Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass.

OBJECTIVES: The diagnosis of an adnexal mass is a prevalent issue among women in the United States, although current methods of identifying those at high risk of malignancy remain insufficient. Ineffective triage of women with malignant masses is associated with delayed or inappropriate treatment and a negative effect on disease outcome. METHODS: We performed an evaluation of 65 ovarian cancer-related biomarkers in the circulation of women diagnosed with an adnexal mass. Our subject group consisted of women diagnosed with benign masses and early- and late-stage ovarian cancer. RESULTS: More than half of the biomarkers tested were found to differ significantly between benign and malignant cases. As individual markers, HE4 and CA-125 provided the greatest level of discrimination between benign and malignant cases, and the combination of these two biomarkers provided a higher level of discriminatory power than either marker considered alone. Multivariate statistical analysis identified several multimarker panels that could discriminate early-stage, late-stage, and combined ovarian cancers from benign cases with similar or slightly improved SN/SP levels to the CA-125/HE4 combination; however, these larger panels could not outperform the 2-biomarker panel in an independent validation set. We also identified a 3-biomarker panel with particular utility in premenopausal women. CONCLUSIONS: Our findings serve to advance the development of blood-based screening methods for the discrimination of benign and malignant ovarian masses by confirming and expanding upon the superior utility of the CA-125/HE4 combination.

A serum based analysis of ovarian epithelial tumorigenesis.

OBJECTIVES: Ovarian epithelial carcinoma can be subdivided into separate histological subtypes including clear cell, endometrioid, mucinous, and serous. These carcinoma subtypes may represent distinctive pathways of tumorigenesis and disease development. This distinction could potentially be reflected in the levels of tumor produced factors that enter into the circulation and serve as biomarkers of malignant growth. Here, we analyze levels of circulating biomarkers from a diverse set of patients diagnosed with ovarian carcinoma to identify biomarker trends and relationships associated with distinct carcinoma histotypes and divergent tumorigenic pathways. METHODS: We utilize multiplexed bead-based immunoassays to measure serum levels of a diverse array of fifty-eight biomarkers from the sera of patients diagnosed with various histological subtypes of ovarian carcinoma and benign lesions. The biomarkers studied include cancer antigens, oncogenes, cytokines, chemokines, receptors, growth and angiogenic factors, proteases, hormones, and apoptosis and adhesion related molecules. Levels of each biomarker are compared statistically across carcinoma subtypes as well as with benign cases. RESULTS: A total of 21 serum biomarkers differ significantly between patients diagnosed with ovarian carcinomas and benign cases. Nine of these biomarkers are specific for carcinomas identified as clear cell, endometrioid, or mucinous in histology, while two biomarkers are specific for the serous histology. In a direct comparison of the histology groups, ten biomarkers are found to be subtype specific. Identified biomarkers include traditional and emerging tumor markers, cytokines and receptors, hormones, and adhesion- and metastasis-related proteins. CONCLUSIONS: We demonstrate here that the divergent histology-based tumorigenic pathways proposed for ovarian epithelial carcinomas are associated with distinct profiles of circulating biomarkers. Continued investigation into the relationships between these factors should reveal new insights into the complex mechanisms underlying ovarian epithelial tumorigenesis.

Novel protein and immune response markers of human serous tubal intraepithelial carcinoma of the ovary.

Ovarian cancer is the leading cause of death among gynecologic diseases in the USA and Europe. High-grade serous carcinoma (HGSC) of the ovary, the most aggressive type of ovarian cancer, is typically diagnosed at advanced stages when the 5-year survival is dismal. Since the cure rate for stage I HGSC is high, early detection of localized initial disease may improve patient outcomes. Serous tubal intraepithelial carcinoma (STIC) is considered to be a precursor lesion of HGSC. Discovery of biomarkers associated with STIC could aid in the development of an HGSC screening algorithm. Using immunohistochemical staining, we have demonstrated overexpression of UCHL1, ADAMTS13, and GAPDH in patients' STIC lesions, but not in cancer-free fallopian tubes. We additionally demonstrated a marked increase of T cells in perineoplastic stroma surrounding STIC lesions (largely CD4 + cells), but not in normal fallopian tubes and HGSC. FOXP3 + T regulatory cells are absent in STIC lesions but are present in HGSC. These observations indicate the microenvironment surrounding a STIC lesion may be immune promoting in contrast to the immune suppressive microenvironment of invasive carcinoma. In summary, we have identified UCHL1, ADAMTS13, and GAPDH as novel potentially useful markers associated with early stages of HGSC tumorigenesis and possibly contribute to STIC immunogenicity. The lack of immune suppression in the STIC microenvironment indicates that the immune system can still recognize and keep STIC controlled at this stage of the tumor development.

