Utilizarea conjugatelor cu anticorpi în cancerul de sân – un scurt raport bazat pe opiniile specialiștilor

Introduction

We set out to create a “state of the art” in the use of anti-HER2 compounds by reproducing a podcast by specialists in the field of antibody-drug conjugates (ADC) in practice: Judy King, Giuseppe Curigliano, Peter Schmid. Antibody-Drug Conjugates in Practice. Contemporary Questions for the Treatment of Metastatic Breast Cancer. Release: 25.08.2025⁽²⁾.

The analysis of the studies that defined the use of ADC in breast cancer, carried out by the authors cited before, reveal the complexity of choosing ADC in the treatment of HER2-positive, low and ultralow breast cancer. This complexity should determine a looser indication in the insurance companies’ guidelines to give the doctor the opportunity to better appreciate all the parameters that must be taken into account for the initiation of this therapy.

We sought to determine what role chemotherapy still has in the therapy of HER2-positive breast cancer and what is the place of first-, second- and third-generation HER2 inhibitors in the therapy of this cancer. In this regard, we reproduce some relevant aspects of the NCCN guideline.

Background

Table 1 presents the evolution of ADC compounds and their use in clinical practice.

Antibody-drug conjugates in practice

Antibody drug conjugates in breast cancer are now quite numerous, and clinical trials have tested their anticancer activity in tumors with different characteristics.

“The development of the synthesis of new ADCs has led to much better efficacy, but it has also brought increased and different toxicity. So, these are all things that we have to consider when trying to introduce these drugs into the clinic, because as the results come out, with each passing congress, we don’t really have one drug pitted against another.

With the creation of new ADCs, this space becomes increasingly competitive and perhaps more complicated to interpret where we should place these drugs, as new targets are developed, newer payloads and so on.

However, as we look at a shift to HER2-low breast cancer, or which is mostly ER-positive, this is a very different disease.

But sequencing one ADC after another? What about the different toxicity profiles? There’s a lot to discuss. Let’s see what we can do.

So, in the DESTINY-04 study, patients with HER2 HR-positive-low disease were randomized after one or two lines of chemotherapy to trastuzumab deruxtecan versus investigator-chosen treatment. The median follow-up period was actually almost three years, and the treatment with trastuzumab deruxtecan improved median progression-free survival from four months to eight months at the latest follow-up period, with an improvement in overall survival as well.

And that’s why DESTINY-06 was designed as a prospective randomized trial for patients with HER2 low and HER2 ultralow disease, comparing trastuzumab deruxtecan with standard chemotherapy.

What we showed is that, if you advance treatment with trastuzumab deruxtecan, you can improve median progression-free survival from eight months to 13 months, with a positive trend for overall survival. But we need a longer follow-up period in terms of response.

The response rate with trastuzumab deruxtecan was 57% versus only 30% in the chemotherapy arm, with a safety profile that was almost equal to that of trastuzumab deruxtecan. A similar benefit was also seen in the ultralow HER2 population, with an improvement in median PFS from eight months to 13 months.

So, why anticipate trastuzumab deruxtecan after progression on one or two lines of endocrine therapy? Of course, some patients with indolent disease, with asymptomatic disease only in the bones, can certainly receive initial chemotherapy. But for any other patient with visceral disease, at least according to the guidelines, we should test for HER2 expression, and we should ultimately consider the opportunity to anticipate ADC, because we know perfectly well that no single chemotherapy can impact overall survival, and we still need to see the DESTINY-06 data in terms of overall survival benefit, given that most of the patients in DESTINY-06 crossed over to T-DXd in the control arm.

We’re talking about endocrine-resistant patients, and we really have a very broad group of patients. If you look at, for example, patients with PIK3 kinase mutation who can progress very rapidly and you would think, absolutely, I would want to use a first-line ADC here, whereas there are other women, maybe postmenopausal, who have a slowly progressive disease and who eventually develop some new lung metastases, and you would think, actually, you know what, from a quality of life standpoint, I’ve seen a lot of these women who do very well on, for example, oral capecitabine, for a very long time. And it’s about maintenance, because I think when you look at the toxicity data, it’s difficult to maintain the dose intensity of T-DXd.

To choose the right therapy, we must take into account the characteristics of the patient; there is no universal therapeutic scheme. Some clinicians believe that we should consider only patients who are refractory to hormonal treatment, not only those resistant to hormonal treatment, because, obviously, we now have multiple combined endocrine therapies that overcome some of the resistance.

Once patients are refractory, then we move on, we have to move on to chemotherapy. These ADCs – and T-DXd is one of them – are chemotherapeutic, although they are a targeted form of chemotherapy, but I would still classify them as a chemotherapy group. Of course, when we choose between different chemotherapies, we have to make choices.

