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Concept: CA-125

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Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III).

Concepts: Type I and type II errors, Hereditary nonpolyposis colorectal cancer, Ovarian cyst, BRCA2, Ovarian cancer, Experimental uncertainty analysis, CA-125, Bloating

28

Serum concentrations of CA-125 are rarely elevated beyond 1000 U/ml in benign conditions of the ovary in postmenopausal women. In this report, the authors present an unusual case of a 78-year-old woman with an extremely elevated CA-125 concentration of 2897 U/ml without the presence of a malignancy, ascites or pleural effusion. Imaging revealed a large intra-abdominal cystic mass with irregular solid deviations on CT scan, most likely arising from an ovary. Exploratory laparotomy was performed with suspicion of ovarian cancer but histopathological analysis revealed benign serous cystic adenofibroma. This case report highlights the diagnostic challenge of extremely increased levels of CA-125 in postmenopausal women. A possible explanation for this CA-125 elevation could be the mechanical stretch of the peritoneum.

Concepts: Cancer, Menopause, Estrogen, Ovarian cancer, Pleural effusion, Hysterectomy, Ovary, CA-125

27

The goal of this study was to evaluate the efficacy of CA-125 area under the curve (CA-125 AUC) as a prognostic factor following surgical treatment for ovarian cancer patients. A retrospective analysis was conducted on ninety-five patients with ovarian cancer who had primary treatment in a tertiary center between 2000 and 2010. After either optimal or cytoreductive surgery, all patients underwent adjuvant chemotherapy. CA-125 AUC was calculated for each patient that had a minimum of three CA-125 serum measurements during the treatment period. The mean age at diagnosis and mean survival were 53.9 years (range, 16-75 years) and 35.6 ± 22.9 months (range, 3.1-95.4 months), respectively. The mean (and median) CA-125 AUC of patients of FIGO stages I, II, III, and IV was 53.0 (42.5), 58.06 (58.06), 97.8 (54.6), and 405.2 (149.3) IU/ml day, respectively (p = 0.004). The mean CA-125 AUC was 57.7, 410.1, and 636.3 IU/ml day for patients with a complete response, partial response, and no response/progressive disease to first-line chemotherapy, respectively (p < 0.001). The CA-125 AUC cut-off level for an overall survival of ≥5 years was 99.75 IU/ml day with a sensitivity of 90.9 % (95 % CI, 70.8-98.6) with 1.27 as positive likelihood ratio. Patients who suffer from ovarian cancer, with a lower CA125 AUC, have a better overall survival than those with a higher CA125 AUC. CA-125 AUC could be used as an independent factor for evaluating the treatment efficacy and chemotherapy response.

Concepts: Metastasis, Oncology, Surgery, BRCA2, Ovarian cancer, Arithmetic mean, CA-125, Endometriosis

23

This study is a comparison of human epididymis protein 4 (HE4) with cancer antigen 125 (CA125), using the Risk of Ovarian Malignancy Algorithm (ROMA), Copenhagen Index (CPH-I), Risk of Malignancy Index (RMI) and Morphology Index (MI) to differentiate ovarian endometriosis from epithelial ovarian cancer (EOC) in premenopausal women.

Concepts: Protein, Molecular biology, Combined oral contraceptive pill, Ovarian cancer, Biochemistry, Hysterectomy, CA-125, Endometriosis

4

Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6-12 monthly CA125>35U/mL.

Concepts: Vitamin D, Cancer, Metastasis, Prostate cancer, Hereditary nonpolyposis colorectal cancer, BRCA2, Ovarian cancer, CA-125

3

There is an urgent need for biomarkers for the early detection of ovarian cancer (OC). The purpose of this study was to assess whether changes in serum levels of lecithin-cholesterol acyltransferase (LCAT), sex hormone-binding globulin (SHBG), glucose-regulated protein, 78 kDa (GRP78), calprotectin and insulin-like growth factor-binding protein 2 (IGFBP2) are observed before clinical presentation and to assess the performance of these markers alone and in combination with CA125 for early detection.

