Search

Introduction Gynecological cancer patients are routinely followed up for five years after primary treatment. However, the value of such follow up has been debated, as retrospective studies indicate that first recurrence is often symptomatic and occurs within two to three years of primary treatment. We prospectively investigated time to first recurrence, symptoms at recurrence, diagnostic procedures, and recurrence treatment in gynecological cancer patients after primary curative treatment. Material and methods Clinicians from 21 hospitals in Norway interviewed 680 patients with first recurrence of gynecological cancer (409 ovarian, 213 uterine, and 58 cervical cancer patients) between 2012 and 2016. A standardized questionnaire was used to collect information on self-reported and clinical variables. Results Within two years of primary treatment, 72% of ovarian, 64% of uterine, and 66% of cervical cancer patients were diagnosed with first recurrence, and 54, 67, and 72%, respectively, had symptomatic recurrence. Of symptomatic patients, 25–50% failed to make an appointment before their next scheduled follow-up visit. Computer tomography was the most common diagnostic procedure (89% of ovarian, 76% of uterine, and 62% of cervical cancer patients), and recurrence treatment in terms of chemotherapy was most frequently planned (86% of ovarian, 46% of uterine, and 62% of cervical cancer patients). Conclusions A majority of patients experienced symptomatic recurrence, but many patients failed to make an appointment earlier than scheduled. Most first recurrences occurred within two years of primary treatment; the mean annual incidence rate for years 3–5 after primary treatment was

Cervical intraepithelial neoplasia grades 2-3 (CIN2-3) are usually treated by cone excision, although only 30% progress to cancer and 6-50% regress spontaneously. Biomarkers predicting CIN2-3 regression would be of great clinical value and could reduce unnecessary cone excision and associated complications. The aim of this study was to investigate whether punch-biopsy derived immunohistochemical biomarkers, local immune response, CIN lesion size and condom use are independently correlated to regression of CIN2-3.A prospective population-based cohort study of 162 women aged 25-40, with first-time onset diagnosis of CIN2-3 in colposcopy-directed biopsies was carried out. The median biopsy-cone interval was 16 weeks. Regression was defined as CIN1 or less in the cone biopsy.The regression rate was 21% (34/162). pRb30% in the lower epithelial half was the strongest predictor for regression (30% regression, p0.0001). If additionally a CIN-lesion was smaller than 2.5mm and CD4+ lymphoid cells in the subepithelial stroma ≤ 195 per 1.04 mm basal membrane, the regression rate was 53%. In CIN-lesions2.5mm and CD4+-stroma ≤195, consistent condom use increased the regression rate from 13% to 67% (p=0.003). If pRb was ≤30%, the regression rate was low (6%).Biomarkers and CIN lesion length can predict CIN2-3 regression, and might be helpful to identify patients who can increase the regression rate of CIN lesions by consistent condom use.

The prognostic value of molecular biomarkers, microsatellite instability, DNA ploidy and morphometric mean shortest nuclear axis in endometrial cancer is conflicting, possibly due to the fact that different studies have used mixtures of histotypes, FIGO stages and different non-standardized non-automated methods. We have evaluated the prognostic value of classical prognostic factors, molecular biomarkers, microsatellite instability, DNA ploidy and morphometric mean shortest nuclear axis in a population-based cohort of FIGO stage I endometrial endometrioid adenocarcinomas. Curettings of 224 FIGO stage I endometrial endometrioid adenocarcinoma patients were reviewed. Clinical information, including follow-up, was obtained from the patients' charts. Microsatellite instability and morphometric mean shortest nuclear axis were obtained in whole tissue sections and molecular biomarkers using tissue microarrays. DNA ploidy was analyzed by image cytometry. Univariate (Kaplan-Meier method) and multivariate (Cox model) survival analysis was performed. With median follow-up of 66 months (1-209), 14 (6%) patients developed metastases. Age, microsatellite instability, molecular biomarkers (p16, p21, p27, p53 and survivin) and morphometric mean shortest nuclear axis had prognostic value. With multivariate analysis, combined survivin, p21 and microsatellite instability overshadowed all other variables. Patients in which any of these features had favorable values had an excellent prognosis, in contrast to those with either high survivin or low p21 (97 vs 78% survival, P

Contains fulltext : 172006.pdf (Publisher’s version ) (Open Access) Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N=893) or ovarian (N=122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants.

