Ovarian Cancer Biomarkers: Advancing Early Detection and Guiding Treatment

Ovarian cancer is a challenging disease that often develops without evident symptoms, making early detection difficult. While the impact of this cancer is significant, researchers are making tremendous strides in understanding the disease and improving diagnostic and treatment strategies. Central to these efforts is the study of ovarian cancer biomarkers: biological clues that can signal the presence of cancer and guide the selection of the most promising therapies for each individual patient.

There is an urgent need for better tools to detect ovarian cancer early and to personalize treatment for each unique patient. That’s why it’s exciting to explore the latest advances in ovarian cancer biomarker research and how these discoveries are bringing us closer to a future where no woman has to face this disease alone.

What are Ovarian Cancer Biomarkers?

Imagine you’re about to embark on a journey through unfamiliar territory. You’ll want a reliable map to guide you, with clear markers indicating where you are and what lies ahead.

In the world of ovarian cancer, biomarkers serve as our map. These measurable indicators can be found in blood, tissue, or other bodily fluids, but they’re not just limited to that.

Biomarkers come in various forms. They can be gene mutations, proteins, enzymes, or even altered versions of proteins that are normally expressed in the body.

Take gene mutations, for example. They’re a crucial type of biomarker, especially when we’re talking about hereditary ovarian cancer. The BRCA1 and BRCA2 gene mutations are the highest known cause of inherited ovarian cancer. It’s important to note that you can have a BRCA mutation without having cancer, but you can’t have a BRCA biomarker without inheriting the mutation. (Learn more about BRCA testing in ovarian cancer here.)

These diverse biomarkers can tell us different things:

• If cancer is present (diagnostic biomarkers)
• How the disease might progress (prognostic biomarkers)
• Which treatment might work best for a particular patient (predictive biomarkers)

By looking at this variety of molecular clues, we’re piecing together a more complete picture of ovarian cancer – one that could lead to earlier detection and more personalized treatment strategies.

According to recent estimates, only about 20% of ovarian cancers are found at an early stage, when the 5-year survival rate is a hopeful 94%. However, for the majority of women diagnosed at a later stage, the 5-year survival drops to 31%. This stark difference highlights the lifesaving potential of early detection through biomarkers.

Current and Emerging Biomarkers for Ovarian Cancer Detection

For many years, a protein called CA125 has been the most widely used biomarker for ovarian cancer. CA125 is a protein produced by some ovarian cancer cells and released into the bloodstream. In a healthy person, the level of CA125 in the blood is usually low. However, in many women with ovarian cancer, the level of CA125 in the blood is elevated, making it a useful indicator of the potential presence of the disease. (Learn more about CA125 ovarian cancer screening here.)

When a woman is diagnosed with ovarian cancer, doctors can use CA125 to monitor how well the treatment is working. If the treatment is effective, the level of CA125 in the blood should decrease over time. After treatment, regular monitoring of CA125 levels can also help doctors detect if the cancer has come back (recurred), even before it’s visible on imaging scans.

This early detection of recurrence through biomarkers is called a chemical recurrence. It’s a critical tool in the ovarian cancer journey. Here’s why:

• Early warning system: A rising CA125 level (or whatever marker was specific to the patient) can signal that cancer might be returning, even if there’s no radiographic proof yet.
• Between-scan detection: Insurance typically only covers PET scans at certain intervals. Biomarker testing can fill the gaps, potentially catching a recurrence earlier than waiting for the next scheduled scan.
• Proactive care: Detecting a chemical recurrence allows doctors and patients to act swiftly, potentially starting treatment earlier when it might be more effective.

By keeping a close eye on these biomarkers, we’re not just waiting and watching; we’re actively seeking clues that could give us a head start in tackling recurrence. It’s another way we’re working to stay one step ahead of this sneaky disease.

However, CA125 is not a perfect biomarker. It can be elevated in other non-cancerous conditions, such as endometriosis, fibroids, and even during menstruation. Additionally, not all ovarian cancers cause an increase in CA125 levels, particularly in the early stages of the disease. These limitations have led researchers to search for other biomarkers that can complement or improve upon CA125 for detecting and monitoring ovarian cancer.

