Liquid Pulse: Reading HER2 in Plasma — What a ctDNA Test Can (and Can't) Tell You About ERBB2-Mutant Lung Cancer

The clinical question

When a patient presents with metastatic non-small cell lung cancer (NSCLC), the modern workup asks a battery of molecular questions in parallel: is there a targetable driver, and if so, which drug class does it open the door to? For a subset of these patients — roughly 2–4% of NSCLC — the answer is an activating mutation in ERBB2, the gene encoding HER2. That's a specific and important distinction: we're talking about activating mutations here, most commonly small insertions in exon 20, not HER2 amplification or protein overexpression, which are separate biological phenomena scored by different assays [LNG-BIO-0010].

The clinical stakes are concrete. An activating HER2 mutation gates eligibility for a HER2-directed antibody–drug conjugate (ADC), trastuzumab deruxtecan (T-DXd). The liquid-biopsy question, then, is narrow but consequential: can a blood draw reliably identify these patients so treatment isn't delayed — or missed entirely — when tumor tissue is scarce, exhausted, or hard to reach?

What's measured, and how

The analyte is circulating tumor DNA (ctDNA) — fragmented tumor-derived DNA shed into the bloodstream, isolated from a plasma sample. The assay is targeted next-generation sequencing (NGS), the same core technology used on formalin-fixed tissue, but tuned to detect low-frequency variants against a background of normal cell-free DNA [LNG-BIO-0010].

Two FDA-approved plasma platforms are relevant here. In August 2024, the FDA approved Guardant360 CDx as a companion diagnostic to identify HER2 (ERBB2) activating mutations in NSCLC and select patients for first-line T-DXd — making it the first liquid biopsy companion diagnostic approved specifically for this indication, and enabling a plasma-first selection pathway that doesn't mandate a tissue biopsy [1]. Separately, FoundationOne Liquid CDx has held FDA approval since November 2022 as a pan-solid-tumor plasma NGS companion diagnostic whose coverage includes ERBB2 mutations, offering a second FDA-cleared ctDNA route for HER2 mutation detection in NSCLC [2].

A word of caution on sensitivity, because this is where plasma testing is most often overstated. ctDNA assays detect what's actually shed into circulation — and shedding varies enormously with tumor burden, site, and biology. A negative plasma result does not rule out a HER2 mutation; it means none was detected in that sample. This is the central asymmetry of liquid biopsy: a positive result is highly actionable, but a negative one is not exculpatory. Where plasma comes back wild-type in a patient with strong clinical suspicion, reflex to tissue NGS remains the appropriate move. The evidence suggests plasma works best as a fast, accessible complement to — not a wholesale replacement for — tissue genotyping.

The evidence

The clinical foundation for T-DXd in HER2-mutant NSCLC comes from the DESTINY-Lung02 phase II trial, published in 2023, which established both the efficacy and the tolerable dose of the ADC in this population [3]. Importantly for the liquid-biopsy story, HER2 mutation status in enrolled patients was confirmed by NGS using both tissue and plasma ctDNA platforms. That's what gives the plasma indication its evidentiary spine: the trial didn't merely tolerate ctDNA-detected mutations, it demonstrated that patients selected on the basis of plasma-detected activating ERBB2 mutations derived benefit from the drug [3]. That predictive linkage — plasma-detected mutation to drug-class benefit — is precisely what a companion diagnostic approval requires.

Concordance between tissue and plasma NGS for actionable NSCLC mutations continues to accumulate. Data summarized in the ASCO 2025 ctDNA highlights reinforce the clinical utility of plasma as a first-line specimen for HER2 mutation testing, including exon 20 insertions, and highlight the turnaround-time advantage of a blood draw in settings where tissue is limited [4]. These are encouraging signals for upfront liquid use, but it's worth flagging that this concordance literature is still maturing and remains, in the strict regulatory sense, investigational for many use-cases beyond the specific approved companion Dx indications. Concordance is not symmetric: positive percent agreement (does plasma find what tissue found?) is more clinically fraught than negative percent agreement, and it's the metric most sensitive to low ctDNA shedding.

Where it stands

The picture divides cleanly into validated and investigational domains.

On the validated side, plasma ctDNA NGS for ERBB2 activating mutations in NSCLC now has a firm regulatory footing. With Guardant360 CDx approved in August 2024 as a dedicated liquid-biopsy companion diagnostic [1], and FoundationOne Liquid CDx available as an FDA-approved pan-tumor plasma option covering ERBB2 [2], clinicians have two cleared pathways to identify HER2-mutant NSCLC from blood and thereby establish eligibility for the HER2-directed ADC class [3]. For a patient whose tissue is insufficient for molecular testing — a common and frustrating scenario in advanced lung cancer — this is a genuine advance. It can shorten the interval to an actionable result and spare a repeat invasive procedure.

What remains investigational, or at least unsettled, is everything beyond this front-line selection question. Using ctDNA to monitor molecular residual disease (MRD), to track response dynamics, or to guide treatment switches in HER2-mutant NSCLC is not part of the approved companion diagnostic framework. The concordance and turnaround-time work surfacing at ASCO 2025 supports upfront liquid use where tissue is constrained [4], but MRD-guided decision-making in this setting stays in the research column for now. It's a fast-moving area, and readers should treat claims about plasma-guided monitoring skeptically until prospective outcome data catch up.

The practical synthesis for a mixed audience: if you or your patient has advanced NSCLC and tissue genotyping is delayed or impossible, an FDA-approved plasma NGS test can now identify an activating HER2 mutation and open the door to a specific ADC drug class. A positive plasma result is actionable. A negative one warrants tissue confirmation, not reassurance. And using these same assays to make longitudinal, MRD-based treatment decisions is a promise the evidence hasn't yet delivered on — an important boundary to hold as the field moves quickly.

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References

1. U.S. Food and Drug Administration. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-mutant non-small cell lung cancer and companion diagnostic. FDA Oncology (Hematology/Oncology) Approval; PMA supplement / De Novo for Guardant360 CDx. 2024. (FDA-CDx-Guardant360-HER2-NSCLC-2024)

2. Foundation Medicine, Inc. FoundationOne Liquid CDx — FDA-approved companion diagnostic and comprehensive genomic profiling test. Foundation Medicine product page / FDA PMA P200010. 2022. (FDA-PMA-P200010-FoundationOneLiquidCDx)

3. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer (DESTINY-Lung02). New England Journal of Medicine. 2023;389(6):514-526. (NEJM-DESTINY-Lung02-2023)

4. Steendam CMJ et al. (summarized in ASCO 2025 ctDNA highlights review). Circulating tumour DNA assays in focus: highlights from ASCO 2025 for clinicians. PMC / ASCO 2025 proceedings summary, PMC12449440. 2025. (PMC12449440)