Diagnostic advances trend toward personalized medicine, providing women and fetuses with the opportunity for improved outcomes.

The differences between men and women have filled books. And research continues to unveil new dissimilarities. Though sometimes surprising, the knowledge also reveals new ways of addressing the disparities, particularly in medicine.

Tailoring diagnostics, prognostics, and treatments to women as a whole, and the individual in particular, has the potential to improve patient outcomes. The resulting collection of more relevant clinical data and its impact on care and cost has been the driver behind the personalized medicine movement. Personalized medicine advocates expect that tailored care can improve outcomes not only through more effective treatments but also through early diagnosis, more accurate prognostic capabilities, and successful prevention efforts.

In looking at some of the advances in women’s diagnostics, CLP found evidence of all these aims and notes that some of today’s new tests seem likely to become tomorrow’s routine diagnostics.

Quest for Improved Ovarian Cancer Prognosis

One extensive area where personalized medicine holds particular promise is cancer, where small genetic differences can often impact prognosis and outcomes. The National Cancer Institute (NCI) estimates that more than 21,000 new cases of ovarian cancer will be diagnosed this year and more than 14,000 women will die of the disease.1 Between 1995 and 2005, the Surveillance Epidemiology and End Results (SEER) found the overall 5-year survival rate for ovarian cancer patients in 17 geographical areas to be 45.9%.2

Unfortunately, this rate worsens with later diagnosis. For patients with metastasized cancer (which is 62% of women diagnosed), the 5-year survival rate drops to 28.2%. It is thought, therefore, that earlier diagnosis may improve outcomes.2

Similarly, the involvement of a gynecological oncologist early in the process, before any surgery, is also associated with better outcomes. According to Quest Diagnostics, a meta-analysis of 18 ovarian cancer studies found that the early involvement of a gynecologic oncologist, rather than a general surgeon or general gynecologist, had a favorable impact on patient outcomes.

Jon R. Cohen, MD

“There is a pretty big difference in therapy in the operating room if you have the gynecological oncologist present,” says Jon R. Cohen, MD, senior vice president and chief medical officer of Quest Diagnostics, headquartered in Madison, NJ. Having the appropriate surgeon present at the time of surgery can prevent having to close the patient and, at a later date, reopen when the gynecological surgeon is available.

However, according to peer-reviewed studies, Quest estimates that only one-third of women who undergo surgery for possible ovarian cancer are referred to gynecological oncologists for that surgery. To help ensure appropriate referrals, Quest has supported the development of the OVA1 Test, a diagnostic developed by Vermillion Inc, Fremont, Calif, to help assess the likelihood of malignancy and ensure appropriate referrals. Recently cleared by the FDA, Quest now holds a 3-year exclusive license in the US clinical reference laboratory market.

Categorized as an In Vitro Diagnostic Multivariate Index Assay (IVDMIA), OVA1 uses a blood sample, five well-established biomarkers, and a proprietary algorithm to produce a numerical score that indicates the likelihood of malignancy of the woman’s pelvic mass. The biomarkers include: Transthyretin (TT or prealbumin), Apolipoprotein A-1 (Apo A-1), Beta 2-Microglobulin (Beta 2M), Transferrin (Tfr), and Cancer Antigen 125 (CA-125).

The FDA approved the test for use in women 18 years of age or older who have an ovarian adnexal mass present for which surgery is planned and who have not yet been referred to an oncologist. The test is not intended as a stand-alone diagnostic nor as a screening tool. Rather, it should be used in conjunction with imaging studies and other clinical assessments.

“The test is really a triage test that provides a high degree of certainty in determining whether or not there is a significant chance [the pelvic mass] is malignant,” Cohen says. In a supporting clinical study, roughly 20% more women with a malignancy were identified using the dual assessment with the OVA1 Test than when using a presurgical assessment alone.

At present, Cohen estimates turnaround for test results will be a couple of days, and the test is expected to be available by the end of the year.

Improving Ovarian Cancer Diagnosis with HE4

As noted, OVA1 is intended for use prior to surgery and in many cases before a diagnosis is confirmed. The current gold standard for monitoring ovarian cancer for treatment success and disease recurrence postdiagnosis is CA-125. Significantly elevated concentrations of this marker may indicate the presence of cancer in the ovaries.

