Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

PErsonalized TReatment for Endometrial Carcinoma (PETREC): study design and methods of a prospective Finnish multicenter trial.

BACKGROUND: Endometrial carcinomas can be classified into four molecular subgroups - mismatch repair deficient (MMRd), p53 abnormal (p53abn), polymerase-ϵ (POLE) ultramutated, and 'no specific molecular profile' (NSMP). Retrospective data imply that the response to adjuvant therapies may depend on the molecular subgroup. These findings emphasize the need for adjuvant therapy trials where patients are randomized to treatment arms separately within each molecular subgroup. PRIMARY OBJECTIVE: The PErsonalized TReatment for Endometrial Carcinoma (PETREC) trial clarifies the value of molecular classification in the determination of adjuvant therapies of high-intermediate risk and early-stage high-risk endometrial carcinoma. STUDY HYPOTHESIS: Compared with vaginal brachytherapy, the utilization of whole pelvic radiotherapy may result in improved outcomes for either MMRd or NSMP high-intermediate risk carcinomas. Early-stage high-risk p53abn and nonendometrioid carcinomas are postulated to gain benefits from chemoradiotherapy, as opposed to chemotherapy alone. POLE ultramutated carcinomas harboring high-intermediate or high-risk clinicopathologic features are speculated to have favorable prognosis without any adjuvant therapy. TRIAL DESIGN: This prospective, multicenter, phase 3 trial compares the efficacy of vaginal brachytherapy vs whole pelvic radiotherapy in high-intermediate risk MMRd and NSMP molecular subgroups, and chemotherapy vs chemoradiotherapy in early-stage high-risk p53abn subtype and nonendometrioid carcinomas. Eligible women who consent to participation in the trial are randomly allocated (1:1) to treatment arms. MAJOR INCLUSION/EXCLUSION CRITERIA: Women with stages I-II molecular integrated high-intermediate risk or high-risk endometrial carcinoma will be included. PRIMARY ENDPOINT: The primary endpoint is the 5 year cumulative incidence of disease recurrence. SAMPLE SIZE: A total sample size of 294 patients (49 subjects in each treatment arm of the three subgroups intended for randomization) was estimated to be sufficient. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed in 2025, and follow-up will be completed in 2030. TRIAL REGISTRATION: NCT05655260.

Long-term risk of cancer among the first-degree relatives of epithelial ovarian cancer patients: A cohort study with 48 years of follow up.

INTRODUCTION: The long-term risk of cancer among first-degree relatives of ovarian cancer patients, especially their offspring, is of apparent clinical importance. Risks caused by known inherited factors such as BRCA1 or BRCA2 pathogenic variants are well established, but these account for only about 15% of ovarian cancer cases. Less is known about the possible familial risks of sporadic ovarian cancers. MATERIAL AND METHODS: Using registry data, we conducted a retrospective cohort study with a total of 6501 first-degree relatives of 559 epithelial ovarian cancer patients. We studied the occurrence of overall cancer and cancer in specific sites known or suspected to be associated with ovarian cancer (breast, cervix, colon, endometrium, lung and trachea, skin melanoma, ovary, pancreas, prostate, rectum, and stomach). RESULTS: The overall number of cancers was not increased among the first-degree relatives of epithelial ovarian cancer patients during the up to 48 years of follow up. Among female relatives, the standardized incidence ratio for ovarian cancer was 1.92 (95% CI 1.27-2.79), mostly explained by a 2.30-fold (95% CI 1.46-3.45) risk among the patients' sisters. There was a decreasing trend in the standardized incidence ratio for ovarian cancer among patients' sisters by increasing age of the index patient. CONCLUSIONS: In our study cohort, we did not observe an increase in the overall cancer risk among the first-degree relatives of epithelial ovarian cancer patients in comparison with the general population. The risk for ovarian cancer, however, was increased. Current recommendations suggest prophylactic removal of the fallopian tubes and ovaries only with identified inherited risk factors. Our results emphasize the role of genetic counseling and testing, particularly in young ovarian cancer patients and their close female relatives.

Improved survival after implementation of ultra-radical surgery in advanced epithelial ovarian cancer: Results from a tertiary referral center.

