For four decades, oncologists have sorted breast cancer into a fundamental binary: HER2-positive or HER2-negative. Patients who tested positive were directed toward one set of treatments; those who tested negative — about 80% of all breast cancer patients — were told the HER2 pathway wasn't relevant to their disease. That boundary, which shaped treatment decisions for millions of women, has now been significantly redrawn. A landmark clinical trial published in the New England Journal of Medicine in June 2024 has demonstrated that a powerful new drug works in patients far beyond the HER2-positive category — and the implications could reach more than three-quarters of all women with metastatic breast cancer.
The HER2 Label: A 40-Year Binary
HER2 stands for human epidermal growth factor receptor 2 — a protein that sits on the surface of cells and acts like an antenna for growth signals. In healthy breast tissue, a small number of HER2 receptors are present on each cell, participating in normal growth and repair. In some breast cancers, a gene amplification error causes the cell to produce 20 to 100 times more HER2 receptors than it should. These HER2-overexpressing tumors grow faster, spread more aggressively, and — before targeted treatments existed — had a worse prognosis than most other breast cancer subtypes.
In 1998, the FDA approved trastuzumab (Herceptin), the first drug designed specifically to block HER2 signaling. It was a milestone in precision oncology: a treatment that worked not for all breast cancers but for a genetically defined subset. The logic was seductive in its clarity. First, test for HER2 overexpression. If positive — roughly 15 to 20% of cases — target it aggressively. If negative, set that pathway aside entirely.
This framework held for more than two decades. But it rested on an assumption that is now cracking: that HER2 expression is truly binary — that you either have it or you don't. As it turns out, a vast middle ground had been lurking in the data all along, largely ignored.
A New Category Hidden in Plain Sight
HER2 status in breast cancer is measured by pathologists using a scoring system called immunohistochemistry (IHC), which stains tissue samples and grades the intensity of HER2 protein staining on a scale from 0 to 3+. A score of 3+, or a 2+ with gene amplification confirmed by a secondary test, is classified as HER2-positive. A score of 0 or 1+, and a 2+ without amplification, has historically been lumped together as HER2-negative — treated as a single, undifferentiated group.
Researchers began to question whether this lumping made biological sense. When they looked more carefully, they found that many tumors scoring IHC 1+ or IHC 2+ without amplification — officially "negative" — still expressed measurable amounts of HER2 protein on their surface. Not enough to drive runaway growth the way HER2-positive tumors do, but detectable nonetheless.
This observation gave rise to the concept of HER2-low breast cancer: tumors that score IHC 1+ or 2+ without amplification. Depending on the analysis methodology, this group accounts for roughly 50 to 60% of all breast cancers. Within what was once called HER2-negative, another subgroup was identified — HER2-ultralow, defined as IHC 0 with faint, incomplete staining in fewer than 10% of cells. This accounts for perhaps another 20% of cases.
In aggregate, true HER2-zero tumors — no detectable expression whatsoever — represent only a minority of what was previously classified as HER2-negative. The clinical significance of this reclassification was purely theoretical until a new class of drugs offered a reason to care about the distinction.
How Enhertu Works: A Guided Missile
The drug at the center of this story is trastuzumab deruxtecan, marketed under the brand name Enhertu and often abbreviated T-DXd. It belongs to a class called antibody-drug conjugates (ADCs) — a category that represents one of the most significant innovations in cancer pharmacology in decades.
To understand how an ADC works, it helps to contrast it with traditional chemotherapy. Conventional chemo drugs are systemic: they circulate throughout the body and kill any rapidly dividing cell they encounter — which is why they cause hair loss, nausea, fatigue, and suppression of the immune system. The cancer cells die, but so do a great many healthy ones.
An antibody-drug conjugate takes a fundamentally different approach. It consists of three components: a targeting antibody, a chemical linker, and a cytotoxic (cell-killing) payload. In the case of T-DXd, the antibody is trastuzumab — the same molecule used in Herceptin — which has a high affinity for the HER2 protein. Even when HER2 is expressed in very small amounts, trastuzumab can find and bind to it.
Once the antibody attaches to HER2 on the surface of a cancer cell, the entire conjugate is pulled inside the cell. There, the chemical linker breaks apart, releasing the payload — a potent chemotherapy agent called DXd — directly into the cancer cell. The cancer cell absorbs a concentrated, lethal dose of chemotherapy. Neighboring healthy cells, which have little or no HER2 on their surfaces, are largely spared.
There is one additional mechanism that makes T-DXd especially effective: a bystander effect. Some of the released DXd can leak out of the targeted cancer cell and kill adjacent tumor cells that may not express HER2 at all. This means the drug does not require every cancer cell to carry the target — it can hit the whole tumor neighborhood from a small number of entry points.