However, other conditions, such as menstruation and endometriosis, can also elevate CA-125 levels, and the low specificity prevents the test’s use as a diagnostic. Research into Human Epididymis Protein 4 (HE4) has shown the potential to expand the value of CA-125. Fujirebio Diagnostics Inc, Malvern, Pa, reports that in a prospective, multicenter study, a combination assay yielded a sensitivity of 91% with a fixed specificity of 75%.

The improved sensitivity and specificity over CA-125 alone should allow clinicians to more accurately distinguish between benign and malignant pelvic masses and begin appropriate treatment earlier. To this end, Fujirebio developed a manual ELISA kit for the quantitative measurement of HE4 in patient blood.

The test has been cleared by the FDA for use as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Currently, the test and corresponding Risk of Ovarian Malignancy Algorithm (ROMA) are pending clearance by the FDA for use in women who present with a pelvic mass.

At present, the Fujirebio test can be obtained exclusively through Quest Diagnostics, which is the exclusive laboratory reference provider of the test in the United States. However, both Abbott Diagnostics, Abbot Park, Ill, and Roche Diagnostics Corp, Indianapolis, have signed licenses with Fujirebio to develop HE4 tests for their immunoassay and integrated analyzers.

“The HE4 test is another important pillar of our broad tumor marker test menu. We expect that the HE4 test will contribute significantly to our future growth in the area of oncology,” said Dirk Ehlers, head of Roche Professional Diagnostics, in a press release.

Clarity in Breast Cancer

Breast cancer patients also benefit from personalized medicine, with tests already existing to help tailor treatment for the more than 192,000 cases that will be diagnosed this year.3 Physicians routinely run tests to determine if a patient has human epidermal growth factor receptor-2 (HER2)-positive breast cancer, which is more aggressive but responds better to targeted treatment. HER2-positive patients therefore undergo different treatment than those with HER2-negative breast cancer.

Clarient, Alisa Viejo, Calif, has launched another tool to aid physicians with prognosis and decision-making in treating breast cancer patients beyond the HER2 question. The Clarient Insight Dx Breast Cancer Profile uses a combination of pathology risk factors and molecular markers to categorize patients with early-stage, hormone-receptor-positive breast cancer as either at high or low risk or recurrence.

According to Dave Daly, Clarient’s senior vice president of commercial operations, statistics show that about 85% of women are cured just with surgery. “You don’t want to unnecessarily give a harsh treatment of chemotherapy to someone who isn’t going to benefit from it, and you also want to ensure that those at high risk are treated the most aggressively to give them the best chance of survival,” Daly says.

To achieve this, the test is designed for use by community pathologists, who typically provide guidance to the oncologist through their understanding of test results. Subsequently, Clarient believes it important to include components that are already well understood by this group.

The traditional prognostic factors for breast cancer have been the number of lymph nodes affected, the tumor size, the histological grade, and hormone receptor status. The Insight Dx test uses the first three in conjunction with seven molecular markers: estrogen receptor (ER), progesterone receptor (PR), HER2, epidermal growth factor receptor (EGFR), BCL2, p53, and MYC. A proprietary algorithm produces a score indicating risk.

The inclusion of traditional prognostic factors provides some continuity with previous methods. “We felt they were the right components in combination with this particular assay and the additional markers we provide, and it gives clinicians and pathologists comfort that we’re using tried and true to generate this score,” Daly says.

Traditionally, most clinicians use the algorithm supplied by Adjuvant! Online, a free Web-based clinical application, to assess risk. Clarient performed validation studies comparing Insight Dx and Adjuvant! and found the test outperformed the online service, accurately identifying about 25% more low-risk patients.

An independent study conducted in Australia by Clarient also provided validation, finding a negative predictive value of about 97% and corresponding positive predictive value of 39%. Additional studies by Prediction Sciences, the exclusive licensor of the Clarient Insight Dx Breast Cancer Profile located in La Jolla, Calif, found similar results.

