The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: Results from a randomized controlled trial.

Background: Guidelines recommend genetic counseling and testing for women who have a pedigree suggestive of an inherited susceptibility for ovarian cancer. The authors evaluated the effect of referral to genetic counseling on genetic testing and prophylactic oophorectomy in a randomized controlled trial.

Methods: Data from an electronic mammography reporting system identified 12,919 women with a pedigree that included breast cancer, of whom 625 were identified who had a high risk for inherited susceptibility to ovarian cancer using a risk-assessment questionnaire.

Evaluating Serum Markers for Hormone Receptor-Negative Breast Cancer.

Introduction: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. Death rates have been declining, largely as a result of early detection through mammography and improved treatment, but mammographic screening is controversial because of over-diagnosis of breast disease that might not require treatment, and under-diagnosis of cancer in women with dense breasts. Breast cancer screening could be improved by pairing mammography with a tumor circulating marker, of which there are currently none.

Identifying post-menopausal women at elevated risk for epithelial ovarian cancer.

Objective: We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma.

Methods: To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data.

Validation of LRG1 as a potential biomarker for detection of epithelial ovarian cancer by a blinded study.

Background: Leucine-rich alpha-2-glycoprotein (LRG1) was found to be differentially expressed in sera from patients with Epithelial Ovarian Cancer (EOC). The aim of this study is to investigate the performance of LRG1 for detection of EOC, including early stage EOC, and to evaluate if LRG1 can complement CA125 in order to improve EOC detection using two independent blinded sample sets.

Methods And Results: Serum LRG1 and CA125 were measured by immunoassays.

Cancer Risk Awareness and Concern among Women with a Family History of Breast or Ovarian Cancer.

Women with a documented deleterious mutation in BRCA1 or BRCA2 are at substantially elevated risk for ovarian cancer. To understand what percentage of women with high-risk family histories know their risk is elevated we surveyed 1,885 women with a high- or moderate-risk family history and no personal history of breast or ovarian cancer, and asked about their perceived risk of breast and ovarian cancer. Among high-risk women, fewer than 20% reported use of genetic counseling, and knowledge of elevated risk of ovarian cancer was low.

Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women.

Background: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.

Methods: We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility.

JAK2 expression is associated with tumor-infiltrating lymphocytes and improved breast cancer outcomes: implications for evaluating JAK2 inhibitors.

Janus kinase-2 (JAK2) supports breast cancer growth, and clinical trials testing JAK2 inhibitors are under way. In addition to the tumor epithelium, JAK2 is also expressed in other tissues including immune cells; whether the JAK2 mRNA levels in breast tumors correlate with outcomes has not been evaluated. Using a case-control design, JAK2 mRNA was measured in 223 archived breast tumors and associations with distant recurrence were evaluated by logistic regression.

Longitudinal screening algorithm that incorporates change over time in CA125 levels identifies ovarian cancer earlier than a single-threshold rule.

Purpose: Longitudinal algorithms incorporate change over time in biomarker levels to individualize screening decision rules. Compared with a single-threshold (ST) rule, smaller deviations from baseline biomarker levels are required to signal disease. We demonstrated improvement in ovarian cancer early detection by using a longitudinal algorithm to monitor annual CA125 levels.

Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer.

Background: Human epididymis protein 4 (HE4) is approved for clinical use with CA125 to predict epithelial ovarian cancer in women with a pelvic mass or in remission after chemotherapy. Previously reported reference ranges for HE4 are inconsistent.

Methods: We report positivity thresholds yielding 90%, 95%, 98%, and 99% specificity for age-defined populations of healthy women for HE4, CA125, and Risk of Ovarian Malignancy Algorithm (ROMA), a weighted average of HE4 and CA125.

Impact of screening test performance and cost on mortality reduction and cost-effectiveness of multimodal ovarian cancer screening.

Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests [CA125 and transvaginal sonography (TVS)]. Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current limits. This study estimates the mortality reduction, years of life saved, and cost-effectiveness achievable by annual multimodal screening using increasing CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counterparts with better performance characteristics.

Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125.

Objective: Evaluate and compare the effectiveness of CA125, HE4, Mesothelin and MMP7 marker levels to monitor ovarian cancer patients after surgery and chemotherapy. Evaluate the lead time of a rise of marker levels before recurrence.

Methods: The study consists of 23 patients with advanced stage ovarian/fallopian tube cancer.

Potential role of HE4 in multimodal screening for epithelial ovarian cancer.