OBJECTIVE: To compare survival rates of surgically treated advanced epithelial ovarian cancer patients before and after a programmatic change in surgical approach from standard surgery towards ultra-radical surgery. METHODS: 247 patients with FIGO stage IIIB-IV ovarian, tubal, and primary peritoneal carcinoma were operated during 2013-2019 either by primary or interval cytoreduction in Tampere University Hospital, Finland. Group 1 (n = 122) patients were operated during 2013 and February 2016. Group 2 patients (n = 125) were operated between March 2016 and March 2019, when a systematic change in surgical approach towards more extensive surgery was implemented. RESULTS: The complete resection (R0) rate increased significantly from 17.2% (21/122) to 52.0% (65/125) within the study period (p < 0.001). The median progression-free survival (PFS) was 15.6 months vs 19.3 months (p = 0.037), and the median overall survival (OS) was 33.5 months vs 54.5 months in Groups 1 and 2, respectively (p = 0.028). Median OS for stage III patients in Group 1 was 36.1 months (95% CI 27.4-44.8) but could not be reached in Group 2 (p = 0.009). In Stage IV patients, OS was 32.0 months (16.4-47.7) and 39.3 months (24.8-53.8) in Group 1 and 2, respectively (p = 0.691). Multivariable Cox regression analysis revealed that OS was independently affected by the amount of residual tumor and complication grade. CONCLUSIONS: The change of surgical approach towards maximal surgical effort improved both progression-free and overall survival. The survival benefit was unquestionable for stage III patients but did not reach statistical significance in stage IV patients.

ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors.

Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Decreasing trend and changing indications of hysterectomy in Finland.

INTRODUCTION: Hysterectomy has been one of the most common surgical procedures in women in Finland. We studied the population-based trends of hysterectomy and its indications from 1986 to 2017. MATERIAL AND METHODS: A retrospective population-based cohort was created from the Care Register for Health Care by identifying women who had a hysterectomy from 1986 to 2017 and calculating the number of women from the Digital and Population Data Services Agency. We estimated the number and incidence of hysterectomy by period and age as well as by indication. We considered the primary diagnosis at the time of surgery as the indication of hysterectomy. RESULTS: The number of hysterectomies increased from 7492 procedures in 1986 to 12 404 procedures in 1998, and reduced substantially after that to 5971 procedures in 2017, the turning point being in 1999. The incidence rate of hysterectomy has decreased on average by 2.5% annually from 432.6 per 100 000 women in 1998-2001 to 224.5 per 100 000 women in 2014-2017. The median age at the time of hysterectomy has increased from 51 years in 1998-2001 to 55 years in 2014-2017. The cumulative burden of hysterectomy by age of 60 years has nearly halved from the first 4-year period (23%) to the last (12%). After 2010, the most common indication has been genital prolapse and incontinence, whereas earlier it was uterine fibroids. CONCLUSIONS: The number and incidence of hysterectomies have fluctuated during the observation period 1986-2017 and decreased considerably during the past 17 years in Finland. This is probably a result of the availability of hormonal and other conservative treatment options for bleeding disorders and uterine fibroids. As hysterectomy practically removes the risk for endometrial cancer, the change in hysterectomy incidence over time emphasizes the importance of correcting endometrial cancer incidence according to hysterectomy incidence.

The Expression of HSD17B12 Is Associated with COX-2 Expression and Is Increased in High-Grade Epithelial Ovarian Cancer.

OBJECTIVE: The aim of this study was to characterize the expression of hydroxysteroid (17ß) dehydrogenase type 12 (HSD17B12), an enzyme involved in the synthesis of arachidonic acid (AA), in ovarian cancer, and to study its coexpression with its upstream and downstream enzymes in the AA pathway, namely elongation of very long chain fatty acids protein 5 (ELOVL5) and cyclooxygenase-2 (COX-2), respectively. MATERIALS AND METHODS: Samples from benign and malignant ovarian neoplastic lesions were immunohistochemically stained with HSD17B12, ELOVL5, and COX-2. The staining intensities were quantified with the QuantCenter program, and the results were confirmed with visual inspection. Statistical significances were calculated with the Student t test, the Mann-Whitney test, linear regression, or ANOVA. RESULTS: The expression of the HSD17B12, ELOVL5, and COX-2 enzymes increased according to the grade of the endometrioid ovarian adenocarcinomas. In contrast, in serous adenocarcinomas, staining with ELOVL5 was constantly weak, whereas the expression of HSD17B12 and COX-2 increased with the grade or FIGO stage of the cancer, respectively. CONCLUSIONS: The expression of HSD17B12 increased along with the severity of ovarian cancer, and the expression mimicked COX-2 expression and intensity. This further suggests the involvement of HSD17B12 in AA production, and its coexpression with COX-2 indicates a role for the enzyme in the increased prostaglandin production during ovarian cancer progression.

18F-FDG-PET/CT based total metabolic tumor volume change during neoadjuvant chemotherapy predicts outcome in advanced epithelial ovarian cancer.

