What if your lung cancer has a treatment hidden in its DNA? | Dr Dilanka De Silva

When someone is diagnosed with advanced lung cancer, one of the most important questions is not simply:

“What type of lung cancer is this?”

It is also:

“What is driving this cancer—and is there a treatment designed specifically for it?”

Sometimes, that answer is hidden within the tumour’s DNA. Lung cancer genomic testing can help us look deeper, searching for molecular changes that may be driving the cancer and, in some patients, reveal a targeted treatment option.

Who is this article for?

This article may be helpful if:

• you have advanced non-small cell lung cancer;
• your initial molecular tests did not find a targetable mutation;
• you have been told you may need broader genomic testing;
• you have heard terms such as NGS, HER2 or ERBB2 mutation;
• you are wondering whether a blood-based genomic test might help; or
• you are seeking a second opinion about targeted treatment.

A patient who made me look deeper

I recently treated a 66-year-old man with lung cancer.

He had smoked when he was younger but had stopped approximately three decades earlier.

His original molecular testing looked for several important lung cancer drivers, including EGFR, ALK and ROS1.

Those are important tests. But the exact number of genes examined varies between laboratories, tests and the time at which testing was performed.

Given his clinical history, I felt we should look more deeply.

I arranged broader next-generation sequencing, usually called NGS.

That decision mattered.

The broader test found molecular alterations that had not been identified on the original panel. One of them opened a potential targeted-treatment pathway.

The lesson was simple:

A negative limited panel does not always mean there is no targetable alteration. Sometimes we need to look more broadly.

Some personal details have been adjusted to protect patient confidentiality.

The short answer

Modern lung cancer treatment increasingly depends on understanding the molecular changes driving the cancer.

Current ASCO guidance supports broad multigene testing using tissue and/or blood in NSCLC, with comprehensive NGS—ideally including RNA-based testing where appropriate—helping detect mutations and gene fusions that smaller panels may miss. Tissue remains important because a negative blood test can miss alterations if the cancer is not releasing enough DNA into the bloodstream.

Finding a mutation does not automatically mean there is a treatment for it.

But if we do not look for an actionable mutation, we cannot use a treatment designed to target it.

What is targeted therapy?

Traditional chemotherapy attacks rapidly dividing cells throughout the body.

Targeted therapy works differently.

Some lung cancers depend heavily on a particular abnormal gene or signalling pathway to grow. We sometimes call this a driver alteration because it is helping to drive the cancer.

Examples of established or clinically important alterations in NSCLC include:

• EGFR mutations;
• ALK and ROS1 fusions;
• BRAF V600E;
• MET exon 14 skipping;
• RET and NTRK fusions;
• KRAS G12C; and
• HER2, also called ERBB2, mutations.

Current guidelines favour broad molecular testing because testing these biomarkers one at a time can use more tissue and may miss less common alterations or gene fusions.

Why can an earlier test miss something?

A smaller panel only looks for what it was designed to detect.

Broader NGS may identify:

• less common driver mutations;
• gene fusions;
• amplifications;
• resistance alterations; or
• findings that may open a clinical-trial option.

The quality of the biopsy also matters.

If there are too few cancer cells in the sample, a negative result may be less reassuring than it first appears.

Blood-based testing—often called a liquid biopsy—can also be useful. But a negative blood result does not completely exclude a mutation because some cancers release very little tumour DNA into the bloodstream.

That is why tissue and blood testing can sometimes complement one another rather than replace one another.

The HER2 mutation that changed the conversation

In this patient, comprehensive sequencing identified an alteration involving HER2, also known as ERBB2.

This is where molecular interpretation becomes important.

Many patients know about HER2-positive breast cancer.

But HER2 does not mean exactly the same thing in every cancer.

There are several different HER2 abnormalities:

• HER2 protein overexpression
• HER2 gene amplification
• HER2 or ERBB2 mutation

They are related, but they are not interchangeable.

For the lung cancer treatment pathway discussed here, the strongest established evidence for trastuzumab deruxtecan has been in cancers containing an activating HER2 mutation.

So simply saying that a lung cancer is “HER2-positive” is not enough.

I want to know exactly what HER2 alteration was found and how it was detected.

What is trastuzumab deruxtecan?

Trastuzumab deruxtecan, or T-DXd, is an antibody-drug conjugate.

I often describe an antibody-drug conjugate as a targeted delivery system.

The antibody recognises HER2. Attached to it is a powerful anti-cancer drug. The aim is to carry that treatment towards HER2-expressing cancer cells and release the drug in or around those cells.

The way we select patients for this treatment in lung cancer is different from the traditional HER2 testing used in breast cancer.

