"ADC use sufficient in neoadjuvant therapy of breast cancer"

Enhertu improved pCR over 10% in clinical trials…overcoming limitations of the existing standard of care

"There are no safety concerns even with earlier use of treatment…opens up the possibility of personalized strategies"

The potential of utilizing the Antibody-Drug Conjugate (ADC) Enhertu is being confirmed in the neoadjuvant setting.

At the European Society for Medical Oncology Asia (ESMO Asia 2025) annual meeting in Singapore, clinical outcomes for Enhertu (trastuzumab deruxtecan) in patients with advanced HER2-positive breast cancer were recently disclosed.

In an interview at the conference, Professor Chang Ik Yoon of the Division of Breast Surgery at Seoul St. Mary's Hospital evaluated Enhertu as an option with sufficient clinical value not only for metastatic breast cancer but also for advanced HER2-positive breast cancer requiring neoadjuvant treatment, demonstrating the potential to overcome the limitations of the existing standard of care.

In the treatment of advanced breast cancer, pathological complete response (pCR) is a key indicator for lowering the risk of recurrence and improving long-term survival. However, a limitation of the existing standard of care TCHP, combining Herceptin (trastuzumab)·Perjeta (pertuzumab)·cytotoxic chemotherapy, is that approximately half of the patients fail to achieve pCR in real-world clinical practice.

Professor Chang Ik Yoon of the Division of Breast Surgery at Seoul St. Mary's Hospital 

The Phase 3 DESTINY-Breast11 study, designed to address this unmet need, evaluated Enhertu's potential as a neoadjuvant therapy in 927 patients with advanced HER2-positive breast cancer. The result showed that the pCR rate in the Enhertu combination group was 67.3%, which was 11.2 percentage points higher than that of the existing standard treatment, the ddAC-THP group (56.3%). This double-digit gap in the early·advanced breast cancer setting is considered a clinically meaningful difference.

Consistent improvement was also confirmed in subgroup analyses. In the Hormone Receptor (HR)- positive patient group, the pCR rate with the Enhertu combination therapy was 61.4%, 9.1 percentage points higher than in the control group (52.3%). Notably, the gap widened further in the HR-negative patient group, highlighting the therapeutic value of this approach in this high-risk population.

Professor Yoon stated, "Even with earlier use of the treatment, there were no distinct disadvantages in terms of side effects. The safety profile showed a more stable pattern." Professor Yoon projected that "the scope of Enhertu's utilization in pre-operative treatment strategies will continue to expand."

Q. We would like to ask about the background of today's session. Regarding the neoadjuvant data presented at ESMO, some medical oncologists expressed the view that the clinical significance was not substantial. Would you share your views?

The answer to this question depends on one's perspective. There have already been several prior studies. The common and crucial endpoint examined in these studies was pCR.

HER2-positive breast cancer accounts for approximately 20–25% of all breast cancers. The pCR rates following conventional chemotherapy range from about 50% for HR-positive, HER2-positive cases to up to 80% for HR-negative/HER2-positive cases. Combining these, approximately 65% achieve pCR, meaning roughly one-third, or 35%, do not.

The pCR rate reported in the latest DESTINY-Breast11 study was around 67%. Placing this figure alone next to the existing data, the difference is not dramatically significant. However, the results were better than those of the control group, which received anthracycline (AC) chemotherapy followed by THP.

However, some points don't align well with the South Korean setting. Doxorubicin (adriamycin) in the AC therapy is an agent with cardiac toxicity, and HER2-targeted therapies also carry a cardiac toxicity risk. Because using both together increases the risk of cardiac side effects, there is a clinical tendency in South Korea to avoid AC whenever possible. In contrast, it is still frequently used overseas. In that sense, the fact that Enhertu showed similar or even better results without using AC is a clear advantage.

