FoundationOne Liquid CDx Test: ctDNA, Cancer Genomics, Mutation Report, and Companion Diagnostic Use

FoundationOne Liquid CDx is a blood-based comprehensive genomic profiling test used in people with solid tumors when a clinician needs information about cancer-related DNA without relying only on a tissue biopsy. The assay analyzes cell-free DNA in plasma, including circulating tumor DNA (ctDNA) shed by cancer cells, and reports genomic alterations that may help with targeted-treatment selection, clinical-trial matching, or broader molecular characterization. It also has FDA-authorized companion-diagnostic uses for specific biomarkers and drugs.

The most important limitation is biological rather than technical: some tumors release little ctDNA into the bloodstream. A blood sample can therefore produce a technically successful report while still missing an alteration that exists in the tumor. A negative result should be interpreted alongside tumor fraction, cancer type, disease burden, treatment history, and the availability of tissue. The report is most useful when an oncology team separates FDA-linked companion-diagnostic findings from other potentially relevant genomic findings and decides whether tissue testing is still needed.

• FoundationOne Liquid CDx analyzes plasma cell-free DNA for cancer-associated genomic alterations; it is not a general cancer screening test.
• A detected actionable alteration may support targeted-treatment selection, but only some findings have an FDA-authorized companion-diagnostic role for a specific drug and cancer setting.
• A negative plasma result does not prove the tumor lacks the alteration because low ctDNA shedding can cause false-negative results.
• Tumor fraction matters: low ctDNA content especially reduces confidence in negative findings and can make some copy-number changes harder to detect.
• Tissue testing may still be needed when blood testing is negative, incomplete, discordant with the clinical picture, or when histology and other tissue-based biomarkers are required.

Table of Contents

• What FoundationOne Liquid CDx Tests
• How the Blood Test Works
• How to Read the Mutation Report
• What Companion-Diagnostic Use Means
• What a Negative or Low-Signal Result Means
• When Liquid and Tissue Results Disagree
• How Results Can Guide Next Steps

What FoundationOne Liquid CDx Tests

FoundationOne Liquid CDx is a next-generation sequencing, or NGS, assay for comprehensive genomic profiling (CGP) from plasma. Instead of removing a piece of tumor, the laboratory extracts cell-free DNA from the blood and searches for molecular changes associated with cancer. The original FDA-approved assay was validated as a 324-gene cfDNA profiling test, and its regulatory companion-diagnostic indications have continued to expand through FDA supplements.

The test can identify several major classes of genomic alteration, including selected:

• single-nucleotide variants, sometimes called substitutions;
• small insertions and deletions;
• gene rearrangements or fusions;
• copy-number alterations such as amplifications or losses; and
• complex genomic biomarkers supported by the assay, including microsatellite instability and blood-based tumor mutational burden in appropriate report contexts.

The report can also provide an estimate of ctDNA tumor fraction. Tumor fraction is the proportion of circulating DNA signal estimated to come from cancer rather than normal cells. It is not the same thing as the variant allele frequency, or VAF, of one mutation. A ctDNA tumor fraction result gives broader context for how much tumor-derived material was available to analyze.

FoundationOne Liquid CDx is designed for patients with known solid malignancies who need molecular profiling. It should not be confused with an early-detection blood test. A cell-free DNA cancer test is a broad concept; FoundationOne Liquid CDx is a specific clinical assay with defined analytical performance and specific FDA-authorized uses.

A broad panel can be valuable because one blood draw may detect alterations across multiple pathways at the same time. That can be more efficient than ordering a series of single-gene tests, especially in advanced cancer where several biomarkers may influence treatment. However, “comprehensive” does not mean every possible genomic change is detectable, nor does it mean every reported alteration has a proven treatment attached to it.

How the Blood Test Works

The test starts with peripheral blood collected in specialized tubes that preserve cell-free DNA. Plasma is separated from blood cells, cfDNA is extracted, and targeted NGS is used to read selected cancer-associated genomic regions. Bioinformatic methods then distinguish likely true variants from sequencing noise and generate the clinical report.

The useful DNA signal can vary widely between patients. Metastatic tumors in highly vascular organs may release abundant ctDNA, while small-volume disease, some lung-only or peritoneal disease, certain brain tumors, and cancers under effective treatment may release much less. Blood collection can be technically adequate even when the amount of tumor DNA is too low for confident detection of every alteration.

This explains an important difference between sample success and biological informativeness. Real-world studies have reported high rates of technically successful FoundationOne Liquid CDx sequencing, yet the proportion of samples with a clearly elevated tumor fraction is much lower. A report can therefore pass laboratory quality checks and still have limited sensitivity for tumor variants because little ctDNA was present.

Different alteration types also have different detection requirements. Small sequence variants can sometimes be detected at very low VAF, while copy-number gains or losses generally need more tumor signal because the assay must distinguish a change in gene dosage against the background of normal cfDNA. The original analytical validation reported different limits of detection for substitutions, rearrangements, amplifications, and losses rather than one universal sensitivity threshold.