Urinary protein biomarkers in the early detection of lung cancer.

The early detection of lung cancer has the potential to greatly impact disease burden through the timely identification and treatment of affected individuals at a manageable stage of development. The insufficient specificity demonstrated by currently used screening and diagnostic techniques has led to intense investigation into biomarkers as diagnostic tools. Urine may represent a noninvasive alternative matrix for diagnostic biomarker development. We performed an analysis of 242 biomarkers in urines obtained from 83 patients with non-small cell lung carcinomas (NSCLC), 74 patients diagnosed with benign pulmonary conditions, and 77 healthy donors. A large number of significant alterations were observed between the NSCLC and control groups. A multivariate analysis identified a three-biomarker panel consisting of IGFBP-1, sIL-1Ra, CEACAM-1, which discriminated NSCLC from healthy controls with a sensitivity/specificity of 84/95 in an initial training set and 72/100 in an independent validation set. This panel performed well among multiple subtypes of NSCLC and early-stage disease but demonstrated only limited efficacy for the discrimination of NSCLC from benign controls and limited specificity for patients with several other cancers and tuberculosis. These findings demonstrate that urine biomarkers may provide screening and diagnostic properties which exceed those reported for serum biomarkers and approach a level necessary for further clinical development.

Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study.

BACKGROUND: The clinical management of pancreatic cancer is severely hampered by the absence of effective screening tools. METHODS: Sixty-seven biomarkers were evaluated in prediagnostic sera obtained from cases of pancreatic cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). RESULTS: The panel of CA 19-9, OPN, and OPG, identified in a prior retrospective study, was not effective. CA 19-9, CEA, NSE, bHCG, CEACAM1 and PRL were significantly altered in sera obtained from cases greater than 1 year prior to diagnosis. Levels of CA 19-9, CA 125, CEA, PRL, and IL-8 were negatively associated with time to diagnosis. A training/validation study using alternate halves of the PLCO set failed to identify a biomarker panel with significantly improved performance over CA 19-9 alone. When the entire PLCO set was used for training at a specificity (SP) of 95%, a panel of CA 19-9, CEA, and Cyfra 21-1 provided significantly elevated sensitivity (SN) levels of 32.4% and 29.7% in samples collected <1 and >1 year prior to diagnosis, respectively, compared to SN levels of 25.7% and 17.2% for CA 19-9 alone. CONCLUSIONS: Most biomarkers identified in previously conducted case/control studies are ineffective in prediagnostic samples, however several biomarkers were identified as significantly altered up to 35 months prior to diagnosis. Two newly derived biomarker combinations offered advantage over CA 19-9 alone in terms of SN, particularly in samples collected >1 year prior to diagnosis. However, the efficacy of biomarker-based tools remains limited at present. Several biomarkers demonstrated significant velocity related to time to diagnosis, an observation which may offer considerable potential for enhancements in early detection.

An extensive targeted proteomic analysis of disease-related protein biomarkers in urine from healthy donors.

The analysis of protein biomarkers in urine is expected to lead to advances in a variety of clinical settings. Several characteristics of urine including a low-protein matrix, ease of testing and a demonstrated proteomic stability offer distinct advantages over current widely used biofluids, serum and plasma. Improvements in our understanding of the urine proteome and in methods used in its evaluation will facilitate the clinical development of urinary protein biomarkers. Multiplexed bead-based immunoassays were utilized to evaluate 211 proteins in urines from 103 healthy donors. An additional 25 healthy donors provided serial urine samples over the course of two days in order to assess temporal variation in selected biomarkers. Nearly one-third of the evaluated biomarkers were detected in urine at levels greater than 1 ng/ml, representing a diverse panel of proteins with respect to structure, function and biological role. The presence of several biomarkers in urine was confirmed by western blot. Several methods of data normalization were employed to assess impact on biomarker variability. A complex pattern of correlations with urine creatinine, albumin and beta-2-microglobulin was observed indicating the presence of highly specific mechanisms of renal filtration. Further investigation of the urinary protein biomarkers identified in this preliminary study along with a consideration of the underlying proteomic trends suggested by these findings should lead to an improved capability to identify candidate biomarkers for clinical development.