Molecular markers to predict prognosis and guide therapy in endometrial cancer
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Background: Endometrial cancer is the most common gynecological malignancy in the Western world. The disease occurs in the epithelial lining of the uterus, called the endometrium. Although prognosis is good and most of the patients are diagnosed at an early stage, 15-20 % of patients experience recurrence. An accurate risk-stratification is lacking and as incidence is increasing due to the increased prevalence of obesity and extended life-expectancy, biomarkers for improved risk-stratification are needed. Main objective: The main objective was to define biomarkers to better identify high-risk patients from low-risk patients in order to individualize therapy and targeted treatment. Materials and methods: A prospectively and population-based series was collected and includes endometrial hyperplasias, primary tumors and metastases (Paper I-IV). Immunohistochemical staining was used for evaluation of HSF1, MSH6, PD-L1 and PD-1 (Paper I, III and IV). ELISA was performed for determination of plasma GDF-15 (Paper II). RNA microarray data were used for evaluation of mRNA levels (Paper I, III and IV). Results: High expression of HSF1 associated with aggressive disease and poor survival in endometrial cancer. Protein level of HSF1 increased from primary tumors to metastasis. We found HSF1 to be an independent prognostic marker within ER-positive patients, a patient group with a presumed favourable prognosis. Gene expression analyses identified HSP90 inhibitors for targeted therapy (Paper I). High plasma levels of GDF-15 associated with aggressive disease characteristics and poor prognosis, also in low-risk patients. GDF-15 can indicate recurrence during follow-up and was an independent marker for recurrence. We validated the role of GDF-15 as an independent marker for lymph node metastasis (Paper II). PD-L1 and PD-1 are frequently expressed in endometrial cancer, 59% and 63%, respectively (Paper III). Expression was similar across MSS and MSI tumors. PD-L1 and PD-1 have no impact on survival, nor when stratified for MSI. In corresponding metastatic lesions, expression was discordant and intra-variable compared to primary tumors. High protein level of MSH6 identified aggressive endometrial cancer, also in low-risk patients (Paper IV). The prognostic value of MSH6 was validated both in curettage and hysterectomy specimen. MSH6 has independent prognostic impact preoperatively adjusted for age, histological risk-classification and hormone receptor status in the whole patient cohort. Also in a subgroup of patients with a putative low-risk disease, MSH6 demonstrated independent prognostic impact adjusted for age and hormone receptor status (Paper IV). Conclusion: High expression of HSF1, GDF-15 and MSH6 predicts aggressive disease and poor survival (Paper I, II and IV). GDF-15 is an independent predictor of recurrent disease and lymph node metastasis (Paper II). PD-L1 and PD-1 are frequently expressed and expression pattern is similar across MSS and MSI tumors. Expression in corresponding metastatic lesions is discordant and intra-variable (Paper III).
Has partsPaper I: Engerud H, Tangen IL, Berg A, Kusonmano K, Halle MK, Oyan AM, Kalland KH, Stefansson I, Trovik J, Salvesen HB, Krakstad C. High level of HSF1 associates with aggressive endometrial carcinoma and suggests potential for HSP90 inhibitors. Br J Cancer 2014, 111(1):78-84. The article is not available in the thesis file due to publisher restrictions. The published version is available at: https://doi.org/10.1038/bjc.2014.262.
Paper II: Engerud H, Hope K, Berg HF, Fasmer KE, Tangen IL, Haldorsen IS, Trovik J, Krakstad C. Plasma growth differentiation factor-15 is an independent marker for aggressive disease in endometrial cancer. PLoS One 2019, 14(1):e0210585. The article is available in the thesis file. The article is also available at: https://doi.org/10.1371/journal.pone.0210585.
Paper III: Engerud H, Berg HF, Myrvold M, Halle MK, Bjorge L, Haldorsen IS, Hoivik EA, Trovik J, Krakstad C. High degree of heterogeneity of PD-L1 and PD-1 from primary to metastatic endometrial cancer. Gynecologic Oncology 2020. The article is not available in the thesis file. The published version is available at: https://doi.org/10.1016/j.ygyno.2020.01.020.
Paper IV: Myrvold M*, Engerud H*, Halle MK, Hoivik EA, Trovik J, Berg HF, Krakstad C. Added value of MSH6 as a prognostic marker in endometrial cancer. *Shared first author. The article is not available in the thesis file.