To improve upon CA125, researchers have been exploring other promising biomarkers:

• HE4: This protein is a protease inhibitor, which means it hinders other enzymes ability to break down other proteins. Its exact role in the body is still unknown. This protein is less likely than CA125 to be elevated in benign conditions, making it a more specific marker for ovarian cancer. Studies suggest that combining CA125 and HE4 could boost detection rates and prognosis. Some studies have even found HE4 can help predict platinum-based chemotherapy response.
• Osteopontin (OPN): This protein regulates immune response, wound healing, and the process of growing blood vessels called vascularization. Levels of this protein are significantly higher in the blood of women with epithelial ovarian cancer compared to healthy women or those with benign ovarian disease. High OPN is also associated with more advanced disease. A study has also found that high OPN is associated with chemoresistance and poor survival rates.
• Kallikreins (KLKs): This family of 15 proteins is overexpressed in ovarian tumor cells and shows potential as a diagnostic and prognostic marker. This protein is also a serine protease, but it works specifically in inflammation and managing blood flow. Certain KLKs have been found to correlate with resistance to chemo, tumor burden, and prognosis. Research is expanding, and scientists are currently looking into this marker as an early detector of ovarian cancer.
• Bikunin: Bikunin is an anti-inflammatory mediator and inhibits many enzymes in the body, including kallikrein. Low levels of this protein before surgery have been linked to later-stage disease, larger residual tumors after surgery, and poorer response to chemotherapy. Recent research has found that bikunin inhibits an enzyme involved in cancer cell metastasis.

Biomarker Testing for Ovarian Cancer

So, how do we actually test for ovarian cancer biomarkers? The most common approach is a simple blood test to measure levels of proteins like CA125 and HE4. These tests use antibodies that specifically attach to the biomarker of interest, allowing us to measure its amount in blood samples.

Advancements in technology are opening up new possibilities for biomarker testing. One such technique is called mass spectrometry-based proteomics, which allows scientists to analyze a large number of proteins from a small sample of blood or tissue. By comparing the protein patterns of women with ovarian cancer to those of healthy women, researchers can identify specific “fingerprints” that are unique to the disease.

In one promising study, a panel of proteins, including CA125, was able to correctly identify early-stage ovarian cancer with a high degree of accuracy – correctly identifying 94% of women with the disease (sensitivity) and 98% of women without it (specificity).

While these new approaches are exciting, it’s crucial to thoroughly test and validate potential biomarkers to ensure they perform well in a clinical setting. Sometimes, complex statistical models can overfit a specific dataset, leading to overestimating a biomarker panel’s accuracy.

To determine whether biomarkers can truly predict ovarian cancer, it’s important to conduct studies that collect samples from women before they are diagnosed with the disease.

There are also other hurdles to overcome in biomarker testing. These include making sure that testing methods are standardized across different laboratories to ensure consistent results, determining the appropriate cutoff values for a positive or negative test result, and taking into account factors like age, menopausal status, and other health conditions that may impact biomarker levels. Scientists are actively addressing these challenges to develop reliable and reproducible biomarker tests for clinical practice.

Prognostic and Predictive Biomarkers for Ovarian Cancer Therapy

Beyond detecting ovarian cancer, some biomarkers can guide treatment decisions and provide crucial prognostic information. One of the most important is BRCA mutation status. It’s a little different from the biomarkers we’ve discussed so far.

BRCA Mutation

BRCA1 and BRCA2 are inherited gene mutations, unlike biomarkers such as CA125 or HE4. These genes normally help repair damaged DNA and prevent tumor growth. When mutated, they increase the risk of developing certain cancers, including ovarian cancer.

