Beyond the Blood Draw: Making Liquid Biopsy More Accurate, One Mutation at a Time

In the United States, over 2 million people will be diagnosed with cancer this year, a daunting number that reflects the realities of an aging population. While molecular profiling is increasingly essential to guide targeted therapies, many current approaches still rely on invasive, hard-to-access tissue biopsies. A simple, minimally invasive blood draw can profile tumor-derived DNA in the bloodstream—offering a less burdensome alternative to tissue biopsy. But it isn’t without its challenges. Liquid biopsy is susceptible to the risk of false positives caused by clonal hematopoiesis (CH). CH is an age-related condition, which can be aggravated by toxic agents like tobacco smoke and chemotherapy, that introduces mutations into the blood and is found in more than 42 percent of cancer patients. However, researchers are now targeting CH and building new solutions to help make liquid biopsy a frontline defense in the fight against cancer.

The problem with false positives: understanding clonal hematopoiesis

As the population ages, the number of cancer cases rises, and so does medical uncertainty—especially when CH enters the picture. Some CH mutations are linked to a small increase in the risk, a rise of about 1 percent per year, of developing blood cancers, and these mutations are not commonly found in solid tumors. Other CH mutations can also commonly be found in solid tumors, which makes interpretation of plasma-only liquid biopsy testing difficult. 

This confusion can yield false positive test results: erroneous findings that point to the presence, changes, or progression of cancer. Critically, the consequences can be far-reaching: patients may undergo ineffective treatments or miss out on therapeutic options that could have been beneficial. In contrast, when CH-derived and tumor-derived mutations are confidently distinguished, unnecessary treatments can be avoided, and patients can be better guided toward therapies with a higher likelihood of success.

Strategies to improve accuracy in liquid biopsy interpretation

Liquid biopsies are becoming increasingly central to cancer profiling and care, and it’s no wonder why. While tissue biopsy allows direct examination of tumors, it is invasive, offers only a snapshot of a single tumor at a single site, and cannot track changes over time. Liquid biopsy, on the other hand, captures tumor content from throughout the body and can more readily monitor dynamic changes in tumors. To ensure these blood-based tests are clinically meaningful, experts across the industry are developing new strategies to improve their reliability, especially in the context of CH. These new approaches include, but are not limited to:

• Tumor-blood comparison: Comparing mutations in blood to those in tumor tissues helps distinguish whether the signals originate from tumors or white blood cells.
• AI-powered bioinformatics: Some parts of the industry are attempting to use artificial intelligence (AI) to automatically distinguish CH-derived mutations and filter out age-related changes to minimize the risk of false positives. However, this technology still has a long way to go and can still miss these changes. 
• Expert molecular review: While AI can accelerate and standardize analysis, the technology does not replace expert knowledge and experience. Cancer treatment data is complex and often patient-specific, so human insight and interpretation remain essential. Directly measuring CH rather than relying solely on AI predictions increases accuracy. 

Alone, none of these strategies can provide the precision needed for accurate patient care. But together, they help liquid biopsy fulfill its promise: a faster, noninvasive, and more informative option for selecting the right cancer therapies. This cancer-profiling strategy enables real-time decision-making and supports personalized patient care, providing reliable and clinically meaningful insights over time. 

Impact on patient care and the future of precision oncology

Despite notable progress in cancer care, finding the right therapy remains too invasive, slow, and inaccessible, leading to delayed or incorrect treatment that can compromise patient care. Liquid biopsy offers a promising, less burdensome alternative by detecting tumor-derived nucleic acid through a simple blood draw. But its full potential depends on solving challenges like false positives caused by CH.

By accurately identifying and accounting for CH, uncertainty can be reduced, ineffective treatments minimized, and care plans aligned with each patient’s true condition. When interpreted correctly, liquid biopsy becomes more than a tool—it becomes a catalyst for personalized, data-driven cancer care.