There are certain patients with very indolent disease who can be treated very well with oral chemotherapy with capecitabine, with very limited hair loss, and the disease can be very well controlled. On the other hand, you can have patients who have a very aggressive visceral crisis, possibly imminent, with multiple liver lung metastases, where you probably want to choose the treatment with the highest chance of response, and in that situation that is T-DXd. One of the things you said right at the beginning is: do we choose the most effective therapy first? And I think that’s a difficult decision. If you look at the delta between the control arm and the T-DXd arm, in both the DB-04 and DB-06, it is relatively similar.

If we look at the response rate in second-line treatment, one of the things that was expressed in this podcast discussion about ADCs, this substantially higher response rate that we see even in pretreated patients, where it often becomes more relevant. So, Peter Schmid (MD, PhD, FRCP) don’t think the answer is that every patient should be getting an ADC or T-DXd as first-line treatment. But some of these patients will really benefit from it, and some patients will benefit from second-line treatment.

There’s also the toxicity aspect. One of our lessons is that the more experience the team has with ADCs, the lower the toxicity, the better the tolerability.

Tests for determining HER2 low
and ultralow

Now, the studies on ADC have determined changes in HER2 lab determinations: HER2 low refers to breast cancer with low levels of HER2 protein expression (IHC 1+ or 2+), while HER2 ultralow indicates even lower levels of expression, often classified as IHC 0 with minimal detectable HER2.

Dr. Curigliano: refer to DESTINY-06 and emphasize that in HER2-ultralow cohort, the central testing was re-done to evaluate the opportunity or not to identify those patients by local testing. And what we discovered was that there was a discordance rate of around 20% for their HER2 low population, increasing to 30% for their HER2 ultralow population.

So, this means that there is still a problem in identifying HER2 low and HER2 ultralow in the local level. What is really essential is that pathologists are trained to better test the level of HER2 in the local analysis testing, of course, and the use of digital pathology will improve eventually the number of patients that can be eligible, of course, to trastuzumab deruxtecan therapy.

Therapy after disease progression under treatment with trastuzumab deruxtecan

Sacituzumab-govitecan

Looking at the sacituzumab-govitecan data, this was a clinical trial that was done on patients who were predominantly third- and fourth-line, with a small percentage of patients in second-line. So, the patients were pretreated more heavily than the patients in the DB-04 study. We saw from the analyses that TROP2 expression matters, but only to a certain extent, because chemotherapy – standard chemotherapy – is actually quite inactive in this context.

Patients with high or low TROP2 levels had a better outcome compared to standard chemotherapy (but especially those with high TROP2).

We see the same thing with agents that target HER2. If you have higher HER2 expression, you have a better response with trastuzumab deruxtecan and high HER2 compared to low HER2.

DATO-DXd (a topoisomerase I [TOP1] inhibitor)

First, we must remember that datopotamab deruxtecan is an investigational antibody-drug conjugate showing significant promise in treating various cancers, particularly triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).”⁽²⁾

In this podcast, dr. Schmid added: DATO-DXd demonstrated a substantial benefit in terms of progression-free survival, did not reach overall survival at this time, but was still sufficient to be licensed and available to patients (the study was performed for patients who were not treated before)”⁽²⁾.

Resistance to ADC

According to the American Association for Cancer Research, presume that payload resistance to datopotamab deruxtecan refers to the phenomenon where the drug’s payload, a topoisomerase I (TOP1) inhibitor, is not effectively delivered to the cancer cells due to various mechanisms. This resistance can be due to factors such as the expression of TROP2, the receptor to which the drug binds, or the intrinsic resistance of the cancer cells to the drug’s payload. Understanding these mechanisms is crucial for developing strategies to overcome resistance and improve the efficacy of Dato-DXd in cancer treatment^(3,4).

The problem of sequencing ADC

An ideal study would be to treat a patient with one ADC and then, at the stage of progression, with another secondary ADC. This is a sequential strategy compared to a sandwich strategy (chemotherapy plus two ADCs administered sequentially), because we need to understand the potential impact of the secondary ADC on median progression-free survival (PFS).

According to ESMO 2025, if you sequence an ADC together with chemotherapy, the impact on the potential pathological complete response rate in the adjuvant setting is better. Therefore, it seems that chemotherapy still has a role in sequencing an ADC.

DESTINY-Breast02 trial confirmed these results in a population of 608 patients with HER2+ MBC who had previously received T-DM1. The median PFS was 17.8 months in the T-DXd group versus 6.9 months in the treatment of physician’s choice (TPC) group (HR: 0.36; 95% CI; 0.28-0.45; p<0.0001). The median overall survival (OS) was 39.2 months (95% CI; 32.7 – not evaluable [NE]) for patients treated with T-DXd, compared to 26.5 months (95% CI; 21 – NE) for those receiving TPC (HR: 0.66; 95% CI; 0.50-0.86; p=0.0021). Regarding safety, drug-related ILD occurred in 10% of patients who received the ADC versus below 1% in the TPC group. Finally, the phase III trial DESTINY-Breast03 demonstrated better efficacy of T-DXd versus T-DM1 in 524 patients with HER2+ MBC previously treated with trastuzumab and a taxane. The median PFS by blinded independent central review was 28.8 months (95% CI; 22.4-37.9) with T-DXd and 6.8 months (95% CI; 5.6-8.2) with T-DM1 (HR: 0.33; 95% CI; 0.26-0.43; p<0.0001). The median OS was not reached in either group, with 72 events (28%) in the T-DXd group and 97 events (37%) in the T-DM1 group (HR: 0.64; 95% CI; 0.47-0.87; p=0.0037). Drug-related ILD occurred in 15% of the patients in the T-DXd group and in 3% of those in the T-DM1 group. These data changed our practice and promoted T-DXd as a new second-line treatment in HER2+ MBC⁽⁵⁾.