OBJECTIVE: To evaluate the predictive potential of total metabolic tumor volume (MTV) reduction during neoadjuvant chemotherapy (NACT) with 18F-FDG-PET/CT in an advanced FIGO stage III/IV epithelial ovarian cancer (EOC) patient cohort. METHODS: Twenty-nine primarily inoperable EOC patients underwent 18F-FDG-PET/CT before and after NACT. The pre- and post-NACT total MTV, in addition to the percentage MTV reduction during NACT, were compared with primary therapy outcome and progression-free survival (PFS). ROC-analysis determined an optimal threshold for MTV reduction identifying patients with progressive or stable disease (PD/SD) at the end of primary therapy. A multivariate analysis with residual tumor (0/>0), FIGO stage (III/IV) and MTV reduction compared to PFS was performed. The association between MTV reduction and overall survival (OS) was evaluated. RESULTS: The median pre- and post-NACT total MTV were 352 cm3 (range 150 to 1322 cm3) and 51 cm3 (range 0 to 417 cm3), respectively. The median MTV reduction during NACT was 89% (range 24% to 100%). Post-NACT MTV and MTV reduction associated with primary therapy outcome (MTV post-NACT p = 0.007, MTV reduction p = 0.001) and PFS (MTV post-NACT p = 0.005, MTV reduction p = 0.005). MTV reduction <85% identified the PD/SD patients (sensitivity 70%, specificity 78%, AUC 0.79). In a multivariate analysis, MTV reduction (p = 0.002) and FIGO stage (p = 0.003) were statistically significant variables associated with PFS. MTV reduction during NACT corresponded to OS (p = 0.05). CONCLUSION: 18F-FDG-PET/CT is helpful in NACT response evaluation. Patients with total MTV reduction <85% during NACT might be candidates for second-line chemotherapy and clinical trials, instead of interval debulking surgery.

Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma.

OBJECTIVE: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. METHODS: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. RESULTS: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P<0.001) of dying of EEC compared to the low-risk group. CONCLUSIONS: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities.

Chemotherapy vs tamoxifen in platinum-resistant ovarian cancer: a phase III, randomised, multicentre trial (Ovaresist).

BACKGROUND: Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC. METHODS: Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m-2 or four weekly pegylated liposomal doxorubicin 40 mg m-2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS). RESULTS: Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0-10.4) compared with 12.7 weeks (95% CI, 9.0-16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16-2.05; log-rank P=0.003). There was no difference in OS between the treatment arms. CONCLUSIONS: Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.

Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer.

Primary chemotherapy treatment response monitoring in advanced epithelial ovarian cancer (EOC) is currently based on CT-imaging and serum CA125 values. Serum HE4 profile during first line chemotherapy has not been previously studied. We evaluated the HE4 profile during first line chemotherapy after primary (PDS) and interval debulking surgery (IDS). In total, 49 FIGO stage III/IV EOC patients were included in the study. 22 patients underwent PDS and 27 patients neoadjuvant chemotherapy (NACT) followed by IDS. Serial HE4 and CA125 serum samples were taken during first line chemotherapy. The association of postoperative tumor markers to surgery outcome, primary therapy outcome and progression free survival (PFS) were determined. The lowest HE4 and CA125 values during chemotherapy were compared to primary therapy outcome and PFS. The postoperative HE4 was associated to residual tumor after surgery (p = 0.0001), primary therapy outcome (p = 0.004) and PFS (p = 0.03) in all patients (n = 40). The postoperative CA125 was associated to PFS after IDS (n = 26, p = 0.006), but not after PDS. In multivariate analysis with FIGO stage (III/IV), residual tumor (0/>0) and postoperative CA125, the postoperative HE4 was the only statistically significant prognostic variable predicting PFS. Both HE4 and CA125 nadir corresponded to primary therapy outcome (HE4 p < 0.0001, CA125 p < 0.0001) and PFS (HE4 p = 0.009, CA125 p < 0.0001). HE4 is a promising candidate for EOC response monitoring. In our study, the performance of HE4 in response monitoring of first line chemotherapy was comparable to that of CA125. Of the postoperative values, only HE4 was statistically significantly associated to primary therapy outcome.

A Nanoparticle-Lectin Immunoassay Improves Discrimination of Serum CA125 from Malignant and Benign Sources.