In practical terms, the analogy often used by oncologists is apt: traditional chemotherapy is a carpet bomb; T-DXd is a guided missile with a blast radius.
The First Breakthrough: DESTINY-Breast04 (2022)
Before DESTINY-Breast06 established the HER2-ultralow frontier, an earlier trial — DESTINY-Breast04 — had already demonstrated something that redrew the original HER2 boundary.
Published in the New England Journal of Medicine in June 2022, DESTINY-Breast04 was the first trial to show that T-DXd could work in HER2-low patients — people who would previously have been told their cancer was HER2-negative. The trial enrolled 557 patients with HER2-low metastatic breast cancer who had received prior chemotherapy.
The results were decisive. In patients with hormone receptor-positive disease, progression-free survival — the length of time the cancer did not grow or spread — was 9.9 months with T-DXd versus 5.1 months with standard chemotherapy. Overall survival improved from 16.8 months to 23.4 months. The hazard ratio for death was 0.64, meaning patients on T-DXd had a 36% lower risk of dying at any given point during the trial.
The FDA approved T-DXd for HER2-low metastatic breast cancer in August 2022 — one of the faster regulatory responses to a major trial result in recent breast cancer history. But the question that DESTINY-Breast04 left unanswered was an obvious one: if the drug works in HER2-low, what about HER2-ultralow? Could a drug this effective really stop working the moment HER2 expression dipped below a certain threshold? That question is what DESTINY-Breast06 was designed to answer.
DESTINY-Breast06: Expanding the Frontier
Published in the New England Journal of Medicine on June 20, 2024, the DESTINY-Breast06 trial (NCT04494425) was a global Phase 3 randomized controlled study conducted across multiple countries, enrolling 866 patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer whose disease had progressed after at least one line of endocrine therapy.
These were not newly diagnosed patients. They were women whose cancer had already been treated with the standard hormonal approaches — aromatase inhibitors, CDK4/6 inhibitors — and had kept growing despite them. This is a pivotal clinical moment in metastatic breast cancer management: when endocrine therapy fails, the next decision is what systemic treatment to use. Historically, that transition meant intravenous chemotherapy. DESTINY-Breast06 was testing whether T-DXd could be the better choice.
Patients were randomly assigned to receive either T-DXd intravenously every three weeks, or the physician's choice of capecitabine, nab-paclitaxel, or paclitaxel — three established chemotherapy regimens commonly used in this setting. The primary endpoint was progression-free survival in the HER2-low cohort. The study also measured outcomes in the HER2-ultralow subgroup as a key secondary endpoint.
What the Numbers Really Mean
In the HER2-low cohort, T-DXd produced a median progression-free survival of 13.2 months compared to 8.1 months with chemotherapy — a hazard ratio of 0.62, meaning patients on T-DXd had a 38% lower risk of disease progression or death at any point. The result was statistically highly significant (p < 0.001).
Critically, the benefit extended into the HER2-ultralow group as well. In patients whose tumors showed only the faintest trace of HER2 staining — previously indistinguishable from true HER2-zero in clinical practice — T-DXd still produced a statistically significant improvement in progression-free survival over chemotherapy.
Five extra months of disease control before the cancer grows again may not sound transformative in isolation. But for a woman managing metastatic breast cancer — balancing treatment schedules, side effects, work, family, and quality of life — the difference between eight months and thirteen months before a treatment stops working is enormous. It represents a larger window of stability, fewer regimen changes, and potentially more months of feeling well rather than dealing with chemotherapy's side effects on a failing regimen.
Dr. Giuseppe Curigliano, the trial's lead author and Head of the Division of Early Drug Development at the European Institute of Oncology in Milan, described the findings as establishing T-DXd as "a new standard of care" for this patient population, and called the HER2-ultralow data "practice-changing."
Overall survival data were not yet mature at the time of primary analysis — the trial will continue to track patients to measure that endpoint. But the trajectory of progression-free survival benefit, and the historical pattern from DESTINY-Breast04 where PFS benefit translated into a substantial OS improvement, makes the long-term picture encouraging.
On the safety side, T-DXd was generally well tolerated. The most common side effects were nausea, fatigue, and hair thinning — familiar territory for anyone who has received chemotherapy. The most important risk to monitor is interstitial lung disease (ILD), a form of lung inflammation that occurred in approximately 11% of patients in DESTINY-Breast06, though most cases were Grade 1 or 2 (mild to moderate). Grade 3 or higher ILD occurred in about 2% of patients. This risk requires regular monitoring but is manageable with standard protocols, and it did not prevent the drug from demonstrating clear benefit in the trial population.