Combinations of ADC

The treatment of metastatic breast cancer with ER-positive, HER2-positive, and ER-negative, HER2-positive was also discussed on a conference from Berlin in 2025. We reproduce the main statements related to the most eloquent studies on this topic and the situation in the real-world study: “DESTINY-Breast09, in particular, the analysis of some subgroup in the DB-09 study. We just remind that the DB-09 is a trial dedicated to patients with metastatic HER2 positive breast cancer without prior treatment. So, it is a first-line therapy. Thus, patients are randomized to three arms, deruxtecan plus placebo, and we don’t know yet the data from this arm to trastuzumab deruxtecan plus pertuzumab or to the standard THP therapy. The primary endpoint of the study was PFS, while the key secondary endpoint was OS. It was really significant in clinically meaningful improvement in PFS for the deruxtecan plus pertuzumab versus THP. And at ESMO we have seen the results according to stage 4, de novo or recurrent. And as you can see, we observe again a significant improvement in PFS. The median PFS is not reached for the de novo stage 4 disease patients, and it is 31.2 months for the patients treated with THP.

And as expected, we have a slightly shorter PFS for the patients presenting with the recurrent disease. Still an important advantage favoring T-DXd plus pertuzumab. The median PFS was 38 months versus 22.5 months in patients treated with THP, so the benefit is consistent regardless of de novo or recurrent status.”⁽⁴⁾

In particular, the authors discussed about the population of patients with PIK3CA mutation. PIK3CA mutation is a prognostic factor, so we can see that the median PFS is shorter in both arms of the study, in patients harboring PIK3CA mutation as compared to patient without the mutation. But again, there was a consistent benefit favoring T-DXd plus pertuzumab versus THP, regardless of the presence of the mutation.

PATINA trial at ESMO is another important study which give us evidence for treating this group of patients. “In this study, patients with hormone receptor positive, HER2-positive metastatic breast cancer, after six to eight cycles of induction therapy with trastuzumab, pertuzumab and taxane in treatment, were randomized to continue trastuzumab, pertuzumab and hormonal therapy plus the addition of palbociclib versus only pertuzumab, trastuzumab, and endocrine therapy. And we have seen really impressive results in terms of the median PFS, which was more than 44 months when adding palbociclib in the treatment plan of these patients as compared to continue the dual HER2 blockade plus hormonal therapy. In the control arm, the median PFS was 29 months.”⁽⁶⁾

A last problem is the indication of CDK4-6 inhibitors in advanced breast cancer with ER-positive and HER2-negative cases. The following conduct is generally accepted: “The decision to change the treatment with CDK inhibitors to ADCs in advanced breast cancer should be based on the patient’s specific clinical situation, including the presence of resistance to previous treatments and the availability of new therapies. The FDA’s Breakthrough Therapy Designation for camizestrant in combination with a CDK4/6 inhibitor indicates a significant reduction in disease progression or death, suggesting a potential benefit from this combination. However, the optimal sequencing post- CDK4/6i progression remains uncertain, and the use of CDK4/6 inhibitors in first-line settings for HR+/HER2-negative breast cancer is recommended by most guidelines.”⁽⁷⁾

In Table 2, we present a synopsis table of the NCCN that largely presents the indications for ADC in advanced breast cancer.

Conclusions

The analysis of studies that defined the use of ADC in breast cancer, carried out by the authors cited before, and the conclusions of conferences on the subject of ADC in breast cancer reveal the complexity of choosing ADC treatment in HER2-positive, HER2 low and HER2 ultralow breast cancer. This complexity should determine a more flexible indication in the guidelines of insurance companies, to give the doctor the possibility to better appreciate all the parameters that must be taken into account for the initiation of this therapy.

Another issue that stands out is the fact that some specialists claim that there is still a problem in identifying HER2 low and ultralow. Last but not least, we emphasize the therapeutic sequence of CDK4-6 inhibitors and HER2 inhibitors.

The review ends with an NCCN table that reveals the current status of the main indications of ADC in advanced breast cancer according to HER2 determinations.   

Corresponding author: Alexandru-Călin Grigorescu E-mail: alexgrigorescu2004@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.