Is it safe to operate selected low-risk endometrial cancer patients in secondary hospitals?

INTRODUCTION: The aim of this study was to assess the accuracy of a preoperative screening algorithm in identifying low-risk endometrial cancer (EC) patients to ensure optimal care. METHODS: A total of 277 patients with primary EC confirmed through biopsy underwent magnetic resonance imaging (MRI). Patients with risk factors for advanced high-risk EC, such as non-endometrioid histology, high-grade differentiation status, deep myometrial invasion, or spread beyond the uterine corpus, were systematically excluded. The remaining preoperatively screened patients with stage IA low-grade endometrioid EC (EEC) (n = 93) underwent surgery in a tertiary hospital. The accuracy of the preoperative diagnosis was evaluated by comparing the findings with the postoperative histopathological results. Disease-free survival (DFS) and overall survival (OS) were analyzed using 8-year follow-up data. RESULTS: Postoperative histopathological analysis revealed that all patients had grade 1-2 EEC localized to the corpus uteri. Only three patients had deep myometrial invasion (stage IB), but they remained disease-free after 6-9 years of follow-up. The median follow-up time for all patients was 8.7 years. The DFS was 7.6 years, and the OS was 8.6 years. Two patients with stage IA grade 1 EEC experienced relapse and, despite treatment, died of EC. No other EC-related deaths occurred. CONCLUSIONS: The screening algorithm accurately identified low-risk EC patients without compromising survival. Therefore, the algorithm appears to be feasible for selecting patients for surgery in secondary hospitals.

HRD related signature 3 predicts clinical outcome in advanced tubo-ovarian high-grade serous carcinoma.

OBJECTIVES: We evaluated usability of single base substitution signature 3 (Sig3) as a biomarker for homologous recombination deficiency (HRD) in tubo-ovarian high-grade serous carcinoma (HGSC). MATERIALS AND METHODS: This prospective observational trial includes 165 patients with advanced HGSC. Fresh tissue samples (n = 456) from multiple intra-abdominal areas at diagnosis and after neoadjuvant chemotherapy (NACT) were collected for whole-genome sequencing. Sig3 was assessed by fitting samples independently with COSMIC v3.2 reference signatures. An HR scar assay was applied for comparison. Progression-free survival (PFS) and overall survival (OS) were studied using Kaplan-Meier and Cox regression analysis. RESULTS: Sig3 has a bimodal distribution, eliminating the need for an arbitrary cutoff typical in HR scar tests. Sig3 could be assessed from samples with low (10%) cancer cell proportion and was consistent between multiple samples and stable during NACT. At diagnosis, 74 (45%) patients were HRD (Sig3+), while 91 (55%) were HR proficient (HRP, Sig3-). Sig3+ patients had longer PFS and OS than Sig3- patients (22 vs. 13 months and 51 vs. 34 months respectively, both p < 0.001). Sig3 successfully distinguished the poor prognostic HRP group among BRCAwt patients (PFS 19 months for Sig3+ and 13 months for Sig3- patients, p < 0.001). However, Sig3 at diagnosis did not predict chemoresponse anymore in the first relapse. The patient-level concordance between Sig3 and HR scar assay was 87%, and patients with HRD according to both tests had the longest median PFS. CONCLUSIONS: Sig3 is a prognostic marker in advanced HGSC and useful tool in patient stratification for HRD.

Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes.

PURPOSE: Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination-deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes. EXPERIMENTAL DESIGN: We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status. RESULTS: fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence-treated patients with longer OS (P = 0.0188). CONCLUSIONS: We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response. See related commentary by Garg and Oza, p. 2957.

Genetic, clinic and histopathologic characterization of BRCA-associated hereditary breast and ovarian cancer in southwestern Finland.