Treatment timing matters as well. A blood draw taken after a strong treatment response can contain less ctDNA than a pretreatment sample. Conversely, progression may increase tumor shedding and reveal resistance alterations that were absent or below detection earlier. For that reason, the clinical question and timing of collection should be documented when the result is interpreted.

How to Read the Mutation Report

A FoundationOne Liquid CDx report may look like a list of mutations, but interpretation works best when the findings are sorted into categories: what was detected, how strong the biological signal was, whether the alteration has an approved treatment association, and whether the finding could have another explanation.

Report element	What it tells you	What it does not prove
Genomic alteration	A cancer-associated DNA change was detected in plasma	That the alteration is driving the cancer or has an approved drug
Variant allele frequency	Fraction of sequenced DNA at that site carrying the variant	The exact percentage of tumor cells with the mutation
Tumor fraction	Estimate of overall ctDNA contribution to the sample	A direct measurement of tumor size or stage
Companion-diagnostic association	The biomarker-test-drug relationship is FDA authorized in a specified setting	That the drug is appropriate regardless of cancer type, line of therapy, or labeling
Other therapy or trial information	Potentially relevant evidence or study options	Guaranteed benefit from an off-label therapy or investigational drug

VAF deserves special caution. A mutation at 10% VAF does not mean 10% of tumor cells carry the mutation. Plasma contains DNA from many normal cells, tumors can have abnormal chromosome copy numbers, and more than one tumor clone can contribute DNA. VAF is therefore a sequencing proportion, not a direct tumor-cell percentage.

Some plasma variants may also arise from clonal hematopoiesis, an age-associated expansion of blood-cell clones that carry somatic mutations. Genes such as DNMT3A, TET2, ASXL1, TP53, and others can be affected. Depending on the variant and context, clinicians may need tissue comparison, blood-cell testing, or another method to determine whether a finding came from the tumor, blood cells, or potentially the germline.

Finally, a broad ctDNA mutation panel can identify multiple coexisting alterations. That makes molecular context important: one finding may be an established driver, another a resistance mechanism, and another a variant with uncertain therapeutic relevance.

What Companion-Diagnostic Use Means

A companion diagnostic is a test that the FDA has authorized to identify patients for whom a particular drug is indicated, according to the drug and device labeling. FoundationOne Liquid CDx has companion-diagnostic indications across specific cancers and biomarkers, and those indications can change as new drug-test pairings receive approval.

Examples in current FDA listings include plasma detection of selected EGFR alterations in non-small cell lung cancer, BRAF V600E in certain lung and colorectal cancer settings, PIK3CA mutations in breast cancer, selected BRCA or homologous-recombination-repair alterations in prostate cancer, and other biomarker-drug pairs. The exact approved combination matters. A mutation can be biologically important without being a companion-diagnostic finding for every drug that targets the same pathway.

This is why a report should not be read as “mutation present = use targeted drug.” The oncology team must verify:

• the cancer type and stage;
• the exact gene and variant detected;
• the treatment line and prior therapies;
• the current FDA labeling for the drug;
• whether the test is an authorized companion diagnostic for that specific use; and
• other clinical factors such as performance status, organ function, contraindications, and resistance mechanisms.

The regulatory distinction also helps explain why a report may contain far more genomic information than the companion-diagnostic section. FDA authorization for a specific biomarker-drug pairing is a defined claim. Other alterations on the same report may be included for tumor profiling under professional oncology guidance, but they are not automatically prescriptive.

For example, an EGFR T790M liquid biopsy result has a specific historical role in EGFR-mutant lung cancer, while other EGFR changes, MET amplification, or resistance mutations may require different evidence and treatment pathways. The report must be interpreted in the context of the patient’s actual disease state rather than by gene name alone.

What a Negative or Low-Signal Result Means

A negative FoundationOne Liquid CDx result can mean several different things. The tumor may truly lack the alteration, the alteration may be outside the assay’s detectable scope, or the tumor may not have released enough ctDNA into plasma for the variant to be seen. This last possibility is common enough that FDA labeling explicitly warns that a negative plasma result does not establish that the tumor is genomically negative.

Low tumor fraction lowers sensitivity most clearly. Recent FoundationOne studies show that plasma-tissue agreement rises when ctDNA fraction is adequate and that many plasma-negative/tissue-positive samples occur when tumor fraction is below about 1%. This does not create a universal 1% pass/fail rule; different alteration classes and clinical settings have different detection behavior. It does show why tumor fraction is critical context for a negative report.

