Biomarkers in Ovarian Cancer: Early Detection and Chemoresistance

Britta Stordal, PhD, and John O'Leary, MD, PhD
Published: Friday, Mar 04, 2011

Abstract

Ovarian cancer is a relatively rare but deadly disease. Biomarker panels for the detection of ovarian cancer are usually combined with screening for CA125, a known marker of ovarian cancer, and transabdominal or transvaginal ultrasonography. Combining these tests increases the sensitivity, specificity, and positive predictive value. However, there are currently no early detection methods suitable for population-wide screening. Women with ovarian cancer are usually treated with a combination of chemotherapy drugs, including cisplatin or carboplatin and paclitaxel. Biomarkers to identify mechanisms of drug resistance in relapsed ovarian cancer could be used to direct the choice of salvage chemotherapy and improve response rates and overall survival. This article discusses the inverse relationship between cisplatin and paclitaxel resistance and the roles of BRCA1, ERCC1 and TLR-4/ MyD88 signalling as potential predictive biomarkers of chemotherapy-resistant ovarian cancer.

Worldwide, there are ~204,000 new cases of ovarian cancer each year, accounting for 4% of cancers diagnosed in women.1 According to the National Cancer Institute (NCI), the incidence of ovarian cancer is 13.1 cases for every 100,000 women.2 While this is much lower than the incidence of breast cancer (128.3 cases for every 100,000 women), 5-year overall survival (OS) rates are much worse for ovarian cancer than for breast cancer: 49.5% compared with 89.1%.2

This is partly due to a lack of early detection methods for ovarian cancer, resulting in more than half of ovarian cancer diagnoses occurring after the disease has metastasized. NCI stage distribution statistics show that 15% of ovarian cancer cases are diagnosed while the cancer is still confined to the primary site (localized stage), 17% are diagnosed after the cancer has spread to regional lymph nodes or directly beyond the primary site, 62% are diagnosed after the cancer has already metastasized (distant stage), and staging information is unknown for the remaining 7% of cases.2 The corresponding 5-year relative survival rates are 93.8% for localized, 72.8% for regional, 28.2% for distant, and 27.3% for unstaged.2

The low incidence of ovarian cancer means that the average general practitioner sees relatively few cases. Women with ovarian cancer often experience symptoms of the disease before they are diagnosed, but these symptoms (persistent pelvic and stomach pain, difficulty eating, early satiety, and increased stomach size or persistent bloating) overlap with the symptomatology of many less serious conditions, making it difficult to make a differential diagnosis. The only well-defined risk factors for ovarian cancer include being postmenopausal, having a family history of breast or ovarian cancer, or having a BRCA mutation.3 Due to the low incidence rate, limited known risk factors, and nonspecific symptoms, the disease is easily overlooked. Treating ovarian cancer while it is still in the early stages improves patient survival, making the discovery of new biomarkers to facilitate early detection paramount.

Ovarian Cancer Screening

A 2009 article in the New England Journal of Medicine addressed the challenges general practitioners face regarding ovarian cancer screening.3 Clarke-Pearson presented the case of an asymptomatic 56-year-old woman with no family history of ovarian or breast cancer who asked to be screened for ovarian cancer after a friend died of the disease. A physical examination of the patient found no abnormalities. In discussing whether the practitioner should screen the patient for ovarian cancer, Clarke-Pearson notes that no professional society recommends routine ovarian cancer screening of the general population.

Making a definitive diagnosis of ovarian cancer requires surgical removal of the abnormal ovary and the related fallopian tube. The author concluded that “the potential harms outweigh the potential benefits,” because the risk of false positives with today’s inexact screening methods could lead to needless surgery if patients were routinely screened for ovarian cancer.3

The prevalence of ovarian cancer is very low in the general population, so any test—whether it is an imaging modality or a biomarker assay—must have very high specificity and sensitivity to yield a positive predictive value (PPV) sufficiently high to justify widespread screening (Table 1). These metrics must be high enough to identify cancer accurately in women reporting symptoms suggestive of the disease and in asymptomatic women at greater risk for the disease.


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