A wave of practice-changing data for early-stage HER2-positive breast cancer, led by the phase 3 DESTINY-Breast11 (NCT05113251) and DESTINY-Breast05 (NCT04622319) trials, is reshaping how high-risk disease is managed in both the neoadjuvant and post-neoadjuvant settings, according to Sara Nunnery, MD, MSCI, and Kelly E. McCann, MD, PhD.
Speaking on an episode of Breast Cancer Briefing, Nunnery sat down with McCann to discuss how the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is moving earlier in the treatment paradigm, the trial data behind that shift, and the practical questions that its use in the curative setting raises.
Nunnery is a breast medical oncologist and the director of Breast Cancer Research at Tennessee Oncology in Nashville.
McCann is an associate professor at the University of California San Diego.
Q: What is the general framework for approaching the management of early-stage HER2-positive breast cancer?
A: Treatment decisions rest on 3 pillars, McCann said: biology, disease stage, and patient characteristics, such as menopausal status. On the biology axis, testing for estrogen receptor (ER), progesterone receptor, and HER2 positivity defines the disease subtype. HER2-positive disease, characterized by amplification of the ERBB2 gene on chromosome 17, accounts for approximately 15% of breast cancers and represents a potent, irreversible growth signal that becomes the primary therapeutic target, she explained.
That signal drives aggressive disease behavior, although an important clinical distinction remains between ER-positive/HER2-positive and ER-negative/HER2-positive disease, which behave and respond differently, McCann noted.
Q: Why is neoadjuvant therapy the standard treatment approach for HER2-positive disease? What is the value of pCR?
T-DXd in HER2+ Early Breast Cancer: Highlights
- In the neoadjuvant DESTINY-Breast11 trial, T-DXd followed by THP significantly improved pCR rate compared with ddAC-THP, with fewer high-grade AEs and less cardiac dysfunction.
- In the post-neoadjuvant DESTINY-Breast05 trial, T-DXd reduced the risk of invasive disease or death vs T-DM1 in patients with high-risk residual disease.
- These data supported the May 15, 2026, FDA approval of T-DXd in both the neoadjuvant and post-neoadjuvant settings, although practical questions have been raised about ILD surveillance, the drug’s long half-life, and patient selection.
A: Delivering chemotherapy and HER2-targeted therapy before surgery can be difficult for patients who want the tumor removed immediately, McCann acknowledged, but the response it produces is informative in several ways. Neoadjuvant treatment can downstage disease, and it yields prognostic information through assessment of residual cancer burden at surgery.
For instance, a pathologic complete response (pCR) carries an excellent prognosis, whereas a suboptimal response opens a second therapeutic window.
“When [a patient] is coming in with a new diagnosis and they ask me: ‘What is my prognosis?’ I tell them: ‘I don’t know. I’ll know more when you have a response,’” McCann said, adding that a poor response allows the care team to change that prognosis for the better with post-neoadjuvant escalation. Due to this, pCR serves as the primary end point in many early HER2-positive trials, including DESTINY-Breast11, the experts noted.
Q: What makes T-DXd mechanistically distinct? Why move it into earlier-stage HER2-positive disease?
A: T-DXd is an ADC that links the trastuzumab antibody to a topoisomerase I inhibitor payload via a cleavable linker, McCann explained. After the antibody binds HER2 and is internalized, the linker is enzymatically cleaved inside the cell, releasing chemotherapy that can also diffuse out to kill neighboring cells, which is often known as the bystander effect, she said. Relative to traditional chemotherapy, ADCs offer a long half-life, more targeted delivery of their cytotoxic payload, and a distinct toxicity profile, which has made them an increasingly successful treatment strategy across breast cancer subtypes, she added. Since T-DXd has dramatically improved survival in metastatic HER2-positive disease, the rationale existed to move it earlier in the treatment paradigm, she reported.
“When we see a drug do so well in stage IV breast cancer or metastatic breast cancer, we all start asking” Why can’t we use that drug in patients who have earlier-stage disease to prevent them from ever getting stage IV disease?” Nunnery said.
Q: What did DESTINY-Breast11 show in the neoadjuvant setting? Why has its control arm been debated?
A: DESTINY-Breast11 randomly assigned patients with high-risk HER2-positive early breast cancer 1:1:1 to receive T-DXd for 8 cycles; T-DXd for 4 cycles followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) for 4 cycles; or dose-dense doxorubicin plus cyclophosphamide followed by THP (ddAC-THP).1 The T-DXd monotherapy arm was closed early on the recommendation of the independent data monitoring committee.
In the remaining arms, the pCR rate was 67.3% (95% CI, 61.9%-72.4%) with T-DXd/THP (n = 216) vs 56.3% (95% CI, 50.6%-61.8%) with ddAC-THP (n = 320), translating to a statistically significant difference of 11.2% (95% CI, 4.0%-18.3%; P = .003). The benefit with T-DXd/THP vs ddAC-THP was consistent across subgroups, with pCR rates of 61.4% (95% CI, 54.9%-67.7%) vs 52.3% (95% CI, 45.8%-58.9%) in patients with hormone receptor–positive disease and 83.1% (95% CI, 73.3%-90.5%) vs 67.1% (95% CI, 56.0%-76.9%) in those with hormone receptor–negative disease. T-DXd/THP was also associated with fewer grade 3 or higher adverse effects (AEs; 37.5% vs 55.8%) and less left ventricular dysfunction (1.3% vs 6.1%), although patients in the 2 arms had comparable rates adjudicated interstitial lung disease (ILD)/pneumonitis (4.4% vs 5.1%).