Q. Why is AC still used overseas despite its cardiac toxicity?

AC is one of the major chemotherapy agents that has traditionally improved survival and recurrence rates in breast cancer treatment. It is a drug that, along with the taxane-type agents, has proven survival benefits. However, its use has somewhat declined since the introduction of HER2-targeted therapies due to concerns about cardiac toxicity.

Despite this issue, there is still the understanding that significant problems do not arise when the cumulative dose is not high. Because the cardiac toxicity of HER2-targeted therapies is relatively manageable, they are still combined with AC in many overseas settings.

Q. Why has the TCHP regimen been used more often in South Korea?

The underlying perception in Korea was that there was no need to deliberately expose patients to the risk of cardiac toxicity if the difference in pCR rates was not significant. Therefore, the regimen most widely used has been the TCHP regimen administered over six cycles.

Following the introduction of Enhertu, number of chemotherapy cycles can be reduced from six to four, and that earlier treatment does not incur a significant safety penalty; in fact, the safety profile appeared more favorable.

Q. How clinically significant do you consider regarding pCR being approximately 10% difference in?

In most studies, pCR is accepted as an indicator correlated with reduced recurrence rates and increased survival. Since actual survival data takes time to mature, pCR is utilized as an essential surrogate marker to predict long-term outcomes. Especially in HER2-positive and triple-negative breast cancer, pCR is almost synonymous with reduced recurrence risk and improved survival.

However, the question of how meaningful a 10% increase is when pCR rates are already approaching 70-80% is fair. It is also possible to interpret that even if the pCR rate is slightly lower, the difference in long-term survival may not be significant because additional treatment is given during the subsequent adjuvant therapy.

Q. Oncologists may have concerns about using such a powerful option too early in the neoadjuvant stage.

Yes. Patients who do not achieve pCR are considered high-risk for recurrence, and choosing subsequent adjuvant therapy is critical. If a superior option has already been used in the neoadjuvant stage, the question of what to use next is unavoidable.

While prospective data on subsequent treatment are currently insufficient, this does not mean that options are entirely nonexistent. As subsequent studies emerge, this aspect will be gradually resolved.

Q. Do you believe the current results alone are sufficient to support the use of Enhertu in the neoadjuvant setting?

In my opinion, it is sufficient for patients who achieve pCR. In these cases, the 5-year recurrence risk is less than 10%, indicating that the current standard treatment is adequate. The issue lies with patients who have residual disease.

The KATHERINE study shows that HER2-positive breast cancer patients with residual disease after neoadjuvant therapy had an 8-year recurrence risk of about 20% even with the existing standard treatment. However, the DESTINY-Breast05 results suggest the possibility of reducing this recurrence risk to approximately 8% at 3 years. The hazard ratio indicates that the risk is nearly half.

In other words, the reason not to be overly relying on pCR is that subsequent treatment options have improved, allowing for further intervention to lower the risk of recurrence.

Q. Can Enhertu be used in the neoadjuvant setting and then used again later?

It is possible. We already know that Enhertu is a better drug than Kadcyla, and a strategy of using it again, if necessary, can be considered. However, cost and reimbursement issues will be separate concerns.

The core strategy is personalized treatment: de-escalating therapy for patients who achieve pCR and intensifying treatment for those with residual disease.

For instance, with the old standard of care, a patient who achieved pCR would still need 14 cycles of Enhertu afterward. If pCR is achieved with only 4 cycles of Enhertu during neoadjuvant therapy, that patient would not require the additional 10 cycles. A patient group clearly benefits from this.

Q. There was also criticism of the study design regarding why it only looked at the neoadjuvant stage and not the perioperative (pre- and post-operative) setting.

The recent trend in research questions whether all patients need to complete the full course of chemotherapy. The approach is to see if treatment can be reduced for patients who show a good response.

For example, studies like PHERGain adjust treatment based on an interim response evaluation. In this context, the design to identify early responders by using Enhertu upfront is a meaningful attempt. However, the failure to clearly define the subsequent strategy for patients with residual disease can be confusing, and may need further research.