Novel ADCs Must Keep Up With Moving Targets in Metastatic Breast Cancer


Barbara Pistilli, MD, discusses the mechanism of action of novel ADCs, the ways in which ADC targets in breast cancer can change over time, and how future research may pave the way for individualized treatment with this class of agents.

Barbara Pistilli, MD

Barbara Pistilli, MD

Genetic testing practices should mirror the dynamic activity of HER2 expression levels in metastatic breast cancer to ensure the most effective use of third-generation antibody-drug conjugates (ADCs) in patients with this disease, according to Barbara Pistilli, MD.

A study of HER2-low status among patients with triple-negative breast cancer (TNBC) found that increases in the proportion of patients with HER2-low disease correlated with the number of successive biopsies they underwent after initial diagnosis. When 1 (n = 194), 2 (n = 233), 3 (n = 48), 4 (n = 29), and 5 to 9 (n = 8) biopsies were conducted, 59%, 73%, 83%, 83%, and 100% of patients had HER2-low results. Furthermore, approximately one-third of patients without a prior HER2-low result converted to HER2-low status with each successive biopsy.1

Additionally, the phase 2 DAISY trial (NCT04132960) demonstrated that HER2 expression determines the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with metastatic breast cancer.2 In this trial, the confirmed overall response rates with T-DXd were 70.6% (95% CI, 58.3%-81%), 37.5% (95% CI, 26.4%-49.7%), and 29.7% (95% CI, 15.9%-47%) in patients with HER2-overexpressing, HER2-low, and HER2 non-expressing disease, respectively.

“We [need to invest time and effort] in the next years to better understand how to use the different ADCs according to the specific characteristics of [each] tumor and patient,” Pistilli said in an interview with OncLive® during the 2023 ASCO Annual Meeting.

In the interview, Pistilli discussed the mechanism of action of novel ADCs, the ways in which ADC targets in breast cancer can change over time, and how future research may pave the way for individualized treatment with this class of agents.

Pistilli is the chair of the Breast Disease Committee in the Department of Medical Oncology at Gustave Roussy Cancer Center in Villejuif, France.

OncLive: Could you provide an overview of your presentation on moving targets in ADC therapy?

Pistilli: I discussed the results of 3 abstracts on new ADCs in metastatic breast cancer. I focused on target expression and the importance of target expression for the activity of the ADCs, [including] how we need to know the target expression level [for] the third generation of ADCs.

These new compounds have lower target expression [thresholds] that are necessary for the ADCs to work. [These thresholds influence] the bystander effect, the immunomodulation of the tumor microenvironment, the high drug-to-antibody ratio, the payload [potency], and the toxicity. On 1 side, the target expression level we need, compared with the second generation of ADCs, is lower. However, on the other side, we don’t yet know the minimum threshold of target expression that we need for the [third generation of] ADCs to be active and have good results and good activity.

How do changing HER2 expression levels influence the use of ADCs in patients with breast cancer?

The target expression [of ADCs] can move in different ways because [it] can change over time. We know this, for example, for HER2. [At the 2023 ASCO Annual Meeting], a retrospective analysis of a large cohort of patients with TNBC was presented, in which the authors studied HER2 expression. They found that an increased number of biopsies increases the number of patients who are found to be HER2 low, even if they were classified as HER2 negative [at diagnosis].

There is a discordance regarding HER2 expression. The question here is: How many times do we need to biopsy patients from the beginning of their [diagnosis with] metastatic breast cancer? The authors found that one-third of the patients obtained a HER2-low result [with subsequent biopsies], even if they were HER2 negative at the beginning. This discordance rate [of HER2 expression] between early breast cancer and metastatic breast cancer was already reported in other retrospective analyses over the past couple years. [Other studies have reported a change] in HER2 expression from early breast cancer to recurrence, with approximate discordance rates of 35% or 40%. We know from the DAISY trial that HER2 expression can even decrease after treatment with T-DXd.

We are in front of some moving targets, targets that can change over time, but we need to keep in mind that the expression of the target is heterogenous across different tumor sites and within the same tumor site. The DAISY trial [showed] that partial distribution of the target can affect ADC activity, particularly the activity of T-DXd. We also know that HER2 expression can be heterogenous across different localizations of the tumor.

Finally, the targets can move from the cell surface, or membrane, to the internal compartments of the cell. This is important because it allows the internalization of the ADC. [We need to further study] this movement because the expression of the target is not enough. We need targets with the capability of internalizing the ADCs. With the new generation of ADCs, we need to [further study] the endocytosis pathways of each target, which can be different for each target, [to determine which targets have] more or less internalization and activity with the ADCs.

What does the future look like for ADCs in breast cancer?

The future of ADCs in breast cancer, as in other solid tumors, is to have a landscape of multiple ADCs targeting different tumor antigens with different payloads, some even targeting antigens that are expressed by the tumor microenvironments [as well as] the tumor cells. This landscape is expanding rapidly. What I would expect in the next 10 years is ADCs almost totally replacing standard chemotherapy. [We may also have the] ability to better understand the best ADC for each patient, [using] an algorithm that is different for each patient according to their type of tumor, type of target expression, and other biomarkers that can be implicated in ADC activity beyond target expression.

What other presentations were you excited to see at the 2023 ASCO Annual Meeting?

[I was looking forward to] the results of the [phase 3] NATALEE trial [NCT03701334]. These results are appealing and challenging, because we have now another CDK4/6 inhibitor, ribociclib [Kisqali], that demonstrated activity and efficacy in patients with early breast cancer. The trial included patients with stage III breast cancer [and those with] stage II [breast cancer]. The results of this first analysis, [with a median] follow-up [of 34] months, showed a 25.2% reduction in the risk of recurrence in patients with early breast cancer.

These results are preliminary. We need longer follow-up to understand the real benefit of this drug because we are adding [it] to adjuvant endocrine therapy for 3 years in patients [with] intermediate and high risk of recurrence. We need to better understand the absolute benefit of the treatment for patients with stage III breast cancer, [those] with stage II breast cancer, and [those] with node-negative breast cancer. On the other side, we need to understand how to manage the adverse effects of the treatment, notably the liver toxicity, for patients who are meant to stay on the treatment for 3 years.


  1. Bar Y, Dedeoglu AS, Fell GG, et al. Dynamic HER2-low status among patients with triple negative breast cancer (TNBC): the impact of repeat biopsies. J Clin Oncol. 2023;41(suppl 16):1005. doi:10.1200/JCO.2023.41.16_suppl.1005
  2. Mosele F, Deluche E, Lusque A, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023;29(8):2110-2120. doi:10.1038/s41591-023-02478-2
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