Tissue assays & hysterectomy pathology: looks like we should ask about overexpression of the oncogen

Stathmin Overexpression Identifies High Risk Patients and Lymph Node Metastasis in Endometrial Cancer
Clin Cancer Res. 2011 Jan 17;[Epub Ahead of Print], J Trovik, E Wik, IM Stefansson, J Marcickiewicz, S Tingulstad, AC Staff, TS Njolstad, I Vandenput, F Amant, LA Akslen, H Salvesen

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In women with endometrial cancer, overexpression of the oncogen stathmin in curettage specimens predicted lymph node metastases and poor survival.

SUMMARY
OncologySTAT Editorial Team
Endometrial cancer that was presumed to be localized at primary treatment recurs in 15% to 20% of patients. Lymph node dissection can identify patients with poor prognosis, but the procedure has been associated with higher complication rates. Better prognostic markers, especially those found in preoperative curettage specimens, are needed to tailor treatment for high-risk patients.

Trovik et al postulated that overexpression of the oncoprotein stathmin, a microtubule destabilizer that promotes cell proliferation, mobility, metastasis, and resistance to antimicrotubule therapy, could identify patients with high-risk endometrial cancer. They also explored whether stathmin expression in curettage specimens could predict the presence of lymph node metastasis.

A total of 1076 patients with endometrial cancer were recruited from 10 centers in Europe. Tumor tissue from curettage was collected from patients at all centers, and corresponding samples from the hysterectomy specimens were collected from the 553 patients enrolled at Haukeland University Hospital, Bergen, Norway. A total of 763 patients (71%) had pelvic lymphadenectomy as part of surgical staging. Median follow-up for survivors was 81 months (range 0–90 months).

Strong strathmin expression was seen in 84 (18%) of hysterectomy specimens and 302 (37%) of curettage specimens. In the curettage specimens, overexpression of stathmin was significantly correlated with aggressive clinicopathologic characteristics, including high International Federation of Gynecology and Obstetrics (FIGO) stage, nonendometriod histology, high histology grade, aneuploidy, and presence of lymph node metastasis. In the hysterectomy specimens, stathmin expression correlated with aggressive histology, grade, and ploidy, but not FIGO stage or lymph node metastasis. Stathmin expression in hysterectomy and curettage specimens were significantly correlated but not completely overlapping: 251 (67%) of samples were cordant, and 126 (33%) were discordant.

In the univariate analysis of curettage specimens, histology, grade, and stathmin expression all were significantly correlated with the occurrence of lymph node metastasis. In multivariate analysis, stathmin expression was the strongest and the only independent predictor.

Highstathmin expression had a significant effect on cause-specific survival in patients who provided both curettage (P < .001) and hysterectomy (P = .002) specimens. In the group of patients with endometriod cancer who were analyzed separately, stathmin expression in curettage specimens was significantly correlated with cause-specific survival (P = .001).
In multivariate analyses adjusted for age, FIGO stage, histologic type, and grade, overexpression of stathmin in curettage specimens had independent prognostic value (adjusted hazard ratio [HR] 1.69). In hysterectomy specimens, the results were similar (HR 1.68).

To the authors’ knowledge, this is the first study to validate in a large, prospective multicenter trial the value of immunohistochemical staining of stathmin as a marker to detect endometrial cancer with an aggressive phenotype, and the first to identify stathmin expression in curettage specimens as an independent predictor for lymph node metastasis in these patients. They suggest that the findings be used in the design of future clinical trials, especially of targeted therapies, in endometrial cancer.

Studies have shown that stathmin overexpression in breast cancer cell lines contributes to taxane resistance. In patients with ovarian cancer, highstathmin expression was linked to worse survival for patients treated with a taxane in combination with a platinum-based agent, compared with those treated with a platinum-based agent alone. Thus, studies of stathmin expression as a predictive marker of taxane response in women with endometrial cancer are warranted.

Activation of the PI3- kinase/mTOR pathway has been associated with aggressive endometrial cancer and stathmin overexpression, suggesting that stathmin should be evaluated as a predictive marker for response to drugs targeting the PI3-kinase pathway