What did the DESTINY-Lung studies show?

The early landmark study was DESTINY-Lung01, led by Professor Bob Li and colleagues. I was privileged to be mentored by Professor Li during my fellowship at Memorial Sloan Kettering Cancer Center.

In that study, 91 patients with previously treated metastatic HER2-mutant NSCLC received T-DXd at 6.4 mg/kg.

Approximately 55 in every 100 patients had their tumour shrink significantly.

However, treatment-related interstitial lung disease or pneumonitis occurred in about 26 in every 100 patients, including two fatal cases.

That led to an important question:

Could we retain the benefit while reducing toxicity?

Why is the dose now lower?

DESTINY-Lung02 compared:

• 5.4 mg/kg every three weeks, and
• 6.4 mg/kg every three weeks.

In the final analysis, approximately:

• 50 in every 100 patients responded at 5.4 mg/kg;
• compared with 56 in every 100 at 6.4 mg/kg.

But the safety difference was important.

Drug-related interstitial lung disease or pneumonitis occurred in approximately:

• 15 in every 100 patients at 5.4 mg/kg;
• compared with 32 in every 100 at 6.4 mg/kg.

The lower 5.4 mg/kg dose therefore produced a better overall balance between benefit and toxicity and is the recommended NSCLC dose.

This is a good example of something I often explain to patients:

The aim is not to give the largest dose possible. It is to give the dose that provides the best balance between controlling the cancer and keeping treatment safe.

What about first-line treatment?

This area has just changed again.

DESTINY-Lung04 is a phase III trial comparing first-line T-DXd with platinum-pemetrexed chemotherapy plus pembrolizumab in advanced HER2-mutant non-squamous NSCLC.

In August 2026, the study reported positive topline results, with T-DXd showing a statistically significant and clinically meaningful improvement in progression-free survival.

However, the detailed results have not yet been presented or published, and overall-survival follow-up is continuing.

So I would not yet translate that headline into:

“Everyone with newly diagnosed HER2-mutant lung cancer should now receive T-DXd first.”

We need to see the detailed data and how regulatory authorities incorporate those results.

In Australia, T-DXd currently has a TGA indication for adults with unresectable or metastatic NSCLC containing an activating HER2 mutation after prior platinum-based chemotherapy, with or without immunotherapy.

The side effect I discuss most carefully: pneumonitis

The most important serious toxicity of T-DXd is interstitial lung disease, often called pneumonitis.

This means inflammation within the lungs.

It may initially cause:

• a new or worsening cough;
• shortness of breath;
• fever;
• chest tightness; or
• reduced exercise tolerance.

Sometimes changes appear on a CT scan before the patient notices symptoms.

Patients receiving T-DXd should report new respiratory symptoms promptly rather than waiting until the next routine appointment.

If asymptomatic Grade 1 pneumonitis is suspected, treatment is generally withheld while the finding is investigated. If symptomatic Grade 2 or more severe pneumonitis is diagnosed, current guidance recommends permanently discontinuing T-DXd and starting corticosteroid treatment promptly.

What about nausea and other side effects?

Nausea is much more common than severe pneumonitis.

In the final DESTINY-Lung02 analysis, nausea occurred in approximately 67 in every 100 patients receiving the 5.4 mg/kg dose, although it was not usually severe.

This is why I prefer to think about anti-nausea treatment proactively rather than waiting for symptoms to become difficult to control.

Other potential side effects include fatigue, reduced appetite, vomiting, reduced blood counts and hair thinning or hair loss.

Blood tests are generally checked regularly, and heart function may also be monitored when clinically appropriate.

Who should consider lung cancer genomic testing?

Broader lung cancer genomic testing is particularly important in advanced NSCLC, especially when identifying a driver alteration could change treatment.

I would be particularly interested in reviewing the original testing if:

• only a limited panel was performed;
• previous testing was inconclusive or there was insufficient tissue;
• a potentially actionable alteration may not have been included;
• blood testing was negative but suspicion remains;
• the disease has changed or progressed; or
• clinical-trial options are being considered.

Smoking history should not be used as a reason to withhold appropriate molecular testing. Actionable alterations can occur in people who have smoked as well as those who have never smoked.

What would I usually consider?

When I review genomic testing in someone with advanced lung cancer, I want to know:

• What exactly did the original test examine?
• Was there enough tumour tissue?
• Were both mutations and gene fusions assessed?
• Would tissue NGS, blood-based testing or both add information?
• Is the alteration genuinely driving the cancer?
• Is there an approved treatment or relevant clinical trial?
• Will finding another alteration realistically change what we do?

The important part is not simply ordering a large genomic panel.

