The strange part is that these tumors were once treated as if HER2 was basically absent, and now that tiny whisper of HER2 may be enough for a drug to find the door, knock politely, and deliver a chemical eviction notice.
That is the mystery at the center of DESTINY-Breast06. The suspect: hormone receptor-positive metastatic breast cancer that is HER2-low or HER2-ultralow. The detectives: Curigliano and colleagues. The evidence bag: 866 patients, scans, response rates, and the clinical equivalent of fingerprints on a martini glass.
The Usual Suspect Had a New Alias
Breast cancers often get sorted by the signals they use to grow. Hormone receptor-positive cancers respond to estrogen or progesterone signals, which is why endocrine therapy is often a first move. Pair that with CDK4/6 inhibitors, drugs that slow the cell-cycle machinery, and many patients can hold the line for a meaningful stretch.
But tumors, those little career criminals, adapt. Some progress quickly despite endocrine therapy plus CDK4/6 inhibition. Others behave for a while, then slip the cuffs. Once that happens, many patients face chemotherapy, often one drug after another, like a grim buffet where nobody asked for seconds.
HER2 used to be a more binary character: positive or negative. HER2-positive tumors had lots of HER2 and could be targeted. HER2-negative tumors supposedly did not. Then HER2-low entered the interrogation room. The National Cancer Institute defines HER2-low breast cancer as having a small amount of HER2 protein without HER2 gene amplification, a group historically treated like HER2-negative disease until newer HER2-targeting drugs changed the plot NCI.
The Weapon Was an Antibody With Baggage
Trastuzumab deruxtecan, or T-DXd, is an antibody-drug conjugate. Translation: it is part bloodhound, part payload truck. The trastuzumab portion homes in on HER2. The deruxtecan payload is chemotherapy. The whole contraption binds to a cancer cell, gets pulled inside, and releases its toxic cargo.
It also has a useful trick called a bystander effect: the payload can affect nearby tumor cells, even if HER2 expression is uneven. That matters because tumors are less like neat apartment buildings and more like suspicious warehouses full of mislabeled boxes.
Earlier, DESTINY-Breast04 showed that T-DXd improved progression-free and overall survival in previously treated HER2-low advanced breast cancer compared with physician’s choice chemotherapy Modi et al., 2022. Then the main DESTINY-Breast06 report pushed the story earlier, after endocrine-based therapy but before chemotherapy for metastatic disease, showing longer progression-free survival with T-DXd than chemotherapy Bardia et al., 2024. The FDA approved fam-trastuzumab deruxtecan-nxki for HR-positive, HER2-low or HER2-ultralow unresectable or metastatic breast cancer after progression on endocrine therapy on January 27, 2025 FDA.
The New Evidence: It Worked Across the Rough Neighborhoods
This Annals of Oncology analysis asks a practical question: did T-DXd still help patients with worse-looking case files?
The researchers sliced the DESTINY-Breast06 population by how quickly disease progressed on prior first-line endocrine therapy plus CDK4/6 inhibitor. That timing matters because early progression can signal endocrine resistance, the tumor’s version of refusing to answer questions without its lawyer.
Across every timing group, T-DXd beat chemotherapy on median progression-free survival:
- Progression in less than 6 months: 14.0 months with T-DXd versus 6.5 months with chemotherapy
- Progression in 6 to 12 months: 13.2 versus 6.9 months
- Progression after more than 12 months: 12.9 versus 8.2 months
That is not one clean footprint in the mud. That is a trail.
The benefit also held up across primary and secondary endocrine resistance, liver metastases, visceral disease, number of disease sites, and baseline tumor size. In plain English: whether the cancer looked more contained or had already started acting like it owned the place, T-DXd generally performed better than chemotherapy.
Response rates told a similar story. Confirmed objective response rates ranged from 36.7% to 67.7% with T-DXd, versus 16.7% to 37.5% with chemotherapy. Responses also tended to last longer. Even time to second progression or death favored T-DXd across subgroups, which is the kind of follow-up clue detectives love because it suggests the first move did not simply create a mess for the next one.
The Fine Print Wearing a Trench Coat
This was a subgroup analysis, and many subgroups were post hoc. That does not make the results useless. It does mean we should not treat every slice like a separate trial carved in marble. Subgroup analyses can reveal patterns, but they can also invite overinterpretation if everyone starts squinting at the chart like it owes them money.
Safety also matters. T-DXd is not a vitamin with a lab coat. It can cause nausea, blood count changes, fatigue, hair loss, and liver enzyme changes. A serious known risk is interstitial lung disease or pneumonitis, which clinicians must watch for carefully. Patient-reported outcomes from DESTINY-Breast06 add useful texture: cancer control improved, but nausea and vomiting remain part of the evidence board ESMO Open, 2025.
Why This Case Matters
If these results keep holding up in real-world practice and longer follow-up, the impact is straightforward: more patients with HR-positive metastatic breast cancer could get an effective targeted option before conventional chemotherapy. That matters because “HER2-low” and “HER2-ultralow” are not rare little footnotes. They may represent a large share of cancers once filed under HER2-negative.
The larger lesson is sneakier. Cancer categories are not permanent mugshots. Sometimes a marker once dismissed as too faint becomes the clue that cracks the case. HER2-low used to look like background noise. With the right drug, it starts looking like an address.
References
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Curigliano G, Hu X, Dent R, et al. Trastuzumab deruxtecan in hormone receptor-positive, HER2-low/-ultralow metastatic breast cancer (DESTINY-Breast06): outcome analyses by time to progression on prior first-line endocrine therapy with CDK4/6 inhibitor and baseline burden of disease. Annals of Oncology. 2026. https://doi.org/10.1016/j.annonc.2026.02.015
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Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. New England Journal of Medicine. 2024. https://doi.org/10.1056/NEJMoa2407086
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Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. New England Journal of Medicine. 2022. https://doi.org/10.1056/NEJMoa2203690
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Tarantino P, Viale G, Press MF, et al. ESMO expert consensus statements on the definition, diagnosis, and management of HER2-low breast cancer. Annals of Oncology. 2023. https://doi.org/10.1016/j.annonc.2023.05.008
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Tsuchikama K, Anami Y, Ha SYY, Yamazaki CM. Exploring the next generation of antibody-drug conjugates. Nature Reviews Clinical Oncology. 2024. https://doi.org/10.1038/s41571-023-00850-2
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.