What This Means for Patients Today
The practical implications of DESTINY-Breast06 for women currently managing breast cancer are significant and concrete. Several action points are worth understanding:
- Ask specifically about HER2-low and HER2-ultralow testing. Standard HER2 testing has traditionally been designed to identify HER2-positive patients for Herceptin-based regimens. The scoring of low-level expression (IHC 1+, 2+, or ultralow 0 with incomplete staining) requires pathologist attention and is not always highlighted in a standard report. If you have hormone receptor-positive metastatic breast cancer and your HER2 report says "negative," ask your oncologist to clarify specifically whether your tumor is HER2-zero, HER2-low (IHC 1+ or 2+ without amplification), or HER2-ultralow. This distinction now has direct treatment implications.
- Understand where T-DXd (Enhertu) fits in your treatment sequence. The FDA approved T-DXd for HER2-low metastatic breast cancer following DESTINY-Breast04 in August 2022. DESTINY-Breast06 data, if followed by regulatory action on the HER2-ultralow indication, could expand that approval further. Ask your oncologist whether T-DXd is currently approved and appropriate for your specific situation, particularly when transitioning off endocrine therapy.
- Discuss the ILD monitoring protocol. If you receive T-DXd, pulmonary symptoms — new or worsening breathlessness, dry cough, fever — should be reported to your care team promptly. Early detection and management of ILD is the key to keeping this risk in the mild-to-moderate range where it remains manageable.
- Ask about clinical trials. Researchers are currently investigating T-DXd in earlier stages of breast cancer — before metastatic disease — including in the neoadjuvant (pre-surgery) and adjuvant (post-surgery) settings, as well as in combination with other agents. If you have recently been diagnosed or are considering next steps, asking your oncologist whether an active trial is appropriate could give you access to data still being generated.
- Know that this research is US breast cancer statistics context. Breast cancer is the most commonly diagnosed cancer in American women, with an estimated 313,510 new cases in 2024 alone. About 6 to 7% of patients — roughly 20,000 women annually — are diagnosed with metastatic breast cancer from the outset, and many more will eventually develop metastatic disease after initial treatment. DESTINY-Breast06 is directly relevant to a substantial portion of this population.
What Comes Next
DESTINY-Breast06 is one trial in a rapidly accelerating field. Several parallel developments are already under way:
FDA review of the HER2-ultralow indication. The data from DESTINY-Breast06 on the HER2-ultralow subgroup provided the basis for a regulatory submission seeking approval of T-DXd for this expanded patient population. A decision from the FDA is expected to follow the established review timelines — and given the strength of the trial results and the precedent of the 2022 HER2-low approval, the pathway is established.
Earlier-stage breast cancer trials. Three large randomized trials are investigating T-DXd in non-metastatic settings. DESTINY-Breast09 is testing T-DXd versus standard first-line chemotherapy in metastatic HER2-low disease. DESTINY-Breast11 and DESTINY-Breast12 are exploring the drug in the neoadjuvant and adjuvant settings — potentially extending T-DXd from end-stage management toward a role in curing the disease before it spreads.
Rethinking the pathology lab. One of the less visible but practically important consequences of DESTINY-Breast06 is that it places new demands on the pathology infrastructure. HER2-low and HER2-ultralow scoring requires careful standardization — the difference between IHC 0 true-negative and IHC 0-with-incomplete-staining is a distinction many labs are not yet consistently capturing. As treatment decisions increasingly hinge on this distinction, pathology departments across the country are updating protocols and standardizing training.
Other ADCs joining the pipeline. Trastuzumab deruxtecan pioneered the ADC approach in HER2-low breast cancer, but it is not alone. Datopotamab deruxtecan (Dato-DXd), patritumab deruxtecan (HER3-DXd), and other ADCs targeting different surface proteins are in late-stage trials for breast cancer. The principle that very low target expression can still be clinically exploited by a well-designed drug is now an established rationale guiding an entire generation of cancer drug development.
For women living with hormone receptor-positive metastatic breast cancer, what DESTINY-Breast06 ultimately represents is a significant expansion of therapeutic options in a disease where options were, not long ago, markedly more limited. A category of patient once told they had tested negative for an important target is now told, on the strength of robust phase 3 data, that the target was always there — and that a drug has been designed to find it.
In oncology, the distance between "negative" and "treatable" is measured in scientific questions and clinical trials. After two landmark NEJM papers in three years, that distance, for HER2-low and HER2-ultralow breast cancer, has effectively closed.