ctDNA Revolution Shapes the Future of Cancer Care

Breakthrough Approvals to Transformative Insights

Foundation Medicine has been at the forefront of liquid biopsy (LBx) advancements for nearly a decade, beginning with the launch of FoundationACTTM in 20161, a laboratory-developed test that marked Foundation Medicine’s entry into blood-based genomic profiling. In 2017, the International Society for Liquid Biopsy (ISLB) was founded2 as a professional organization dedicated to helping oncologists integrate this emerging tool into clinical practice. A significant milestone occurred in August 2020, when the U.S. Food and Drug Administration (FDA) approved FoundationOne®Liquid CDx3 for cancer treatment selection. That same year, the company introduced our first-generation tumor fraction algorithm which estimated the amount of circulating tumor-derived DNA (ctDNA) in the blood sample. Over time, Foundation Medicine has refined its ctDNA analysis, implementing an advanced ctDNA tumor fraction algorithm in November 20234. Today, Foundation Medicine remains the only comprehensive genomic profiling (CGP) lab to report ctDNA tumor fraction as high or low, providing oncologists with clarity in guiding treatment decisions*. With ctDNA insights incorporated into multiple clinical trials and growing recognition of liquid biopsies in professional guidelines, Foundation Medicine continues to drive the evolution of precision oncology. 

Despite the growing adoption of LBx, challenges remain in fully harnessing its potential alongside traditional tissue biopsies. While tissue biopsies are invasive and often limited by sample availability, liquid biopsies provide a minimally invasive alternative. However, variability in ctDNA levels, as well as age-related expansion of blood cells with mutations known as clonal hematopoiesis (CH), and germline variants can complicate result interpretation. The future of precision oncology lies in effectively integrating these complementary tools to provide accurate, actionable insights for patient care. 

At the 2024 International Society of Liquid Biopsy (ISLB) 6th Annual Congress5, experts from Foundation Medicine emphasized how ctDNA-driven insights are transforming cancer treatment. Their presentations underscored the role of next-generation biomarkers and real-time monitoring in advancing personalized medicine. 

Innovation Spotlight: ctDNA Tumor Fraction

One of the key innovations driving progress in LBx is tumor fraction — a determination of the amount of tumor-derived DNA in a patient’s blood sample. The level of ctDNA can vary significantly between cancer types, within a tumor type, and even within the same patient over time. Foundation Medicine’s advanced ctDNA tumor fraction methodology measures ctDNA levels using a multi-omic approach that integrates variant allele frequency (VAF), aneuploidy, fragmentomics, and filtering of CH and germline variants. This approach does not require a matched normal sample, making it a practical tool for clinical use. FoundationOne®Liquid CDx leverages a validated 300+ gene panel and a sophisticated ctDNA tumor fraction algorithm to quantify tumor-derived DNA. 

Foundation Medicine researchers and collaborators have published on the clinical validity of ctDNA tumor fraction in multiple tumor types, showing that ctDNA tumor fraction of 1% or higher is associated with high sensitivity to detect driver alterations. Analytical validation data presented at the 2024 Association for Molecular Pathology (AMP) Annual Meeting & Expo, further confirmed robust exclusion of CH and germline variants using ctDNA tumor fraction, delivering results comparable to matched white blood cell sequencing. 

Innovation Spotlight: Machine Learning Enabled Clonal Hematopoiesis Solution 

Liquid biopsy can detect CH variants that overlap with targetable alterations in solid tumors, causing uncertainty about how to interpret LBx results. Foundation Medicine recognizes this challenge and anticipates launching a new CH solution for individual variants detected by FoundationOne®Liquid CDx in 2025. This machine learning-based solution is trained using equal-depth sequencing of thousands of matched plasma buffy coat samples and leverages fragmentomic information and other sequencing features to predict variant origin. This solution offers time and cost benefits over performing matched buffy coat sequencing for each LBx sample and may also increase the sensitivity of CH detection beyond buffy coat sequencing. 

The breakthrough CH algorithm confidently distinguishes CH and tumor-derived variants, minimizing the risk of misinterpreting CH-related markers as clinically significant cancer mutations. Reducing uncertainty enhances the reliability of LBx results and ensures that identified markers are truly associated with therapeutic sensitivity. 

Practical Application: Treatment Response Monitoring

Building on the innovations of ctDNA tumor fraction and machine learning-based variant origin detection, Foundation Medicine has developed FoundationOne®Monitor, set to launch in 2025. Unlike tissue-informed ctDNA monitoring assays, FoundationOne Monitor does not require baseline tissue samples. This test quantifies and longitudinally reports changes in ctDNA levels over time, enabling clinicians to inform assessment of therapy response, disease progression, and resistance alterations in patients with metastatic cancer. This multi-modal approach allows clinicians the opportunity to optimize patient treatment strategies. 

FoundationOne Monitor complements standard imaging techniques, particularly in cases where imaging results may be ambiguous or when it’s unclear if a patient with stable disease on imaging is benefiting from therapy. Additionally, FoundationOne Monitor can detect acquired resistance alterations across 300+ genes, providing an early indication of resistance ahead of imaging. 

Real-World Impact: Clinical Evidence

The impact of these innovations extends beyond theoretical advancements—real-world clinical evidence underscores their effectiveness. FoundationOne Monitor directly employs ctDNA tumor fraction to assess treatment response and the emergence of resistance. Tracking molecular response provides real-time insights into disease progression, enabling more precise and timely treatment decisions. The clinical validity of FoundationOne Monitor has been demonstrated in multiple studies published over the past year, highlighting its value in clinical care and monitoring treatment response across various cancer types. Evidence supports its effectiveness in monitoring treatment response for patients with: metastatic castration-resistant prostate cancer (mCRPC) receiving hormonal therapies, advanced non-small cell lung cancer (NSCLC), and HR+/HER2- breast cancer treated with hormonal therapies. Moreover, FoundationOne Monitor can also be used in the pan-solid tumor setting for patients receiving immunotherapy. 

Pioneering Research and Driving Informed Treatment Decisions

Foundation Medicine remains committed to advancing ctDNA-driven technologies. The company is shaping the next era of precision cancer care through multi-omic methodologies, machine learning-based solutions, and close collaboration with the broader oncology community. The upcoming launch of FoundationOne Monitor represents another critical step—offering real-time, noninvasive tools to track treatment response and resistance, ensuring clinicians have the insights they need to optimize patient outcomes.