We have analyzed the histopathological, clinical, and genetic characteristics in hereditary breast and ovarian cancer patients of counselled families from 1996 up to today in the southwestern Finland population. In this study we analyzed the incidence of different BRCA1 and BRCA2 pathogenic variants (PV). 1211 families were evaluated, and the families were classified as 38 BRCA1 families, 48 BRCA2 families, 689 non-BRCA families and 436 other counselled families (criteria for genetic testing was not met). In those families, the study consisted of 44 BRCA1 breast and/or ovarian cancer patients, 58 BRCA2 cancer patients, 602 non-BRCA patients and 328 other counselled patients. Breast cancer mean onset was 4.6 years earlier in BRCA1 carriers compared to BRCA2 (p = 0.07, a trend) and ovarian cancer onset almost 11 years earlier in BRCA1 families (p < 0.05). In BRCA families the onset of ovarian cancer was later than 40 years, and BRCA2-origin breast cancer was seen as late as 78 years. The BRCA PV (9%) increases the risk for same patient having both ovarian and breast cancer with a twofold risk when compared to non-BRCA group (4%) (95% CI p < 0.05). Triple-negativity in BRCA1 (42%) carriers is approximately 2.6 times vs more common than in BRCA2 carriers (16%) (p < 0.05). The risk ratio for bilateral breast cancer is approximately four times when compared BRCA2 (17%) and other counselled patients' group (4%) (p < 0.05). 27% southwestern BRCA2-families have a unique PV, and correspondingly 39% of BRCA1-families. The results of this analysis allow improved prediction of cancer risk in high-risk hereditary breast and ovarian families in southwestern Finland and improve long term follow-up programs. According to the result it could be justified to have the discussion about prophylactic salpingo-oophorectomy by the age of 40 years. The possibility of late breast cancer onset in BRCA2 carriers supports the lifelong follow-up in BRCA carriers. Cancer onset is similar between BRCA2 carries and non-BRCA high-risk families. This study evaluated mutation profile of BRCA in southwestern Finland. In this study genotype-phenotype correlation was not found.

Network-guided identification of cancer-selective combinatorial therapies in ovarian cancer.

Each patient's cancer consists of multiple cell subpopulations that are inherently heterogeneous and may develop differing phenotypes such as drug sensitivity or resistance. A personalized treatment regimen should therefore target multiple oncoproteins in the cancer cell populations that are driving the treatment resistance or disease progression in a given patient to provide maximal therapeutic effect, while avoiding severe co-inhibition of non-malignant cells that would lead to toxic side effects. To address the intra- and inter-tumoral heterogeneity when designing combinatorial treatment regimens for cancer patients, we have implemented a machine learning-based platform to guide identification of safe and effective combinatorial treatments that selectively inhibit cancer-related dysfunctions or resistance mechanisms in individual patients. In this case study, we show how the platform enables prediction of cancer-selective drug combinations for patients with high-grade serous ovarian cancer using single-cell imaging cytometry drug response assay, combined with genome-wide transcriptomic and genetic profiles. The platform makes use of drug-target interaction networks to prioritize those combinations that warrant further preclinical testing in scarce patient-derived primary cells. During the case study in ovarian cancer patients, we investigated (i) the relative performance of various ensemble learning algorithms for drug response prediction, (ii) the use of matched single-cell RNA-sequencing data to deconvolute cell population-specific transcriptome profiles from bulk RNA-seq data, (iii) and whether multi-patient or patient-specific predictive models lead to better predictive accuracy. The general platform and the comparison results are expected to become useful for future studies that use similar predictive approaches also in other cancer types.

Molecular subtype diagnosis of endometrial carcinoma: comparison of the next-generation sequencing panel and Proactive Molecular Risk Classifier for Endometrial Cancer classifier.

The Cancer Genome Atlas-based molecular classification of endometrial carcinoma (EC) has the potential to better identify those patients whose disease is likely to behave differently than predicted when using traditional risk stratification; however, the optimal approach to molecular subtype assignment in routine practice remains undetermined. The aim of this study was to compare the results of two different widely available approaches to diagnosis the EC molecular subtype. EC specimens from 60 patients were molecularly subclassified using two different methods, by using the FoundationOne CDx next-generation sequencing (NGS) panel and using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classifier and performing immunostaining for mismatch repair proteins and p53. POLE mutation status was derived from FoundationOne results in both settings. Molecular classification based on ProMisE was successful for all 60 tumors. Microsatellite instability status could be determined based on the NGS panel results in 53 of 60 tumors, so ProMisE and NGS molecular subtype assignment could be directly compared for these 53 tumors. Molecular subtype diagnosis based on NGS and ProMisE was in agreement for 52 of 53 tumors. One tumor was microsatellite stable but showed loss of MLH1 and PMS2 expression. Molecular subtype diagnosis of EC based on the NGS panel of formalin-fixed paraffin-embedded ECs and based primarily on immunostaining (ProMisE) yields identical results in 98.1% (52/53, kappa = 0.97) of cases. Although results obtained using these two approaches are comparable, each has advantages and disadvantages that will influence the choice of the method to be used in clinical practice.

Waveform analysis of the fetal ECG in labor in patients with intrahepatic cholestasis of pregnancy.

AIM: Intrahepatic cholestasis of pregnancy (ICP) is reported to be associated with an increased risk of sudden fetal death. The possible mechanism is thought to be cardiac arrhythmia. Prolonged QT interval of the electrocardiogram (ECG) is associated with arrhytmogenic events. The aim of the study was to compare the fetal ECG QT interval during labor in pregnancies complicated with ICP to healthy controls. METHODS: The fetal ECG and QT interval was reviewed retrospectively. The intrapartum QT interval was measured in 61 fetuses born to mothers with ICP and in a control group of similar size. The corrected QT interval (QTc) was calculated using Bazett's formula: QT/√RR. The occurrence of ST segment depression was also included in the analysis. RESULTS: The groups were similar regarding to maternal age, parity, BMI, gestational age and smoking habits. The rate of labor induction was significantly higher in ICP patients (P < 0.001). The QTc at the beginning and the end of recording was analyzed and there were no significant differences in these values between the ICP patients and healthy controls (P = 0.467). Most ICP patients used ursodeoxycholic acid (UDCA) for mediation. We analyzed separately patients who had elevated liver enzymes before labor. No significant differences in the QTc were noted in these patients either. Nor were there any significant ST depressions in ICP patients. CONCLUSIONS: The etiology of adverse perinatal outcome and even sudden fetal death in ICP is still controversial. No differences in QTc intervals and ST waveforms during labor were found in our study material.

Intrahepatic cholestasis of pregnancy: observational study of the treatment with low-dose ursodeoxycholic acid.

BACKGROUND: To exam the biochemical, obstetric management and pregnancy outcome in women with intrahepatic cholestasis of pregnancy (ICP) and treatment with ursodeoxycholic acid (UDCA). METHODS: Pregnancy outcome in patients with ICP (N = 307) was studied and patients treated with UDCA (N = 208) vs. no UDCA were compared. The data of the antenatal visits, deliveries and neonatal outcome of 307 pregnancies with ICP was collected from the hospital computerized delivery room log book. UDCA was used in 208 pregnancies. The diagnosis was made by maternal pruritus and elevation of total fasting bile acid (BA) (>6 µmol/l) and elevation of serum alanine aminotransferases (ALT) (>45 U/l). Maternal and neonatal data was analysed and data of the patients who used UDCA during pregnancy was analysed separately and compared with the data from patients without medication. RESULTS: UDCA was well tolerated. Mothers receiving UDCA had ICP diagnosed five weeks earlier than mothers without medication. At the diagnosis, levels of total BA and ALT were higher in the group using UDCA compared to the group without medication. Most deliveries were induced and perinatal outcome was good. Apgar scores at 5 min were significantly lower in UDCA group (p < 0.05), but fetal umbilical artery pH values were similar in both groups (p > 0.05). There were 30 patients with total BA > 40 µmol/l at diagnosis, 24 with UDCA and 6 without medication and those deliveries were induced soon after diagnosis. The preterm labour was also more common in these patents (p < 0.05). Women with preterm babies had significantly early onset pruritus and ICP was diagnosed earlier. Serum ALT and total BA levels were significantly higher in those pregnancies at diagnosis and also at first control. CONCLUSIONS: Preterm labour was associated in severe ICP (total BA > 40 µmol/l), ALT levels were also significantly higher and ICP was diagnosed earlier (p < 0.05). Apgar scores were lower in preterm babies (p < 0.05), but umbilical artery pHvalues were not significantly lower. UDCA was well tolerated by pregnant women. With low-dose UDCA treatment the obstetric outcome was good. We still recommend careful obstetrical follow-up.

Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: a randomized controlled trial.