Concepts: Vitamin D, Metastasis, Hereditary nonpolyposis colorectal cancer, BRCA2, Ovarian cancer, CA-125, Endometriosis, Lecithin-cholesterol acyltransferase

2

Data on CA-125 as a predictor of disease progression (PD) in ovarian cancer come predominantly from patients with platinum-sensitive disease receiving chemotherapy alone. We assessed concordance between CA-125-defined and RECIST-defined PD using data from the Gynecologic Cancer InterGroup (GCIG) randomized phase III AURELIA trial in platinum-resistant ovarian cancer (PROC).

Concepts: Cancer, Metastasis, Oncology, BRCA2, Ovarian cancer, Hysterectomy, CA-125, Gynecologic oncology

2

The standard approach for the treatment of advanced-stage ovarian cancer is upfront cytoreductive surgery followed by a combination of platinum-based and taxane-based chemotherapy. The extent of residual disease following upfront cytoreductive surgery correlates with objective response to adjuvant chemotherapy, rate of pathological complete response at second-look assessment operations, and progression-free survival and overall survival. Contemporary data and meta-analyses indicate a correlation between volume of residual disease and patient outcome, with those patients undergoing complete gross resection having the best outcomes. Thus, attention has focused on surgical efforts to remove as much disease as possible with the metric of ‘optimal’ cytoreduction being R0 disease. Because patients with R0 resection seem to have the best overall outcomes, preoperative or intraoperative assessment to avoid unnecessary primary debulking surgery has become common. The use of serum CA-125 levels, physical examination and CT imaging have lacked accuracy in determining if disease can be optimally debulked. Therefore, an algorithm that identifies patients in whom complete gross resection at primary surgery is likely to be achieved would be expected to improve patient survival. We discuss contemporary definitions of ‘optimal’ residual disease, and opportunities to personalize surgical therapy and improve the quality of surgical care.

Concepts: Medicine, Cancer, Hospital, Surgery, Chemotherapy, Physician, Ovarian cancer, CA-125

1

To determine if, among women with peritoneal endometriosis, the incidence of ovarian endometrioma at first laparoscopy differs between those with and without a history of hormonal contraceptive use.

Concepts: Hormonal contraception, Combined oral contraceptive pill, Ovarian cyst, Ovarian cancer, Menstrual cycle, Hysterectomy, CA-125, Endometriosis

1

The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are frequently increased, and the highest levels of MUC16 expression are linked to a significantly worse survival. To examine the biologic effect of the proximal portion of MUC16/CA125, NIH/3T3 (3T3) fibroblast cell lines were stably transfected with the carboxy elements of MUC16. As few as 114 amino acids from the carboxy-terminal portion of MUC16 were sufficient to increase soft agar growth, promote matrigel invasion, and increase the rate of tumor growth in athymic nude mice. Transformation with carboxy elements of MUC16 was associated with activation of the AKT and ERK pathways. MUC16 transformation was associated with up-regulation of a number of metastases and invasion gene transcripts, including IL-1β, MMP2, and MMP9. All observed oncogenic changes were exclusively dependent on the extracellular “ectodomain” of MUC16. The biologic impact of MUC16 was also explored through the creation of a transgenic mouse model expressing 354 amino acids of the carboxy-terminal portion of MUC16 (MUC16c354). Under a CMV, early enhancer plus chicken β actin promoter (CAG) MUC16c354 was well expressed in many organs, including the brain, colon, heart, kidney, liver, lung, ovary, and spleen. MUC16c354 transgenic animals appear to be viable, fertile, and have a normal lifespan. However, when crossed with p53-deficient mice, the MUC16c354:p53+/- progeny displayed a higher frequency of spontaneous tumor development compared to p53+/- mice alone. We conclude that the carboxy-terminal portion of the MUC16/CA125 protein is oncogenic in NIH/3T3 cells, increases invasive tumor properties, activates the AKT and ERK pathways, and contributes to the biologic properties of ovarian cancer.

Concepts: Protein, Gene, Gene expression, Cancer, Molecular biology, Ovarian cancer, CA-125, Genetically modified organism