Here’s the deal with BRCA mutations:

• They’re typically identified through genetic testing, often done after a cancer diagnosis or due to family history.
• Having a BRCA mutation doesn’t guarantee you’ll get cancer, but it significantly ups the odds. Women with BRCA1 mutations have a 39-44% lifetime risk of ovarian cancer, while for BRCA2 it’s 11-17%.
• BRCA status can be a game-changer for treatment. Women with BRCA-mutated ovarian cancers often respond well to PARP inhibitors.

PARP inhibitors are like kryptonite for BRCA-mutated cancer cells. They block DNA repair in these already repair-deficient cells, causing them to accumulate so much damage they eventually die. The FDA has green-lit three PARP inhibitors (niraparib, olaparib, and rucaparib) for certain ovarian cancers.

In one trial, olaparib slashed the risk of cancer progression or death by 70% compared to placebo in women with advanced BRCA-mutated ovarian cancer. This is why genetic testing is so crucial. It’s not just about understanding risk; it’s about tailoring treatment. Some clinical trials only enroll patients with specific gene mutations, opening doors to potentially life-saving treatments.

Remember, every ovarian cancer is unique. Your genetic profile, including BRCA status, helps paint a clearer picture of your disease and guides your medical team in choosing the most effective treatment plan for you.

Lynch Syndrome

While BRCA mutations are well-known, they’re not the only genetic players in ovarian cancer. Lynch syndrome, primarily associated with colorectal cancer, also increases the risk of ovarian and other cancers. This hereditary condition is caused by mutations in mismatch repair genes, most commonly MLH1 and MSH2.

Women with Lynch syndrome have a 4 to 12% lifetime risk of developing ovarian cancer, significantly higher than the general population. Like BRCA testing, identifying Lynch syndrome through genetic testing can guide screening and treatment decisions. Some clinical trials for ovarian cancer specifically target patients with Lynch syndrome, highlighting the importance of comprehensive genetic testing in personalizing care.

Emerging Biomarkers

Researchers are also constantly exploring new biomarkers for early detection of ovarian cancer. One promising candidate is mesothelin, a surface glycoprotein that interacts with CA125. It’s particularly interesting because:

• It’s detectable in urine, potentially aiding early diagnosis.
• It’s expressed in 100% of borderline serous and serous cystadenocarcinoma urine samples.
• It could help monitor treatment response.

Other biomarkers under investigation include exosomes, microRNAs, and proteins like Apolipoprotein A1. While promising, these need more research before clinical use.

• Higher levels of the protein Creatine Kinase B (CKB) in ovarian tumors are associated with worse survival. 
• Apolipoprotein A1 (ApoA1) and transthyretin (TTR) are two proteins found at lower levels in the blood of ovarian cancer patients compared to healthy women. Low ApoA1 or TTR may indicate a poorer prognosis. ApoA1 is the major protein component of high-density lipoprotein (HDL) particles in the blood. HDL is often referred to as “good cholesterol” because it helps remove excess cholesterol from tissues and transport it to the liver for processing or elimination. ApoA1 plays a crucial role in this cholesterol transport process and has additional anti-inflammatory and antioxidant properties.

With advances in genomic sequencing and computational analysis, researchers are also discovering new types of biomarkers, such as lncRNAs and mRNAs, that are differentially expressed in ovarian cancer.

For example, a recent study identified an 8-marker panel, including KIAA1324, PAM, PGR, and WT1, that showed promising results in distinguishing between endometrioid and high-grade serous ovarian carcinomas. This panel correctly classified 90% of the samples in the study, which speaks more to its sensitivity rather than overall accuracy. It’s an exciting step forward, but as with all biomarker research, more studies are needed to validate these findings across larger and more diverse patient populations.