Ten BRCA mutations were demonstrated to be frequent in the Norwegian population. We present maps verifying the uneven distribution of prevalences according to municipality. We tested incident breast cancer cases treated in Mid-Norway from 1999 onwards for these mutations. Uptake of testing was 97% and 2.5% were demonstrated to be mutation carriers. Ten (77%) were outside families previously known to carry a mutation. Ten (77%) did not meet clinical criteria to be selected for mutation testing. We tested incident ovarian cancer cases in South-West Norway from 2001 onwards. Uptake of testing was 80% and 23% were mutation carriers. Twenty-one (88%) were outside families previously known. Twelve (67%) did not meet clinical criteria to be selected for testing. All patients with mutation collaborated actively to give our offer of predictive genetic testing to their relatives. No complaint on the activity was received.

5521 Background: Post-OP TR is a strong prognostic factor in AOC; the best prognosis is observed after complete resection (TR0). TR assessment is performed at the end of the surgery and may be exposed to personal bias. Pre-Chemo CT may improve post-OP assessment, however, it may also be prone to findings by post-OP tumor re-growth, tissue repair or scarring. Methods: Pts with FIGO IIB-IV AOC recruited into the double-blind randomized frontline AGO-OVAR12 trial were scheduled for baseline CT before the 1st chemo cycle. SA and RA of TR were compared. Additionally, a measurement of TR integrating both approaches were assessed (IA). For this IA information of surgical and path reports were reviewed by two of the authors. Results: 1355 pts had complete data for all 3 assessment methods. Of 689 pts with TR0 in SA, 497 (72%) and 539 (78%) had also TR0 pre-Chemo (RA and IA), but showed TR>0 in 192 (28%) and 150 pts (22%), respectively. Pts with SA defined TR0 had a similar median PFS of 27.6 mos compared to TR0 defined by RA (27.8 mos) and IA (28.9 mos). Pts with concordant TR0 (SA/ IA and SA/ RA) had a median PFS of 28.9 mos. In contrast, pts with discordant SA TR0 - RA TR>0 or SA TR0 - IA TR>0 showed inferior median PFS of 19.2 mos (HR: 1.89, 95%CI: 1.48-2.40; p0 had an even lower median PFS of 13.5 (SA and IA) and 12.9 mos (SA and RA). PFS of the experimental therapy or placebo dependent if SA, RA or IA were used, will be presented. Conclusions: Pre-Chemo CT provides information separating the group of pts with post-OP TR0 in pts with TR0 and pts with TR> 0 pre-Chemo. The latter group showed PFS values in between those with surgically assessed post-OP TR0 and those with post-OP TR> 0, forming a third prognostic group. Detailed analysis should evaluate to what extend tumor biology, surgical bias, or imperfect imaging contribute to the discrepancies. Integrating all this may lead to better definition of prognostic groups and the need for specific treatment strategies.

Background The major cause of cervical intraepithelial neoplasia (CIN) is persistent infection with human papillomavirus (HPV). Most CIN grade 2 and 3 lesions are treated with cone excision, although a substantial proportion (6-50%) of CIN2-3 lesions will regresses spontaneously. Predictors for regression of CIN2-3 are desirable in order to reduce this overtreatment. Methods In this prospective cohort study, 145 consecutive women with first-time onset CIN2-3 in colposcopy-directed biopsies and standardized biopsy-cone excision interval were included. The genotype of the high-risk human papillomaviruses (=hr HPV) and clinical factors including sexual behaviour, parity, contraception and smoking were assessed. Patients were divided into two groups according to lesions containing HPV16 (hr HPV16+) and high-risk non-HPV16 (hr HPV16-) genotypes. Results Women whose partners consistently used condoms showed a significantly higher regression rate than women using other types of contraception (53% versus 13%, phr HPV16- patients (73% regression rate versus 13%, pHr HPV16+ patients had a significantly higher number of sexual partners and more current smokers compared to hr HPV16- patients. The regression rate was not significantly different in CIN2-3 lesions containing HPV16 (hr HPV16+) versus hr HPV16- genotypes. Conclusions Heterogeneity among hr HPV genotypes excists. HPV-genotype analyses can identify women who significantly increase their chance of regression by consistent condom use.

