breast cancer patients treated with post-neoadjuvant cisplatin. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-23.