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Faced with advanced hormone-dependent cancers, the options may ultimately be limited to chemotherapies that are not very effective and not devoid of side effects. But a new type of treatment, a conjugated antibody, is proving effective
Faced with hormone-dependent breast cancers (the most common), hormonal therapy can be prescribed to block this stimulation. Often, this hormonal therapy is even offered for 5 to 10 years after surgery, chemotherapy and/or radiotherapy treatments, in order to reduce the risk of recurrence caused by certain cancer cells which would have escaped these first lines of treatment.
But if the cancer is detected at a metastatic stage (with spread of the cancer to other organs) or if it becomes so after several treatments with hormone therapy. Other treatments must take over: CDK4/6 inhibitors, targeted therapies before resorting to chemotherapies with limited effectiveness and significant side effects.
But a new study presented as part of the World Cancer Congress (ASCO 2024) could give doctors a new weapon against these formidable cancers.
Conjugated antibodies, stars of ASCO 2024
This weapon is a conjugated antibody, a therapy which is the “star” of this 2024 congress, the results of which could change the management of lung cancer, lymphoma and other tumors. The principle is that of a targeted missile which combines the advantages of targeted therapies and chemotherapy: the conjugated antibody will be capable of specifically targeting certain cancer cells and directly administering a chemotherapy compound. Theoretically therefore a very targeted action, very effective with fewer side effects.
The originality of the study presented in plenary session at ASCO is that it evaluates the use of a drug, trastuzumab deruxtecan (or Enhertu ®) normally intended for cancer cells which express increased quantities of the human epidermal growth factor receptor 2 (HER2). But this drug was given to women whose cancer cells expressed HER2 at low or very low levels (HER-low and HER2-ultralow). · About 60-75% of breast cancers are HR+ and about 55% are HER2-low.
Effectiveness even on tumors expressing little HER2
A total of 866 participants with HER2-low (713 participants) or HER2-ultralow (153 participants) metastatic breast cancer were recruited. All had received at least one hormonal therapy, and almost all participants (90.4%) had also received targeted treatment with a CDK4/6 inhibitor. Participants were randomly assigned to receive either trastuzumab deruxtecan (436 participants) or chemotherapy of their doctor’s choice (430 participants).
Results :
- For patients with HER2-low cancer, the time after the disease progressed again (median progression-free survival) was 13.2 months for those who received trastuzumab deruxtecan versus 8.1 months for those who received chemotherapy. Similar results were observed in the small group of patients with ultra-low HER2 cancer.
- Overall, patients with HER2-low cancer who received trastuzumab deruxtecan were 38% less likely that their cancer would grow or spread compared to those who received chemotherapy.
- Among patients with HER2-low cancer, the proportion of those who saw their tumor regress (objective response rate – ORR) was 56.5% with trastuzumab deruxtecan compared to 32.3% for those who received a chemotherapy. And in the case of HER2-ultralow cancer, this proportion more than doubled (61.8% versus 26.3%, respectively).
- Participants who received trastuzumab deruxtecan were able to receive their treatment for longer without experiencing serious side effects, with a median treatment duration of 11 months compared to 5.6 months for those who received chemotherapy. This does not mean, however, that the treatment is devoid of side effects: serious side effects were more frequent in the trastuzumab deruxtecan group, with approximately 41% of participants having experienced a serious side effect compared to approximately 31% of those having. received chemotherapy, with more nausea and increased risk of interstitial lung disease (ILD), a known serious side effect of trastuzumab deruxtecan.
Researchers will continue to follow patients to find out if these positive results translate into a gain in survival.
Towards a new classification of tumors?
“These results also represent a potential change in how we classify and treat metastatic breast cancer, as we could tomorrow use trastuzumab deruxtecan earlier in the treatment of hormone-dependent metastatic breast cancer and expand its use to new patients with metastatic breast cancer who could not benefit from targeted therapy after endocrine therapy“, said Prof. Giuseppe Curigliano, from the University of Milan and European Institute of Oncology.
The specificity of these conjugated antibodies, here trastuzumab deruxtecan but also datopotamab deruxtecan (an anti-TROP2 targeting another protein presented for this same indication during the ESMO 2023 European congress) offers new weapons to doctors.
At the same time, these drugs are partly changing the classification of cancers, knowing that the even limited presence of certain targets in cancer cells would be sufficient to use them.
Today, the sometimes serious toxicity of these compounds does not allow them to be given straight away to all patients, but we can think that other classification techniques will make it possible in the future to better identify those who would benefit the most. Liquid biopsy, with the search for circulating tumor cells (CTC), could be a good option, as several studies have already suggested.