Neoadjuvant trastuzumab deruxtecan (T-DXd) combination therapy reduces the residual cancer burden in patients with high-risk HER2-positive early breast cancer over more conventional treatment, shows a preplanned analysis.

The research also indicated that giving T-DXd followed by paclitaxel plus trastuzumab and pertuzumab (THP) was beneficial in reducing the residual cancer burden (RCB) in patients who did not achieve a pathologic complete response (pCR) to neoadjuvant therapy.

The current findings therefore “reinforce the primary pCR analysis” of the trial, which showed that T-DXd-THP increases the pCR rate compared with dose-dense doxorubicin plus cyclophosphamide (ddAC) followed by THP, said study presenter and author Lajos Pusztai, MD, DPhil.

Moreover, the results “demonstrate that T-DXd-THP is more effective than ddAC-THP for the neoadjuvant treatment of high-risk HER2-positive early breast cancer.”

Pusztai, scientific co-director of the Center for Breast Cancer at Yale Cancer Center, New Haven, Connecticut, presented the results of the analysis of DESTINY-Breast11 at the ESMO Breast Cancer 2026 on May 6.

DESTINY-Breast11 is a global, multicenter, open-label phase 3 trial that enrolled patients aged 18 years or older with previously untreated high-risk HER2-positive early-stage breast cancer. High risk was defined as clinical stage T3 or higher disease with nodal status N0-3 or cT0-4 with N1-3, or inflammatory breast cancer. The patients were randomly assigned to four cycles each of T-DXd followed by THP (n = 321), four cycles each of ddAC followed by THP (n = 320), or eight cycles of T-DXd alone (n =286), with all patients subsequently undergoing surgery.

Previous results from the T-DXd-THP and ddAC-THP arms presented at ESMO 2025, and reported by Medscape Medical News, showed that significantly more patients in the T-DXd combination arm had a pCR, at 67.3% vs 56.3% (P = .003). Pusztai characterized this as a “clinically meaningful improvement.”

Turning to the current preplanned analysis of those two arms, he explained that the focus was on the RCB, a continuous, quantitative measure of residual invasive disease in the breast and axillary nodes after neoadjuvant chemotherapy.

When categorized into classes RCB-0 to RCB-III, both RCB-0 (no residual disease) and RCB-I (minimal residual disease) are associated with marked improvements in event-free survival (EFS) in HER2-positive breast cancer over RCB-II (moderate residual disease) and RCB-III (extensive residual disease), regardless of hormone receptor (HR) status, Pusztai noted.

He reported that T-DXd-THP therapy was associated with a reduction in the proportion of patients in the RCB-II class over ddAC-THP when looking at both the overall patient population and the 199 patients who did not achieve a pCR to neoadjuvant therapy. This represented a shift in patients’ class toward RCB-0/RCB-I from RCB-II with T-DXd-THP vs ddAC-THP.

Overall, there was a 12.2% increase in the proportion of patients in RCB-0 or RCB-I with T-DXd-THP, at 81.3% vs 69.1% with ddAC-THP, and a corresponding 8.2% reduction in the proportion in class RCB-II, at 10.6% vs 11.6%, respectively.

This increase in the proportion of patients in RCB-0 or RCB-I with T-DXd-THP was seen across a range of prespecified subgroups, including in HR-positive patients (13.3%), and those with HR-negative disease (9.2%), as well as in both stage II (12.0%) and stage III tumors (12.9%).

Pusztai highlighted that T-DXd-THP was also associated with an increase in the proportion of RCB-0 or RCB-I patients compared with ddAC-THP in both node-negative (12.2%) and node-positive disease (11.8%).

Giampaolo Bianchini, MD, who was not involved in the study, said that a degree of caution is needed when interpreting the results.

He underlined that having a pCR does not mean that a patient is cured, but on the other hand, having residual disease does not necessarily mean that they will experience disease recurrence.

Bianchini, who is head of breast oncology at the Department of Medical Oncology of the IRCCS San Raffaele Hospital, Milan, Italy, also pointed out that dividing the RCB into categories, as was done in the current analysis, risks missing some crucial information that is gained when looking at it as a continuous variable.

He explained: “The continuous spectrum of the residual cancer burden after neoadjuvant therapy provides a more precise estimate of treatment efficacy and may improve [its] surrogacy for long-term benefit.”

Nevertheless, Bianchini’s take-home message from the analysis was that the RCB shift in patients with residual disease after T-DXd-THP adds to the sense of a benefit with the combination following the increase in pCR rates seen in the primary analysis and “reinforces the positive expectation of a long-term EFS benefit” with T-DXd-THP compared to ddAC-THP.

The research was funded by AstraZeneca.

Pusztai declared having relationships with AstraZeneca, Merck Sharp & Dohme (MSD), Pfizer, Daiichi Sankyo, Jazz Pharmaceuticals, BeOne Medicines, Radionetics, Exact Sciences, and Ataraxis. Bianchini declared having relationships with AstraZeneca, MSD, Roche, Menarini, Novartis, Eli Lilly and Company, Daiichi Sankyo, Seagen, Tethis, Gilead Sciences, Pfizer, Seagen, Exact Sciences, Takeda, Standard BioTools, and Helsinn.