Other biomarkers are emerging as potential predictors of response to targeted therapies:

• Tumors with homologous recombination deficiency (HRD) may benefit from PARP inhibitors, even without a BRCA mutation. HRD means the cancer cells can’t properly repair certain types of DNA damage. It’s like the cells lost their ability to swap matching parts between DNA strands: a process that normally happens when, say, mom and dad’s DNA mix to form a baby. New tests are being developed to identify HRD-positive ovarian cancers, potentially opening up PARP inhibitor treatment to more patients.
• Overexpression of proteins that promote blood vessel growth, like VEGF, is associated with more aggressive disease. Bevacizumab, an antibody that targets VEGF, is approved in combination with chemotherapy for advanced ovarian cancer. Measuring VEGF levels might help identify patients most likely to benefit from anti-angiogenic drugs (a type of medication that works by preventing the formation of new blood vessels, a process known as angiogenesis).
• Immune checkpoint proteins like PD-1 and PD-L1 are potential targets for immunotherapy. Ovarian cancers with high levels of these proteins may be more susceptible to checkpoint inhibitors like pembrolizumab or nivolumab.

To harness the power of multiple biomarkers, researchers have developed algorithms that integrate different variables into a risk score:

• The Risk of Malignancy Index (RMI) combines serum CA125 level, ultrasound score, and menopausal status into a numerical score. An RMI above 200 suggests a high risk of ovarian malignancy. A 2016 analysis found that using the RMI in a two-step strategy could improve ovarian cancer detection rates from 72% to 85%.
• The Risk of Ovarian Malignancy Algorithm (ROMA) calculates a risk score based on a woman’s CA125 and HE4 levels and menopausal status. ROMA has demonstrated higher sensitivity than CA125 alone, although its specificity is slightly lower.

While these multi-marker approaches show promise, more validation is needed to confirm their usefulness in diverse patient populations.

By integrating these prognostic and predictive biomarkers, we can envision a future of precision medicine for ovarian cancer, where each patient’s molecular profile guides their individual treatment plan. 

Instead of a one-size-fits-all approach, women with BRCA mutations might receive PARP inhibitors, those with high VEGF could benefit from bevacizumab, and patients with elevated PD-L1 may be good candidates for immunotherapy. This personalized strategy can potentially improve outcomes by matching the right treatment to the right patient at the right time.

Non-profit organizations like Not These Ovaries are working tirelessly to fund research and clinical trials that can accelerate the development and implementation of these life-saving tools.

Future Directions in Ovarian Cancer Biomarker Research 

As our understanding of ovarian cancer biology deepens, so does our ability to identify and harness novel biomarkers. The future of ovarian cancer biomarker research is multidisciplinary and data-driven, integrating insights from genomics (DNA), transcriptomics (RNA), proteomics (proteins), and other “omics” technologies.

Artificial intelligence and machine learning will play a key role in analyzing these complex datasets to uncover patterns and signatures of disease. As computational tools become more sophisticated, we may be able to develop predictive models that integrate clinical, imaging, and molecular data to detect ovarian cancer at its earliest, most curable stages.

Scientists are also working on developing new tests for ovarian cancer that are easy to do and less invasive than current methods. While blood tests are the most common, researchers are also looking for unique biomarkers in other body fluids like urine, saliva, and even the breath that a person exhales.

However, turning these exciting biomarker discoveries into tests that can be used in everyday medical care is not a simple task. It involves a lot of detailed work to ensure the tests are accurate and reliable. This includes testing the biomarkers in large groups of people from different backgrounds, ensuring that the testing methods are consistent across different labs, and creating clear guidelines for doctors on how to use these biomarker tests in their practice.

To achieve this, many different groups need to work together. This includes the scientists doing the research, the doctors who treat patients, companies that develop medical tests, and most importantly, the patients and advocates who provide valuable insights and support. By collaborating and sharing their expertise, these groups can overcome the challenges and turn the potential of ovarian cancer biomarkers into a reality that benefits women everywhere.

Ovarian cancer biomarkers represent a beacon of hope in the fight against this devastating disease. Organizations like Not These Ovaries support ovarian cancer research, funding innovative studies and clinical trials that can transform biomarker discoveries into life-saving realities.

With continued investment in biomarker research, we can envision a day when no woman has to face this disease alone: when early detection is the norm, when treatment is tailored to each patient’s unique molecular profile, and when survival rates are measured in decades, not years. Together, we can make this vision a reality and bring hope to the thousands of women affected by ovarian cancer worldwide.