Purpose: Inherited ovarian cancer carries a serious prognosis. Prophylactic oophorectomy has been advocated. The degree to which inherited ovarian cancer is restricted to BRCA mutation carriers is not fully known. We wanted to determine the prevalence of BRCA mutation carriers in women at high risk from ovarian cancer. Experimental Design: Healthy women who were found to be at increased risk judged by family history were followed prospectively. Full BRCA1/2 mutation analysis was conducted on all patients who contracted pelvic cancer. Results: We identified 1,582 women at risk during 5,674 person-years. Forty infiltrating epithelial ovarian cancers, six peritoneal cancers, and one fallopian tube cancer were diagnosed. All but one of these patients (98%) had a BRCA mutation, a frequency that was significantly higher than for the 3 patients with borderline ovarian cancers, who were all mutation negative (P = 0.0002). Eighty-two percent of the detected mutations belonged to one of the 10 Norwegian founder mutations previously reported. At prophylactic bilateral salpingo-oophorectomy, cancer was found in 18 of 345 (5.2%) of mutation carriers compared with none in the 446 mutation negative (P = 0.0000). Conclusions: In healthy women with a family history of ovarian cancer, high risk for ovarian cancer was restricted to BRCA1/2 mutation carriers. A woman at risk for ovarian cancer according to her family history should have access to full BRCA1/2 mutation testing before deciding on prophylactic bilateral salpingo-oophorectomy.

We tested the hypothesis that PTEN inactivation may stratify cancer progression risk among putative endometrial hyperplasias, classified prognostically by means of the morphometric D score (DS). The DS, calculated from 3 morphometric variables measured in routine hematoxylin-eosin-stained endometrial biopsy slides, is the most sensitive and specific method of endometrial cancer risk prediction currently available. Clinical outcomes of 103 women with endometrial hyperplasia on biopsy were tallied according to the DS. Seven (7/103; 7%) patients with carcinoma during follow-up were all distributed within the high-risk prognostic group (ie, DS1 = endometrial intraepithelial neoplasia [EIN]) (7/21; 33% progression). None of the 82 cases with a DS higher than 1 progressed. All cases that progressed were PTEN null, indicating that this genotype is capable of further stratifying cancer progression risk in hyperplasias irrespective of histological categorization. However, only 16% of the PTEN-null cases progressed. When PTEN expression pattern was combined with EIN, the prognostic power was greatly increased (specificity from 63% for PTEN and 85% for EIN to 93% when combined; positive predictive value from 16% and 33% to 50%). We conclude that loss of PTEN expression is the first biomarker in EIN that increases the accuracy of the prognostic DS to predict cancer progression risk. Unless endometrial hyperplasias are stratified by histological morphometric D-Score, PTEN has a low positive predictive value.