PURPOSE: To test the efficacy and safety of ursodeoxycholic acid (UDCA) in the treatment of patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: In the randomized (double-blind, placebo-controlled) study 20 pregnant women with ICP received (random allocation of) either 450 mg/day UDCA or placebo for 14 days during the third trimester of pregnancy. The severity of pruritus was registered and itching scores were assessed before the treatment and weekly thereafter. The effects of UDCA on liver function and fetoplacental hormone production were measured with covering laboratory testing: serum levels of alanine aminotransferase (ALAT), total bile acids (TBA), estradiol, progesterone, prolactin, cholesterol, HDL-cholesterol, triglycerides, activated partial thromboplastin time, fibrinogen D-dimers (FIDD) and platelet count were assessed before the treatment and weekly thereafter. Data on pregnancy and delivery outcome were recorded and analyzed. RESULTS: UDCA was well tolerated. A significant improvement in itching scores was detected in 2 weeks in the group receiving UDCA. Serum levels of ALAT and TBA fell after 2 weeks treatment. The other laboratory values were not modified by the treatment. CONCLUSIONS: UDCA improves maternal itching scores and liver function tests without interfering with the fetoplacental estrogen production in patients with ICP. UDCA is well tolerated by pregnant women. No fetal or neonatal side-effects could be detected.

A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families.

OBJECTIVE/DESIGN: We performed a systematic review of studies that evaluate the role of gynecological cancer surveillance in women who carry a hereditary nonpolyposis colorectal cancer (HNPCC) mutation or belong to a family that fulfills the criteria for HNPCC. METHODS: The PubMed database and a clinical trials database were used to identify relevant studies. We included studies that reported results of gynecological cancer surveillance in women who carry a HNPCC mutation, belong to a family in which a HNPCC mutation was detected or belong to a family fulfilling the Amsterdam II criteria. MAIN OUTCOME MEASURES: Number and stage of cancers, interval cancers and cancer precursor states detected at screening. RESULTS: Five studies fulfilled our review criteria. Surveillance modalities for endometrial cancer included transvaginal ultrasound combined with endometrial sampling when indicated, or transvaginal ultrasound with a routine endometrial biopsy, and, in certain studies, the tumor marker CA-125. The highest yield of pathological findings in surveillance visits, from 5 to 6.5%, occurred in studies that included routine endometrial biopsies. Without a routine sampling, 7/14 cancers and 11/18 hyperplasias would have been missed. One case of advanced ovarian cancer was detected at surveillance. CONCLUSIONS: Currently available published studies on gynecological cancer surveillance in women with HNPCC do not adequately allow for evidence-based clinical decisions. Detection of endometrial cancer or hyperplasia in nonsymptomatic women belonging to an HNPCC family is improved by adding routine endometrial sampling along with transvaginal ultrasound for surveillance visits. No benefit was shown for ovarian cancer surveillance.

Hepatocellular enzyme glutathione S-transferase alpha and intrahepatic cholestasis of pregnancy.

OBJECTIVE: To evaluate and compare plasma glutathione S-transferase alpha (GSTA) concentrations in the third trimester of pregnancy in patients with intrahepatic cholestasis of pregnancy (ICP) and in healthy pregnant women. DESIGN: Non-randomized clinical study. SETTING: Maternity unit and Department of Clinical Chemistry, Turku University Central Hospital, Turku, Finland. POPULATION: Twenty-seven women with ICP and 49 healthy pregnant women. METHODS: GSTA concentrations were assessed in plasma samples in the third trimester of pregnancy using an enzyme-linked immunoassay (HEPKIT Alpha, Biotrin, Sinsheim-Reihen, Germany). MAIN OUTCOME MEASURES: Plasma GSTA, serum alanine and bile acid concentrations were compared between study and control group. Correlation between plasma GSTA levels and serum alanine aminotransferase and bile acid levels in the ICP patients were tested by Spearman correlation coefficients. Main perinatal outcome was compared between the groups. RESULTS: GSTA concentration in the control group was 1.62 microg/l (range: 0.25-6.1). In the ICP patients, the mean plasma GSTA concentration was 51.0 microg/l (range: 2.1-183.5), the mean serum alanine aminotransferase concentration was 145.70 U/l (range: 6-393) and the mean bile acid concentration was 19.2 micromol/l (range: 3-63). There was a statistically significant correlation in ICP patients between plasma GSTA concentration and serum alanine aminotransferase concentration (r=0.694, p=0.0001), but not with serum bile acid concentration. Nor was there any statistically significant correlation between gestational weeks and plasma GSTA concentration in the study group. CONCLUSION: Plasma GSTA measurements may provide a more sensitive and specific diagnostic tool for diagnosis of ICP than the evaluation of transaminases or bile acid concentrations alone. Further studies are needed to evaluate the role of GSTA in the follow-up of patients with ICP and its prognostic value for threatening fetal distress in patients with ICP.