High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study

Abstract

Objective: Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin.

Methods: We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer.

Results: We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin.

Conclusions: Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Keywords: Endometrial cancer; Paclitaxel; Stathmin.

Figure 1. Representative images of stathmin staining by IHC

High modified H-score (A) and low modified H-score (B). Images were acquired at 200X magnification.

Figure 2. Stathmin expression is associated with progression-free survival and overall survival in GOG177; addition of paclitaxel blunts the impact of stathmin overexpression

Kaplan-Meier analysis of the association of stathmin with PFS (A, C, E) and OS (B, D, F) for all samples regardless of treatment (A, B), or for only Arm 1 cisplatin/adriamycin (AP, C, D) or only Arm 2 cisplatin/adriamycin/paclitaxel (TAP, E, F).

Figure 3. High stathmin mRNA levels predicts for poor PFS and OS in TCGA dataset for endometrial cancer

Kaplan-Meier analysis of the association of stathmin mRNA levels (STMN1) with PFS (A, C) or OS (B, D). STMN1 was dichotomized into low and high categories using a cut-off of either >50% (A, B) or >75% (C, D). NA= not achieved, the number of observed events (deaths) did not reach threshold to calculate median survival; Median= median survival, the amount of time (months) wherein 50% of the patients are alive.

Figure 4. High stathmin mRNA expression is associated significantly decreased PFS for endometrial patients with the serous histologic subtype

Kaplan-Meier analysis of TCGA dataset for endometrial cancer for the association of STMN1 with PFS for serous adenocarcinoma (A, B) or endometrioid adenocarcinoma (C, D). STMN1 was dichotomized into low and high categories using a cut-off of either >50% (A, C) or >75% (B, D). NA= not achieved, the number of observed events (deaths) did not reach threshold to calculate median survival; Median= median survival, the amount of time (months) wherein 50% of the patients are alive.