BACKGROUND. The objective of this study was to compare the accuracy of disease progression prediction of the molecular genetics and morphometry-based Endometrial Intraepithelial Neoplasia (EIN) and World Health Organization 1994 (WHO94) classification systems in patients with endometrial hyperplasias. METHODS. A multicenter, multivariate analysis was conducted on 477 patients with endometrial hyperplasia who were required to have a 1-year minimum disease-free interval from the time of the index biopsy (1-18 years of follow-up). The results from that analysis were compared with the results from 197 patients who had < 1 year of follow-up. RESULTS. Twenty-four of 477 hyperplasias (5.0%) progressed to malignant disease over an average of 4 years (maximum, 10 years). According to the WHO94 classification, 16 of 123 atypical hyperplasias (13%) and 8 of 354 nonatypical hyperplasias (2.3%) progressed (hazard ratio [HR] = 7). Twenty-two of 118 EINs (19%) and 2 of 359 non-EINs (0.6%) progressed (HR = 45). EIN was prognostic within each WHO94 subcategory. Progression rates were 3% in simple hyperplasias, 22% in complex hyperplasias, 17% in simple atypical hyperplasias, and 38% in complex atypical hyperplasias with EIN, compared with progression rates of 0.0-2.0% in all hyperplasias if EIN was absent. EIN detected precancerous lesions (sensitivity, 92%) better than WHO94 atypical hyperplasias collectively (67%) or complex atypical hyperplasias alone (46%). In a Cox regression analysis, EIN was the strongest prognostic index of future endometrial carcinoma. The same was true for patients with < 1 year of follow-up (HR for EIN, atypical hyperplasia, and complex atypical hyperplasia: 58, 7, and 8, respectively). CONCLUSIONS. The EIN classification system predicted disease progression more accurately than the WHO94 classification and identified many women with benign changes that would have been regarded as high risk according to the WHO94 classification system.

Endometrial hyperplasia (EH) is a common disease. An estimated 180,000–200,000 new cases occur annually in the Western world; approx 39,200 new cases and 6600 deaths were expected in the United States in 2002 (1). About 8–20% of all EH is associated with subsequent endometrial cancer of the endometrioid type. Major problems in treating EH include poor diagnostic reproducibility and inaccurate prediction of cancer progression. This has resulted in enormous overtreatment. The World Health Organization (WHO)’s 1994 histologic classification is widely used but is not reproducible, does not adequately predict the risk of cancer progression, and lacks a molecular and cell biology basis. Computerized morphometric analysis has identified a multivariate combination of architectural and nuclear features, called the DS, which is reproducible, fits with therapeutic options, and accurately predicts cancer outcome. Cases with DS ≥1 have a negligible progression risk (0.3%), contrasting with a 37% progression risk for those with DS < 1 found in a large multicenter study with more than 18 yr of follow-up. Moreover, molecular-genetic studies have found a {tly|464-1} strong correlation between clonality and DS; monoclonal cases nearly always have DS < 0; cases with DS ≥ 1 are mostly polyclonal. This has resulted in a new classification, endometrial intraepithelial neoplasia (EIN), which does not mimic subjective WHO hyperplasia diagnoses but rather uses new criteria for prognostic prediction of cancer endpoints. Moreover, high-risk EIN-DS lesions often show clonal inactivation of the phosphatase and tensin homologue (PTEN) tumor-supressor gene by immunohistochemistry. Based on EIN-DS, patients can now be reproducibly assigned with high accuracy to high- and low-risk categories, permitting appropriate management. EIN-DS application is easy, can be done on standard histologic sections, and has reasonable cost. EIN-DS thus can be assessed in any pathology laboratory, but sections can also be sent to reference laboratories for measurement if necessary.

Objective To analyze the prognostic value of molecular biomarkers in curettages of endometrioid endometrial cancer pathologic FIGO stages 1 and 2. Study Design Population-based survival analysis in 258 patients of classical prognostic features and molecular biomarkers of cell cycle regulation, (anti)apoptosis, proliferation, squamous differentiation, and PTEN/Akt pathway. Results With 74 months median follow-up (range, 1-209), 24 (9.3%) patients had metastases develop. Pathologic FIGO stage 2B (6% of all cases) and age > 68 years had independent multivariate prognostic value. Many molecular biomarkers were prognostic, particularly cell-cycle regulators p16, p21, p27, p53, p63, and the antiapoptosis marker survivin (which mostly stains mitoses). The strong prognostic value of a multivariate model with survivin, p21, and p53 overshadowed all other prognosticators in pathologic FIGO 1 and 2A. Conclusion In pathologic FIGO stage 1 and 2A endometrioid endometrial cancer curettages, combined biomarkers survivin, p21, and p53 expression patterns are prognostically stronger than classical feature combinations.