BACKGROUND: Measurement of serum cancer antigen 125 (CA125) is the standard approach for epithelial ovarian cancer (EOC) diagnostics and follow-up. However, the clinical specificity is not optimal because increased values are also detected in healthy controls and in benign diseases. CA125 is known to be differentially glycosylated in EOC, potentially offering a way to construct CA125 assays with improved cancer specificity. Our goal was to identify carbohydrate-reactive lectins for discriminating between CA125 originating from EOC and noncancerous sources. METHODS: CA125 from the OVCAR-3 cancer cell line, placental homogenate, and ascites fluid from patients with cirrhosis were captured on anti-CA125 antibody immobilized on microtitration wells. A panel of lectins, each coated onto fluorescent europium-chelate-doped 97-nm nanoparticles (Eu(+3)-NPs), was tested for detection of the immobilized CA125. Serum samples from high-grade serous EOC or patients with endometriosis and healthy controls were analyzed. RESULTS: By using macrophage galactose-type lectin (MGL)-coated Eu(+3)-NPs, an analytically sensitive CA125 assay (CA125(MGL)) was achieved that specifically recognized the CA125 isoform produced by EOC, whereas the recognition of CA125 from nonmalignant conditions was reduced. Serum CA125(MGL) measurement better discriminated patients with EOC from endometriosis compared to conventional immunoassay. The discrimination was particularly improved for marginally increased CA125 values and for earlier detection of EOC progression. CONCLUSIONS: The new CA125(MGL) assay concept could help reduce the false-positive rates of conventional CA125 immunoassays. The improved analytical specificity of this test approach is dependent on a discriminating lectin immobilized in large numbers on Eu(+3)-NPs, providing both an avidity effect and signal amplification.

18F-FDG-PET/CT can identify histopathological non-responders to platinum-based neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to examine the relationship between the reduction of maximum standardized uptake values (SUVmax) in 18F-FDG-PET/CT to histopathological changes obtained with neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). We wanted to evaluate whether 18F-FDG-PET/CT is useful for identifying patients who will not respond to NACT and would therefore benefit from second-line chemotherapy instead of interval debulking surgery (IDS). METHODS: Twenty-six primarily inoperable EOC patients treated with NACT were enrolled in this study. 18F-FDG-PET/CT imaging was performed before diagnostic laparoscopy and after three to four NACT cycles. The relationship between the decrease in omental SUVmax from before to after NACT with omental histopathological response was examined in samples taken from the corresponding anatomical sites during IDS. Patients were divided into three groups according to chemotherapy-induced histopathological changes. Serum CA125 and HE4 halftimes during NACT as well as Ki-67 antigen expression in IDS samples were determined. RESULTS: The median omental SUVmax change during NACT was -64% (range-16% to -84%), and it was associated with histopathological response (p=0.004, OR 0.9, CI 0.84-0.97). A SUVmax decrease of less than 57% identified histopathological non-responders. Progression-free survival (PFS) differed between the poor, moderate and good histopathological response groups (0.9 year vs. 1.2 years vs. 1.4 years, respectively, p=0.05). The SUVmax change was not associated with PFS. CONCLUSION: 18F-FDG-PET/CT was able to identify patients who would not respond to NACT. To obtain a histopathological response in EOC, a substantial metabolic response in 18F-FDG-PET/CT is necessary.

Loss of ASRGL1 expression is an independent biomarker for disease-specific survival in endometrioid endometrial carcinoma.

OBJECTIVE: For endometrial carcinoma, prognostic stratification methods do not satisfactorily identify patients with adverse outcome. Currently, histology, tumor grade and stage are used to tailoring surgical treatment and to determine the need for adjuvant treatment. Low-risk patients are not considered to require adjuvant therapy or staging lymphadenectomy. For patients with intermediate or high risk, some guidelines recommend tailoring adjuvant treatment according to additional negative prognostic factors. Our objective was to evaluate the biomarker potential of the ASRGL1 protein in endometrial carcinoma. METHODS: Using The Human Protein Atlas (www.proteinatlas.org), the l-asparaginase (ASRGL1) protein was identified as an endometrial carcinoma biomarker candidate. ASRGL1 expression was immunohistochemically evaluated with an extensively validated antibody on two independent endometrial carcinoma cohorts (n=229 and n=286) arranged as tissue microarrays. Staining results were correlated with clinical features. RESULTS: Reduced expression of ASRGL1, defined as <75% positively stained tumor cells, was significantly associated with poor prognosis and reduced disease-specific survival in endometrioid endometrial adenocarcinoma (EEA). In multivariate analysis the hazard ratios for disease-specific survival were 3.55 (95% CI=1.10-11.43; p=0.003) and 3.23 (95% CI=1.53-6.81; p=0.002) in the two cohorts, respectively. Of the 48 cases with Grade 3 Stage I tumor all disease-related deaths were associated with low ASRGL1 expression. CONCLUSIONS: Loss of ASRGL1 in EEA is a powerful biomarker for poor prognosis and retained ASRGL1 has a positive impact on survival. ASRGL1 immunohistochemistry has potential to become an additional tool for prognostication in cases where tailoring adjuvant treatment according to additional prognostic factors besides grade and stage is recommended.

