Novel preoperative biomarkers and evaluation of altered treatment strategies to improve outcome for endometrial cancer patients
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Background: Endometrial cancer is the most common gynecological cancer among women in countries with a high developmental index, and the incidence is expected to rise. Major controversies in the treatment of endometrial cancer revolve around the identification of women at risk of recurrence and optimal modes of treatment to minimize this risk. In addition, optimizing treatment-related quality of life is gaining attention. In recent years, several biomarkers have been identified and gradually implemented through changes in treatment algorithms, but further refinement is needed. Also, continuous evaluation of the resulting treatment changes is vital to improve survival and quality of life for endometrial cancer patients. Aims: The overall aim was to improve endometrial cancer treatment through better preoperative stratification and evaluation of the effects of different treatment modalities on survival and morbidity. Methods: In Paper I, 100 postmenopausal patients were selected from a population-based cohort, reflecting the clinical characteristics of the whole cohort. Preoperative blood samples were analyzed by liquid chromatography-tandem mass spectrometry, using a clinically implemented steroid hormone panel. Steroid levels were related to survival, tumor characteristics, radiologic assessment of fat distribution and gene expression. In Paper II, all consenting endometrial cancer patients receiving primary treatment at Haukeland University Hospital over the period 2001-2019 were reviewed with a focus on comparing outcomes before and after implementing major treatment changes. These treatment changes were 1) a discontinuation of radiotherapy as an adjuvant treatment from 2009 (due to changes in national guidelines) and 2) a local initiative to implement a biomarker- and imaging-based selective lymphadenectomy policy in 2012-2013 to reduce the rate of patients undergoing lymphadenectomy. We assessed recurrence and survival and performed a trend analysis of changes in clinical and pathological factors over the time period. In Paper III, we determined the effects of treatment modalities on quality of life and treatment-related symptoms in Norwegian patients enrolled in the ongoing Molecular Markers in the Treatment of Endometrial Cancer 2 (MoMaTEC2). Patients were grouped by received treatment modalities. Patient-reported outcomes at baseline and one and two years postoperatively were analyzed and compared to a Norwegian reference population. We used linear mixed models to assess the individual contribution of different treatment modalities. Results: Low preoperative levels of 17-hydroxyprogesterone, 11-deoxycortisol and androstenedione were associated with aggressive tumor characteristics and poor disease-specific survival. 17-hydroxyprogesterone and 11-deoxycortisol were associated with prognosis independently of preoperative histological type and grade. Gene expression analysis revealed that tumors in patients with lower levels of these hormones expressed gene sets related to proliferation and cell cycle progression to a higher degree, whereas tumors in patients with higher levels expressed more inflammation-related genes. Higher levels of estrone and estradiol were associated with higher levels of body fat, expression of hormonal receptors and estrogen signaling-related gene expression, but not with survival (Paper I). After omitting radiotherapy as an adjuvant modality, 5-year overall survival increased in FIGO stage III (0.49 to 0.61, p=0.04) and recurrence-free survival increased from 0.51 to 0.71 (p=0.03). In other stages, survival outcome was maintained. For patients with stage I high-risk disease, the rate receiving adjuvant chemotherapy increased from 40% to 79%, but was not associated with any gain in survival (Paper II). The proportion of patients undergoing lymphadenectomy was reduced from 78% in 2001-2012 to 53% in 2013-2019 (p<0.001), with a maintained proportion of all patients with lymph node metastasis (9% versus 8%, p = 0.58). Patients not undergoing lymphadenectomy after 2012 were signified by low-intermediate risk based on MRI and histology of preoperative samples, negative PET/CT imaging and ER/PR positivity. Stage I patients, not undergoing lymphadenectomy, had maintained recurrence-free survival when comparing the time periods (Paper II). We found quality of life and functioning in endometrial cancer survivors comparable to a healthy age- and sex-matched cohort but significantly lower at baseline and increasing at year one and two post-operatively. Patients treated with adjuvant chemotherapy reported more tingling/numbness, lymphedema, and muscular pain at follow-up. There were no observable differences between patients in the groups not receiving chemotherapy (with or without lymph node staging). In multivariable mixed models, adjuvant chemotherapy was associated with tingling/numbness, lymphedema, fatigue and reduced physical functioning (Paper III). Conclusions: Blood steroids have prognostic value, can be assessed from a preoperative blood sample with existing routine methods and may provide additive value to established preoperative biomarkers (Paper I). Replacing adjuvant radiotherapy with adjuvant chemotherapy had no negative impact on survival and showed improved survival for stage III patients (Paper II). However, a marked increase in chemotherapy to stage I high-risk patients was not accompanied by an improved survival or recurrence rate, indicating an important area for further stratification of patients by biomarkers (Paper II). A selective lymphadenectomy algorithm based on hormonal and imaging biomarkers allowed for a substantial reduction of patients undergoing lymphadenectomy. The rate of patients with diagnosed lymph node metastasis and recurrence-free survival was maintained (Paper II). Overall quality of life is good for endometrial cancer patients. The group receiving adjuvant chemotherapy, however, reported increases in several symptoms, whereas patients undergoing lymphadenectomy without receiving chemotherapy did not. Removal of lymph nodes to select patients for adjuvant therapy therefore seems justified from the patient’s viewpoint (Paper III). In addition, the combination of unchanged survival and worse symptoms for early-stage patients receiving adjuvant chemotherapy warrants more focus on ways to optimize treatment for this group (Paper II/III).
Består avPaper I: Forsse D, Tangen IL, Fasmer KE, Halle MK, Viste K, Almås B, Bertelsen BE, Trovik J, Haldorsen IS, Krakstad C. Blood steroid levels predict survival in endometrial cancer and reflect tumor estrogen signaling. Gynecol Oncol. 2020 Feb;156(2):400-406. The article is available at: https://hdl.handle.net/1956/22358
Paper II: Forsse D, Berg HF, Bozickovic O, Engerud H, Halle MK, Hoivik EA, Woie K, Werner HMJ, Haldorsen IS, Trovik J, Krakstad C. Maintained survival outcome after reducing lymphadenectomy rates and optimizing adjuvant treatment in endometrial cancer. Gynecol Oncol 160(2): 396-404. The article is available at: https://hdl.handle.net/11250/2753451
Paper III: Forsse D, Barbero ML, Werner HMJ, Woie K, Nordskar N, Berge Nilsen E, Ellstrøm Engh M, Vistad I, Rege A, Sævik-Lode M, Andreasen S, Haldorsen IS, Trovik J, Krakstad C. Longitudinal effects of adjuvant chemotherapy and lymph node staging on patient-reported outcome in endometrial cancer survivors: a prospective cohort study. Am J Obstet Gynecol 2021. The submitted version is available in the thesis file. The published version is available at: https://doi.org/10.1016/j.ajog.2021.08.011