A result stating that no reportable alterations were detected should therefore trigger questions rather than a simple conclusion:

1. Was the sample technically adequate?
2. Was ctDNA detected, and what was the estimated tumor fraction?
3. Is the suspected biomarker one that plasma testing detects well?
4. Was blood collected during low disease burden or after treatment?
5. Is recent tumor tissue available?
6. Would missing the biomarker change treatment enough to justify another specimen?

If the answer to the last question is yes, tissue testing is often the appropriate next step when feasible. Tissue can also provide information that plasma cannot, including tumor architecture, histologic subtype, protein expression, and microenvironment features.

A low-signal result should not be “rescued” by treating very low VAF findings as automatically important. Small variants near an assay’s detection limit require careful context, and apparent low-level changes may come from biological or technical sources other than the dominant tumor clone.

When Liquid and Tissue Results Disagree

Liquid and tissue biopsy are complementary because they sample cancer differently. Tissue provides a detailed snapshot of one sampled lesion at one time. Plasma can capture DNA released from multiple metastatic sites, potentially revealing tumor heterogeneity that a single biopsy misses. Neither approach is universally superior.

Three common discordance patterns have different implications.

Tissue positive, plasma negative: Low ctDNA shedding is a leading explanation. This pattern is especially plausible when tumor fraction is low. The tissue result may be the more informative source for the missed alteration if specimen quality and timing are appropriate.

Plasma positive, tissue negative: The blood finding may reflect a tumor clone from a different metastatic site, a change acquired after the archived tissue was collected, or a variant that was below detection in tissue. Clonal hematopoiesis and other non-tumor sources must also be considered for some genes.

Both positive but not identical: Tumor evolution can produce a shared core of alterations plus additional site-specific or treatment-selected clones. Serial resistance mutation testing can therefore reveal acquired changes after targeted therapy that were not present at diagnosis.

Recent multicenter evidence supports this complementary view. In the ROME trial, actionable alterations were sometimes found only in tissue and sometimes only in plasma. Other studies have shown that agreement improves substantially when liquid-biopsy tumor fraction is high. These findings argue against treating a discordant result as a laboratory failure by default. The right interpretation depends on sample timing, disease distribution, therapy exposure, assay coverage, and whether the disputed alteration has a strong treatment implication.

When a major treatment decision depends on one unexpected result, clinicians may confirm it with an orthogonal method, repeat plasma at progression, or test tissue if safely obtainable.

How Results Can Guide Next Steps

The most useful FoundationOne Liquid CDx result is one that answers a specific clinical question. In advanced cancer, that often means finding an actionable driver before therapy, identifying a resistance mechanism at progression, or obtaining molecular information when tissue is unavailable or inadequate.

A practical review can follow this sequence:

1. Confirm the clinical setting. Know the tumor type, stage, prior therapies, and reason the test was ordered.
2. Check sample signal. Review tumor fraction and whether the report suggests limited ctDNA shedding.
3. Separate companion-diagnostic findings from other genomic findings. Verify the current biomarker-drug labeling rather than assuming every listed therapy is equivalent.
4. Look for co-alterations and resistance mechanisms. A targetable driver can coexist with genomic changes that influence expected benefit.
5. Consider tissue needs. Histology, protein biomarkers, and a plasma-negative result may still require biopsy.
6. Discuss uncertain findings. Variants of uncertain significance and possible clonal-hematopoiesis findings generally should not drive treatment by themselves.
7. Reassess at progression when appropriate. Tumors evolve, and a later liquid biopsy test may reveal newly acquired alterations.

A positive actionable result can speed treatment planning because blood sampling is less invasive and may be obtained when tissue is scarce. A negative result can still be useful if it clarifies that plasma had insufficient tumor signal and prompts tissue reflex testing rather than false reassurance.

The test is best viewed as one component of precision oncology, not a stand-alone treatment selector. Molecular findings should be integrated with pathology, imaging, the patient’s treatment history, current drug labeling, and the judgment of the oncology team. When those pieces are combined, FoundationOne Liquid CDx can provide a broad and clinically useful view of tumor genomics while preserving the advantages of a blood-based specimen.

References

• List of FDA-Authorized Companion Diagnostic Devices (In Vitro and Imaging Tools) 2026
• The Impact of Concordance between Liquid and Tissue Biopsy for Actionable Mutations: Insights from the ROME Trial 2026
• Clinical Validity of FoundationOne Liquid CDx for Detection of BRAFV600E in Colorectal Cancer 2025
• Real-world pan-tumor comprehensive genomic profiling sample adequacy and success rates in tissue and liquid specimens 2024
• ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group 2022 (Guideline)
• Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin. 2020 (Validation Study)

Disclaimer

FoundationOne Liquid CDx results should be interpreted by qualified oncology professionals in the context of the current FDA labeling, tumor type, pathology, treatment history, and ctDNA signal. A negative plasma result does not exclude a tumor alteration, and tissue testing may still be necessary when clinically feasible. Do not start, stop, or change cancer treatment based on a genomic report without guidance from the treating oncology team.