Altogether, more than 1,000 patient results have been analyzed during development. Those in the low-risk group are expected to have a less than 5% rate of recurrence at 10 years; those in the high-risk group have at least a 10 times greater risk of recurrence, on average, according to Clarient’s study.

The stratification of risk will, ideally, lead to improved patient outcomes through tailored treatments. “Our desire is to improve patient care by bringing clarity to the disease of cancer,” Daly says.

GBS Testing—Faster Methods, New Controls

As tools for personalized medicine become more available, there is an increased focus on prevention. Molecular studies provide one way to enable early detection and, ideally, prevention of disease progression. This is particularly evident in the field of neonates, where many tests are conducted before the child is even born.

One such test is that for Group B strep (GBS), the most common cause of sepsis and meningitis in newborns and a frequent cause of newborn pneumonia.4 Approximately 25% of women may carry the bacteria at any time, putting them at higher risk for transmitting the infection to their infants during birth.4 To prevent this, medical guidelines recommend universal prenatal screening for colonization between 35 and 37 weeks’ gestation. Patients found to be positive with GBS are given antibiotics at the start of labor.4

Traditional methods, which rely on culture only, can take 3 to 4 days and may miss some true positive samples. “When the culture is overgrown with normal flora that might have come from the sample taken, it can be difficult to identify non-beta-hemolytic strains,” says Joen T. Johansen, director of marketing for AdvanDx, Woburn, Mass.

AdvanDx recently received clearance from the FDA for its GBS PNA FISH, a new test for the detection of Streptococcus agalactiae or GBS that combines the use of Lim Broth culturing and the PNA FISH molecular platform. Following an overnight culture inoculated with vaginal and rectal swabs taken from the patient, the GBS PNA FISH test is run the next morning and results are produced within 90 minutes.

A clinical study cited by AdvanDx found that in addition to the faster turnaround, the test also showed increased sensitivity, detecting up to 42% more GBS positives than conventional culture methods. In addition, the streamlined test avoids multiple cultures, thus saving labor, and garners higher reimbursements with the use of PNA FISH.

Ultimately, however, the goal is improved patient care. “The test will enable labs to provide fast and sensitive detection of Group B Strep that in turn may help clinicians provide better preventive care for more pregnant women and their newborns,” Johansen adds.

Another company has also sought to aid this effort, launching a new quality control. AcroMetrix, Benicia, Calif, a manufacturer of quality control standards and controls, released OptiQual GBS Positive Control, the first standardized control for GBS testing. “This means the values assigned to the control have metrological traceability to a higher standard, and you’ll see reproducible and consistent results,” product specialist Brian McLucas says.

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The control was designed to help clinical laboratories comply with CLIA guidelines for qualitative molecular assays and can fit into a laboratory’s quality control program as needed. “It could be used as a daily run control—although that isn’t necessarily required. It could be used between reagent lots of assay to detect any lot-to-lot variation. It can also be used to detect any variation between operators,” McLucas says.

The OptiQual GBS Positive Control is unassayed and contains inactivated whole GBS bacteria. Its standardization and resulting reproducibility are designed to lead to more accurate result reporting. “The control itself can help lab technologists more easily and efficiently monitor the performance of molecular GBS assays. And with better quality control, labs can minimize treatment costs associated with inaccurate results and ensure that the patient is receiving the best care possible,” McLucas says.

Renee Diiulio is a contributing writer for CLP.


  1. National Cancer Institute, Ovarian Cancer. US National Institutes of Health. Available at: www.cancer.gov/cancertopics/types/ovarian. Accessed October 5, 2009.
  2. Surveillance Epidemiology and End Results. Seer Stat Fact Sheets—Ovary Cancer. National Cancer Institute. Available at: seer.cancer.gov/statfacts/html/ovary.html. Accessed October 5, 2009.
  3. National Cancer Institute, Breast Cancer. US National Institutes of Health. Available at: www.cancer.gov/cancertopics/types/breast. Accessed October 5, 2009.
  4. Centers for Disease Control and Prevention. Group B Strep Prevention (GBS, baby strep, Group B streptococcal bacteria)/General Public FAQs. Available at: www.cdc.gov/groupbstrep/general/gen_public_faq.htm. Accessed October 6, 2009.