Many women with metastatic breast cancer could benefit from a new drug, trastuzumab deruxtecan, rather than being treated with chemotherapy. We are talking about patients with cancer that has a low expression of the HER2 protein, defined for this HER2-low, so far associated with the so-called “HER2 negative” for which the drugs that hit this target are not effective. But now the DESTINY-Breast04 study, presented at the American Society of Clinical Oncology congress in Chicago, identifies a new group of patients, those who express little HER2 but still sufficient to be attacked by the new conjugated antibody. In fact, the results speak for themselves: trastuzumab deruxtecan doubles progression-free survival (ie the period in which the tumor regresses or does not progress) compared to traditional chemotherapy. Treatment also significantly improved overall survival.
The results
The trial was conducted on 557 patients in Asia, Europe and North America with metastatic or unresectable HER2-low, hormone-sensitive and non-hormone-sensitive (HR-positive and HR-negative) breast cancer treated with trastuzumab deruxtecan or chemotherapy. At a follow-up (median) of 18.4 months, patients with HER2-low and hormosensitive cancer who received the new antibody conjugate had a 49% reduction in the risk of progression and a reduction in the risk of death of the 36% compared to chemotherapy. “In these patients, progression-free survival was almost double for trastuzumab deruxtecan (10.1 months) compared to the standard of care (5.4 months),” comments Giuseppe Curigliano, Professor of Medical Oncology at the University of Milan and Director of the Development Division of New Drugs for Innovative Therapies at the IEO in Milan: “The most important result is related to overall survival, significantly better in the HER2-low / HR + subgroup of patients who received trastuzumab deruxtecan (23.9 months) compared to the standard (17.5 months). The study therefore shows that trastuzumab deruxtecan may be an available therapeutic option for the HER2-low patient population ”.
How many patients have HER2-low cancer?
Of all breast cancer diagnoses (55,000 in Italy), about 15-20% are HER2 positive, i.e. they have a certain amount of this protein, which has been identified for over 20 years as a target of targeted therapies. The remaining about 80% of tumors are considered HER 2 negative, because the protein is absent or present in low quantities: too little for the tumor to respond to anti-HER2 drugs. However, the DESTINY-Breast04 study overturns this view. “HER2-low breast tumors do not have high expression or amplification of the HER2 receptor”, explains Saverio Cinieri, President of AIOM – Italian Association of Medical Oncology: “They constitute 55% of all breast cancers, of which 85% in endocrine responsive group and 15% in the triple negative group. At present, these patients are receiving chemotherapy. However, the results of the experimentation will change the treatment algorithm. A new subtype of breast cancer is therefore outlined, the HER2-low one, with important therapeutic implications, because targeted therapies can be used in a large population of patients, previously considered HER2-negative “.
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Measure the HER2 protein
The expression of the HER2 protein on cancer cells is measured with two types of tests: one detects the amount of the protein, the other counts the copies of the gene present in the tumor DNA. “Our study shows that trastuzumab deruxtecan could represent a highly effective new treatment option for a new patient population,” explained study first author Shanu Modi of Memorial Sloan Kettering Cancer Center in New York. know the levels of HER2 expressed by their tumor, and not only if they are ‘positive’ or ‘negative’, since the HER2-low status can be determined using readily available tests ”. Trastuzumab deruxtecan is currently being studied in patients with HER2-low metastatic breast cancer in several trials, which are also trying to understand the minimal level of HER2 expression at which the drug is effective.
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The new drug
Trastuzumab deruxtecan arises from the union of a monoclonal antibody – trastuzumab (a targeted drug already widely used) – with the particularly powerful chemotherapy deruxtecan. Each molecule of trastuzumab binds to itself 8 chemotherapy molecules. The mechanism by which it works is this: trastuzumab recognizes and binds to the HER2 receptors present on the cancer cell and, at that point, releases the 8 molecules of the chemotherapy. The first important data on this drug dates back to December 2019, when at the breast cancer congress in San Antonio, Texas, the Destiny-Breast03 study demonstrated significant advantages over TDM-1 (trastuzumab emtansine, the current standard of treatment for patients with HER 2 positive tumors), for patients who had previously received many treatments.
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Confirmation for HER2 positive breast cancers
During the plenary session of the Asco, the updated data of this study were also presented, confirming the advantages previously emerged for HER2 positive patients: among the 524 patients assigned to one of the two groups, the percentage of those who were alive without progression disease at 12 months was 75.8% with trastuzumab deruxtecan and 34.1% with trastuzumab emtansine; the percentage of patients alive at 12 months was 94.1% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. “The study – concludes Curigliano – shows that trastuzumab deruxtecan is a safe drug, with a significant impact in the treatment of HER2-positive tumors”.
The future scenario
Breast data confirm a new innovative therapeutic line, that with combined antibodies. Which promise to replace the chemotherapy needed today against cancers of the colon, cervix, lung, and bladder.