TP53 K351N mutation-associated platinum resistance after neoadjuvant chemotherapy in patients with advanced ovarian cancer

Highlights

• TP53 K351N mutation is associated with platinum resistance after platinum-based NACT in patients with advanced ovarian cancer.

• The selection of further chemotherapy after platinum-based NACT-IDS for advanced ovarian cancer should be based on TP53 K351N mutation.

Abstract

Objective

TP53 K351N mutation is associated with acquired cisplatin resistance in ovarian cancer cells following exposure to cisplatin. We investigated the effect of TP53 K351N mutation on outcome in patients with epithelial ovarian cancer (EOC) who received platinum-based chemotherapy.

Methods

We assessed TP53 K351N mutations by allele specific real-time PCR (AS-PCR) and DNA sequencing in tumor samples of 153 patients with stage IIIC/IV EOC. Clinicopathologic and follow-up data were collected by a retrospective chart review.

Results

TP53 K351N mutations were detected in 8 (11.27%) of 71 patients who underwent neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) but not in 82 patients who underwent primary debulking surgery (PDS) (P < 0.01). In patients with relapse within 6 months, the relapse rate was 14 (19.72%) of 71 patients for NACT-IDS compared to 15 (18.29%) of 82 patients for PDS (P = 0.49), and TP53 K351N mutation was observed in 8 of NACT-IDS 14 patients (57.14% P < 0.01). In the patients retreated at first recurrence within 6 months, 7 with TP53 K351N mutation of 14 NACT-IDS patients exhibited progression of disease, compared to 2 of PDS 15 patients (50.00% vs. 13.33%, P = 0.04). The median disease-free survival (DFS) for NACT-IDS was 13.0 months compared to 15.0 months for PDS (P = 0.02). In multivariate analysis, TP53 K351N mutation is an independent factor for shorter DFS in the patients who underwent NACT-IDS (HR = 19.05; P = 0.01).

Conclusions

TP53 K351N mutation may be associated with induction of platinum resistance after NACT in advanced EOC.

Introduction

Epithelial ovarian cancer (EOC) remains a leading cause of death from gynecological malignancies among the women in the world [1]. Approximately 70% of EOC patients present with advanced stage disease at the time of diagnosis and with poor response of recurrent disease to treatment [2]. Furthermore, the most effective regimen for second line chemotherapy has not yet been determined. The objective responses achieved by the second line chemotherapies are dependent on the initial progression free survival. Resistance to platinum chemotherapy, either de novo or acquired, presents a substantial obstacle to attempt to improve the prognosis of patients with advanced EOC. Initially responsive, 20–30% of patient will have recurrence within 6 months of completion of primary platinum therapy [3], [4]. Currently, around 50% of the patients with stage IIIC/IV ovarian cancer are selected for neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) as a treatment option [5], [6], [7]. Recently, the findings from several trials reported that patients with stages IIIC/IV EOC randomized to NACT-IDS had the same survival as patients undergoing primary debulking surgery (PDS) followed by chemotherapy and that NACT-IDS was not inferior to PDS [8], [9], [10]. Despite recent data appear to support a paradigm shift toward NACT-IDS for a subset of patients with stages IIIC/IV EOC, it remains controversial whether the better outcome is due to NACT-IDS followed by platinum-based chemotherapy [11], [12]. However, a recent data reported that in patients with stages IIIC/IV EOC who had a relapse within 6 months and are retreated with platinum-based chemotherapy, NACT-IDS contributed to an increased risk of platinum resistance [13]. But the causes of further relapse with platinum-resistant disease after NACT remain unclear. Despite increasing efforts in terms of more radical surgery and more efficient systemic treatment, survival of women with advanced EOC has changed little since platinum-based treatment was introduced over 30 years ago. Accordingly, it is important for the management of advanced EOC to elucidate the mechanisms of chemoresistance and to get over the resistance. Both intrinsic and acquired resistance during treatment results from the numerous genetic and epigenetic changes occurring in cancer cells [14]. The success of platinum-based chemotherapy is limited due to its pre-existed or acquired drug resistance.

It is well established that more than 50% of advanced ovarian cancers contain TP53 mutations that are mostly missense [15]. Although TP53 mutation status was not predictive of survival (disease free and overall) or of chemoresistance [16], [17], [18], [19], [20], the TP53 missense mutation-mediated cisplatin resistance may be associated with reduced transactivation and expression of BAX, an apoptosis-inducing gene, in ovarian carcinoma cell systems [19]. These studies reported that TP53 mutations in ovarian cancers were mostly involved in exons of DNA binding domains (17) but not involved in the tetramerization domain of TP53 that is responsible for its nuclear export signal (NES) and translocation to mitochondria (Supplementary Fig. 1).

A missense mutation of G to T transversion at codon 351 (Lys 351 to Asn, K351N) in the tetramerization domain (TD) in exon 10 of TP53 in cisplatin-resistant subpopulation of human EOC cell line (A2780CIS) has been found to be related to acquired resistance to cisplatin. A2780CIS cell line has been developed by chronic exposure of the parent cisplatin-sensitive A2780 cell line to cisplatin [21], [22], [23]. An increased ability to repair DNA damage as well as cytogenetic abnormalities has been observed in A2780CIS cell line [24]. TP53 K351N mutation results in a combined loss of tetramerization and nuclear export or translocation to mitochondria of TP53 protein which mediates the activation of BAX, leading to defects in TP53 apoptosis activity [19], [25], [26]. This defect in TP53 apoptosis activity is critical for the development and maintenance of resistance to platinum in EOC cells. If tumors of patients with stages IIIC/IV EOC after platinum-based NACT-IDS are found to have a TP53 K351N mutation, their tumors likely become resistant to further platinum-based chemotherapy.

The objective of this study is to investigate whether TP53 K351N mutations emerge in tumors of patients with stages IIIC/IV EOC after platinum-based NACT and to assess the effect of TP53 K351N mutation on outcome of treatment in a clinical setting.