Editor’s Note: At the 2026 ESMO Breast Cancer Congress (ESMO BC), Professor Lajos Pusztai from Yale University presented an analysis from the neoadjuvant DESTINY-Breast11 (DB-11) study. The results demonstrated that the T-DXd-THP regimen not only increased the pathological complete response (pCR) rate to 67.3%, but also significantly shifted the overall distribution of residual cancer burden (RCB) toward lower categories.This “global downstaging” phenomenon suggests the potential for improved long-term event-free survival (EFS). Notably, the RCB benefit appeared particularly pronounced in the HR-negative subgroup. Oncology Frontier invited Professor Lajos Pusztai for an on-site interview during the conference to discuss the study findings and their clinical implications.
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Oncology Frontier: At this meeting, you reported that the RCB-0+I rate reached 81.3% in the T-DXd-THP arm compared with 69.1% in the control arm. How do you interpret this additional absolute benefit of 12.2% in the context of the previously reported pCR improvement? What additional information does the continuous RCB index provide beyond pCR alone?
Professor Lajos Pusztai:
“At the 2026 ESMO BC meeting, I presented the residual cancer burden findings from the neoadjuvant DB-11 study. One important question raised about this study was: what additional value does the distribution of residual cancer burden provide beyond simply reporting pathological complete response rates?
The primary efficacy endpoint of DB-11 was pCR, and the study successfully met this endpoint. Results presented at the 2025 ESMO Congress showed that the pCR rate was 67.3% with T-DXd-THP compared with 56.3% with ddAC-THP, representing an absolute improvement of 11.2%. These findings essentially confirmed the efficacy advantage of replacing ddAC-THP with the T-DXd-THP regimen.
At this year’s ESMO BC meeting, however, we observed that the benefit associated with T-DXd extended beyond simply increasing pCR rates. Among patients who still had residual disease and did not achieve a pathological complete response, the regimen actually shifted residual cancer burden toward lower categories.
This is highly important because we know that the amount of residual disease is strongly associated with long-term outcomes. Patients with minimal residual disease generally have better prognoses than those with moderate residual disease, and substantially better outcomes than patients with extensive residual disease.
What we observed was an overall shift in the RCB distribution toward lower values. In the T-DXd-THP arm, there were significantly fewer patients with moderate or extensive residual disease. At the same time that pCR rates increased, many patients effectively moved from the RCB-II and RCB-I categories into RCB-0, while the proportion of patients with extensive residual disease also declined.
The RCB index provides a continuous and quantitative assessment of residual invasive disease in both the breast and axillary lymph nodes following neoadjuvant therapy. Categorizing patients according to RCB class offers important prognostic information for patients with residual disease and serves as a valuable complement to pCR assessment.
We are very encouraged by these findings because similar shifts toward lower residual disease burden—including more patients achieving complete eradication of disease—have been observed in several other randomized clinical trials and have correlated with improvements in event-free survival in the T-DXd-THP group.
This pattern may ultimately prove to be an even better early surrogate marker for future clinical benefit. As the DESTINY-Breast11 data continue to mature, we sincerely hope to see not only improvements in pCR and RCB distribution, but also meaningful improvements in event-free survival.
That is the true significance of this study, and it aligns closely with patterns previously observed in earlier neoadjuvant HER2-targeted therapy trials.”
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Oncology Frontier: The benefit in RCB-0+I appeared particularly pronounced in the HR-negative subgroup, with an absolute difference of 9.2% (90.4% vs. 81.2%), whereas the HR-positive subgroup showed a 13.3% difference (78.0% vs. 64.7%). How do you interpret these differences in magnitude of benefit? Could the biological differences associated with HR status help guide the optimal use of T-DXd in the neoadjuvant setting?
Professor Lajos Pusztai:
“Another important question arising from this analysis is whether improvements in pCR and RCB-0/RCB-I rates—that is, complete eradication or minimal residual disease—vary according to estrogen receptor status. This is not surprising because many previous studies have consistently shown that improvements in pCR or minimal residual disease rates with chemotherapy plus HER2-targeted therapy tend to be greater in the HR-negative/HER2-positive subgroup than in the HR-positive/HER2-positive subgroup.
This finding simply reflects the ongoing influence of estrogen receptor biology even in patients receiving highly active HER2-targeted therapies.
We already know that in HR-positive breast cancer, pCR rates achieved with chemotherapy alone are considerably lower than those seen in HR-negative or triple-negative breast cancer. Therefore, observing the same pattern in HR-negative/HER2-positive disease is entirely consistent with prior experience.”
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Oncology Frontier: For patients who still have residual disease after neoadjuvant T-DXd-based therapy, how should postoperative adjuvant treatment decisions be made? Could the RCB index help stratify risk and guide post-neoadjuvant treatment selection?
Professor Lajos Pusztai:
“Another major clinical question concerns how to manage the small subset of patients who still have residual disease despite receiving the T-DXd-THP regimen.
The study did not mandate specific postoperative treatment approaches, although recommendations were provided. The suggested strategy was to administer T-DM1, which is currently the standard treatment in the United States for patients with residual disease after neoadjuvant therapy. For patients who achieved pCR, physicians could choose either trastuzumab alone or trastuzumab plus pertuzumab as postoperative therapy.
A previous multinational clinical trial conducted across 18 countries showed that by the end of the study, approximately 50% of patients with residual disease received T-DM1, while the remaining 50% received alternative therapies. This likely reflected the fact that in many participating regions, T-DM1 was either not readily accessible or patients were reluctant to commit to another full year of antibody-drug conjugate therapy.
However, in both the United States and the European populations included in the study, approximately 80% of patients did in fact receive T-DM1.
Therefore, from a practical clinical standpoint, the most reasonable default recommendation is that if a patient still has residual disease after neoadjuvant T-DXd-THP, subsequent treatment should most likely consist of T-DM1.
Evidence from the metastatic setting has also improved our understanding of sequential ADC therapy. The primary mechanism of resistance to ADCs appears to involve resistance to the cytotoxic payload rather than resistance to the antibody component itself.
Although T-DM1 and T-DXd share the same HER2-targeting antibody backbone, their cytotoxic payloads are fundamentally different. T-DM1 carries DM1, a microtubule inhibitor derived from maytansine, whereas T-DXd carries DXd, a topoisomerase I inhibitor with a mechanism somewhat analogous to anthracyclines.
For that reason, both indirect evidence from the metastatic setting and the treatment strategies actually implemented in this trial support the use of T-DM1 for patients who continue to have residual disease after neoadjuvant T-DXd therapy.”
Professor Lajos Pusztai