Serum HE4 and CA125 as predictors of response and outcome during neoadjuvant chemotherapy of advanced high-grade serous ovarian cancer.

Human epididymis protein 4 (HE4) is a novel tumour marker in epithelial ovarian cancer (EOC). Data on its profile and predictive potential for subsequent outcome after neoadjuvant chemotherapy (NACT) are still under investigation. The aim of this study was to compare CA125 and HE4 profiles with radiologic response after NACT and to evaluate their potential as predictors of clinical outcome in a primarily inoperable EOC patient cohort. Twenty-five EOC patients of high-grade subtype (HGSC) treated with NACT were enrolled in the study. Serum HE4 and CA125 samples were taken at the time of diagnosis and before interval debulking surgery (IDS). Pre-NACT and pre-IDS HE4 and CA125 and their percentage changes were compared with NACT response seen on CT and surgical outcome in IDS. We also evaluated the biomarkers' abilities to predict platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). All 25 patients were considered inoperable in laparoscopy at the time of diagnosis. HE4 and CA125 changes during NACT did not correlate with the changes seen on CT. Surgical outcome in IDS was associated with pre-IDS biomarker values but not with those taken before diagnosis. In IDS, 87 % had <1-cm residual tumour. In patients with HE4 change >80 and <80 % during NACT, the median OS was 3.38 and 1.60 years (p = 0.01), respectively. Serum HE4 is a promising additional tool when evaluating advanced HGSC patient's response to NACT. It may be helpful when deciding whether to proceed to IDS or to second-line chemotherapy.

Sensitive circulating tumor DNA-based residual disease detection in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related death in women worldwide, and is characterized by a high rate of recurrence after surgery and chemotherapy. We sought to implement a circulating tumor DNA (ctDNA)-based blood test for more accurate post-operative surveillance of this disease. We analyzed 264 plasma samples collected between June 2016 and September 2021 from 63 EOC patients using tumor-guided plasma cell-free DNA analysis to detect residual disease after treatment. Assay specificity was verified using cross-patient analysis of 1,195 control samples. ctDNA was detected in 51 of 55 (93%) samples at diagnosis, and 18 of 18 (100%) samples at progression. Positive ctDNA in the last on-treatment sample was associated with rapid progression (median 1.02 versus 3.38 yr, HR = 5.63, P < 0.001) and reduced overall survival (median 2.31 versus NR yr, HR = 8.22, P < 0.001) in patients with high-grade serous cancer. In the case of 12 patients, ctDNA assays detected progression earlier than standard surveillance, with a median lead time of 5.9 mo. To approach the physical limits of ctDNA detection, five patients were analyzed using ultra-sensitive assays interrogating 479-1,856 tumor mutations, capable of tracking ctDNA fractions down to 0.0004%. Our results demonstrate that ctDNA assays achieve high sensitivity and specificity in detecting post-operative residual disease in EOC.

Is perioperative visual estimation of intra-abdominal tumor spread reliable in ovarian cancer surgery after neoadjuvant chemotherapy?

OBJECTIVE: Most cases of epithelial ovarian cancer (EOC) are diagnosed in an advanced stage. When the disease has spread intra-abdominally, complete surgical tumor debulking is the single most important prognostic factor. Neoadjuvant chemotherapy (NACT) before surgery can cause fibrosis and adhesions in the peritoneal cavity and may interfere with the perioperative evaluation of tumor spread. In this prospective study, we evaluated whether perioperative visual assessment of tumor dissemination is similar in patients undergoing primary and interval surgery for EOC. METHODS: Systematic visual evaluation of tumor spread was performed at the start of primary surgery/diagnostic laparoscopy (n=39) or interval surgery (n=16). Peritoneal cavity was divided into 22 anatomical regions. The carefully documented results of the visual assessment were compared with the histopathological analysis of 220 biopsies from primary and 92 biopsies from interval surgery. RESULTS: In primary surgery, perioperative visual estimation of tumor spread showed 98% sensitivity, 76% specificity and 95% accuracy compared to histopathology. The corresponding figures after NACT were 86%, 76% and 84%, respectively. The difference in sensitivity and accuracy in primary and interval operations was statistically significant (p<0.001). CONCLUSIONS: In advanced EOC, microscopically carcinomatous areas have a benign visual appearance more often after NACT than at primary surgery. NACT may interfere with the perioperative visual evaluation of tumor spread and thus lead to incomplete resection of tumor in potentially resectable areas.