In screening for epithelial ovarian cancer, unnecessary surgery can be reduced by limiting use of transvaginal ultrasound (TVU) to women with increasing CA125 serum levels. Replacing or augmenting TVU with measurement of a serum marker specific for malignancy might further improve screening performance. Serum samples from 112 invasive ovarian cancer patients and 706 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian trial were used to evaluate human epididymis protein 4 (HE4), mesothelin, matrix metalloproteinase 7 (MMP7), SLPI, Spondin2, and insulin-like growth factor binding protein 2 (IGFBP2) for their potential use in screening.

Irradiation effect after mastectomy on breast cancer recurrence in patients presenting with locally advanced disease.

Background: Current guidelines recommend postmastectomy irradiation (PMI) for patients with tumors >5 cm and/or ≥4 positive lymph nodes. This study evaluates the effect of PMI on recurrence and survival within tumor size and node status groups.

Methods: Locoregional and distant recurrences and survival for different tumor and treatment characteristics were analyzed in 2,797 patients with invasive breast cancer treated with mastectomy.

Assessing lead time of selected ovarian cancer biomarkers: a nested case-control study.

Background: CA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 have been identified as potential ovarian cancer biomarkers. Except for CA125, their behavior in the prediagnostic period has not been evaluated.

Methods: Immunoassays were used to determine concentrations of CA125, HE4, mesothelin, B7-H4, DcR3, and spondin-2 proteins in prediagnostic serum specimens (1-11 samples per participant) that were contributed 0-18 years before ovarian cancer diagnosis from 34 patients with ovarian cancer (15 with advanced-stage serous carcinoma) and during a comparable time interval before the reference date from 70 matched control subjects who were participating in the Carotene and Retinol Efficacy Trial.

Integrated proteomic analysis of human cancer cells and plasma from tumor bearing mice for ovarian cancer biomarker discovery.

Background: The complexity of the human plasma proteome represents a substantial challenge for biomarker discovery. Proteomic analysis of genetically engineered mouse models of cancer and isolated cancer cells and cell lines provide alternative methods for identification of potential cancer markers that would be detectable in human blood using sensitive assays. The goal of this work is to evaluate the utility of an integrative strategy using these two approaches for biomarker discovery.

Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125.

Objective: To evaluate the effect of ovarian cancer risk on the performance of the serum biomarkers mesothelin, human epididymis protein 4 (HE4), and CA125.

Methods: We measured mesothelin, HE4, and CA125 levels from women with invasive ovarian cancer (n = 143), benign gynecologic conditions (n = 124), and controls (n = 344). Demographic, epidemiologic, reproductive, medical, and family history data were collected using a standardized questionnaire.

Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer.

Objective: To evaluate if serum levels of candidate ovarian cancer biomarkers vary with individual characteristics of healthy women who are likely candidates for an ovarian cancer screening program.

Methods: We analyzed serum CA125, mesothelin, and HE4 levels in a sample of 155 healthy postmenopausal women at increased risk for developing ovarian cancer based on personal and family cancer history. Information on reproductive, family and medical histories, lifestyle factors, and anthropometry was collected by self-report.

Systematic evaluation of candidate blood markers for detecting ovarian cancer.

Background: Epithelial ovarian cancer is a significant cause of mortality both in the United States and worldwide, due largely to the high proportion of cases that present at a late stage, when survival is extremely poor. Early detection of epithelial ovarian cancer, and of the serous subtype in particular, is a promising strategy for saving lives. The low prevalence of ovarian cancer makes the development of an adequately sensitive and specific test based on blood markers very challenging.

Use of yeast-secreted in vivo biotinylated recombinant antibodies (Biobodies) in bead-based ELISA.

Purpose: To measure circulating antigens, sandwich ELISA assays require two complementary affinity reagents. Mouse monoclonal antibodies (mAb) and polyclonal antibodies (pAb) are commonly used, but because their production is lengthy and costly, recombinant antibodies are emerging as an attractive alternative.

Experimental Design: We developed a new class of recombinant antibodies called biobodies (Bb) and compared them to mAb for use in serodiagnosis.

Effects of blood collection conditions on ovarian cancer serum markers.

Background: Evaluating diagnostic and early detection biomarkers requires comparing serum protein concentrations among biosamples ascertained from subjects with and without cancer. Efforts are generally made to standardize blood processing and storage conditions for cases and controls, but blood sample collection conditions cannot be completely controlled. For example, blood samples from cases are often obtained from persons aware of their diagnoses, and collected after fasting or in surgery, whereas blood samples from some controls may be obtained in different conditions, such as a clinic visit.