It is interpreting the result correctly.

What surprised me most

A genomic report may contain pages of mutations.

But only one of those findings may matter to the next treatment decision.

That is why the value of NGS is not simply in producing more information.

It is in finding the piece of information that is clinically actionable.

The one message I want patients to remember

A negative initial lung cancer panel does not always mean there are no targeted-treatment options.

Sometimes the test genuinely tells us there is no actionable driver.

Sometimes, however, the test was limited, the tissue was inadequate or the relevant alteration was not examined.

Before concluding that there is nothing left to target, it is reasonable to ask:

“Have we looked deeply enough into the cancer’s DNA?”

Key takeaways

• Modern lung cancer treatment depends increasingly on molecular testing as well as what the cancer looks like under the microscope.
• Broad genomic testing can sometimes identify an actionable alteration missed by more limited testing.
• HER2 mutation, HER2 amplification and HER2 protein overexpression are not the same finding.
• T-DXd can produce meaningful responses in previously treated HER2-mutant NSCLC, but careful monitoring for lung inflammation is essential.
• A genomic result only becomes useful when it is interpreted in the context of the individual patient and the available evidence.

Key evidence

1. Puri S, Ismaila N, Azar IH, et al. Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO Living Guideline, version 2026.3.2. J Clin Oncol. Published online June 29, 2026. doi:10.1200/JCO-26-01479
2. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431
3. Jänne PA, Goto Y, Kubo T, et al. Final analysis results and patient-reported outcomes from DESTINY-Lung02—a dose-blinded, randomized, phase 2 study of trastuzumab deruxtecan in patients with HER2-mutant metastatic NSCLC. J Thorac Oncol. 2025;20(12):1814-1828. doi:10.1016/j.jtho.2025.07.129
4. Swain SM, Nishino M, Lancaster LH, et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis: focus on proactive monitoring, diagnosis, and management. Cancer Treat Rev. 2022;106:102378. doi:10.1016/j.ctrv.2022.102378
5. Therapeutic Goods Administration. ENHERTU (AstraZeneca Pty Ltd). Accessed September 3, 2026. https://www.tga.gov.au/resources/prescription-medicines-registrations/enhertu-astrazeneca-pty-ltd-4
6. Daiichi Sankyo. Enhertu demonstrated statistically significant and clinically meaningful improvement in progression-free survival as first-line treatment of patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 phase 3 trial. Accessed September 3, 2026. https://daiichisankyo.us/press-releases/-/article/enhertu-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-pfs-as-first-line-treatment-of-patients-with-her2-mutant-advanced-nsclc-in-destiny-lung04-phase-3-trial

Current 2026 update: DESTINY-Lung04 has reported positive topline progression-free survival results in the first-line setting; detailed results and overall-survival data remain pending.

Frequently asked questions (FAQs)

1. Does every patient with lung cancer need comprehensive NGS?

Not every situation is the same, but broad molecular profiling is particularly important in advanced NSCLC when the result could identify a driver alteration and change treatment.

2. Can someone who previously smoked still have a targetable mutation?

Yes. Smoking history changes the likelihood of finding certain alterations, but it does not exclude them.

3. What does a negative genomic test mean?

It means that the test did not identify an actionable alteration that it was able to detect. It does not always prove that no driver alteration exists, particularly if the panel was limited or the sample was inadequate.

4. Can a blood test replace a tumour biopsy?

Sometimes blood-based testing provides the information we need, but a negative liquid biopsy does not reliably exclude a mutation. Tissue remains important when feasible.

5. Is HER2-positive lung cancer the same as HER2-positive breast cancer?

No. HER2 biology and the way patients are selected for treatment differ between cancers. In the NSCLC pathway discussed here, identifying an activating HER2/ERBB2 mutation is particularly important.

6. How effective is T-DXd in HER2-mutant lung cancer?

In the final DESTINY-Lung02 analysis, about 50 in every 100 patients receiving 5.4 mg/kg had a confirmed tumour response. This does not mean everyone will respond, and responses may not last indefinitely.

7. Is a second opinion useful after genomic testing?

It can be, particularly if there is uncertainty about whether the original test was comprehensive, whether a finding is genuinely actionable or whether additional tissue, blood testing or a clinical trial should be considered.

About Dr Dilanka De Silva

Dr Dilanka De Silva is a Melbourne-based Medical Oncologist and Cancer Genetics Physician with experience in precision oncology, lung cancer and complex molecular second opinions.

He completed fellowship training at Memorial Sloan Kettering Cancer Center in New York and reviews Australian and international patients, including patients from Sri Lanka, the Maldives, Indonesia and the Philippines.

Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)