However, controversy centers on the comparator arm of this trial. McCann noted she has never prescribed an anthracycline-based regimen in this setting, noting, “if a patient is [receiving] an anthracycline and develops cardiomyopathy, they can’t go on to receive the lifesaving drug trastuzumab after that.”
Most US oncologists instead use a taxane plus carboplatin, trastuzumab, and pertuzumab (TCHP), a 6-cycle, anthracycline-free regimen. The enrollment distribution of DESTINY-Breast11, in which 46.2% of the patients were from Asia and only 14.7% were from North America, adds to questions of the clinical applicability of this regimen, the experts noted. Both agreed, however, that ddAC-THP remains a highly effective regimen and that the trial results are valid.
Q: How did T-DXd perform in the post-neoadjuvant setting in DESTINY-Breast05?
A: DESTINY-Breast05 is “a mirror of the phase 3 KATHERINE trial [NCT01772472],” McCann said, referencing the trial that established adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) as the standard for patients with residual invasive disease after neoadjuvant therapy. DESTINY-Breast05 enrolled patients with high-risk disease, defined as inoperable disease at diagnosis or residual nodal disease after neoadjuvant treatment and randomly assigned them 1:1 to receive T-DXd or T-DM1 for 14 cycles.2 Unlike T-DXd, T-DM1 carries a microtubule inhibitor payload (emtansine) that is not released outside the cell, producing no bystander effect and contributing to the agent’s well-tolerated safety profile, she noted.
T-DXd (n = 818) significantly improved the primary end point of invasive disease–free survival (IDFS), reducing the risk of invasive disease or death by 53% vs T-DM1 (n = 817; HR, 0.47; 95% CI, 0.34-0.66; P < .0001). The 3-year IDFS rate was 92.4% (95% CI, 89.7%-94.4%) with T-DXd vs 83.7% (95% CI, 80.2%-86.7%) with T-DM1. The OS data remained immature at the interim analysis. McCann viewed the result as expected given historical data in the metastatic setting, although she cautioned that T-DM1 should not be fully discarded from the treatment paradigm, as it remains a well-tolerated therapy.
Q: Why is central nervous system protection a recurring theme in discussions about HER2-positive breast cancer care?
A: HER2-positive disease has a distinct propensity to recur in the brain, and preventing that is a priority, Nunnery said. T-DXd crosses the blood-brain barrier, whereas neither T-DM1 nor trastuzumab-based regimens like trastuzumab plus pertuzumab (HP) do. In DESTINY-Breast05, the brain metastasis-free interval favored T-DXd (HR, 0.64; 95% CI, 0.35-1.17). For patients treated with agents that do not cross the blood-brain barrier, the extended-adjuvant option neratinib can provide additional central nervous system protection, McCann added.
Q: How should ILD and pneumonitis be managed in HER2-positive breast cancer when the goal is cure?
A: In the metastatic setting, ILD occurs in approximately 10% to 15% of patients, according to the experts. In DESTINY-Breast05, it was reported in 9.6% of those who were evaluable in the T-DXd arm (n = 806) vs 1.6% of those in the T-DM1 arm (n = 801), including 2 grade 5 (fatal) events with T-DXd. In DESTINY-Breast11, adjudicated ILD rates were comparable between the arms, with 1 grade 5 event reported in each.1
“It’s much better to catch ILD and manage it with steroids when it’s grade 1, so we need to catch it before there’s symptoms,” Nunnery explained.
This requires regular CT surveillance, which is a departure from the standard adjuvant monitoring employed with HP or T-DM1 and raises questions about patient access to and insurance coverage of these scans, the experts noted. T-DXd’s long half-life further complicates disease management, since the drug persists in the system even after treatment is stopped. T-DXd rechallenge in patients with asymptomatic grade 1 disease is a practice that is being cautiously investigated.
Q: How are experts incorporating T-DXd into neoadjuvant and post-neoadjuvant HER2-positive breast cancer management strategies?
A: On May 15, 2026, the FDA approved T-DXd for 2 early-stage indications3:
- In the neoadjuvant setting followed by THP for adult patients with HER2-positive stage II or III breast cancer, based on data from DESTINY-Breast11
- In the post-neoadjuvant setting for adult patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment, based on findings from DESTINY-Breast05
For McCann, the post-neoadjuvant use of T-DXd in high-risk residual disease is straightforward, given its blood-brain barrier penetration. However, she said that identifying the right candidates for the neoadjuvant strategy is harder, particularly because her preferred comparator in the DESTINY-Breast11 trial would have been TCHP.
Nunnery said she leans toward the neoadjuvant approach for patients with high-risk disease, preferring to “do just the 4 cycles of T-DXd first to try to get that pCR and that great response early.”
Open questions remain, chief among them whether to continue T-DXd in the post-neoadjuvant setting when a patient does not achieve pCR after 4 neoadjuvant cycles, and how induction-then-switch strategies from the metastatic setting might inform curative-intent sequencing, they concluded.
References
- Harbeck N, Modi S, Pusztai L, et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. 2026;37(suppl 2):166-179. doi:10.1016/j.annonc.2025.10.019
- Geyer CE, Park YH, Shao Z, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with high-risk HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy: interim analysis of DESTINY-Breast05. Ann Oncol. 2026;37(suppl 2):S1556-S1557. doi:10.1016/j.annonc.2025.09.021
- FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. FDA. May 15, 2026. Accessed August 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage
