For patients with metastatic breast cancer and low expression of the Her2 protein (Her2 low), reimbursement has been approved in Italy for trastuzumab deruxtecan, the monoclonal antibody drug-conjugate from Daiichi Sankyo and AstraZeneca which has shown to substantially improve both progression-free survival and overall survival, halving the risk of disease progression or death even in this group previously excluded from the benefits of targeted Her2 therapies. In 2023, in Italy, 55,900 new cases of breast cancer were estimated. The 5-year survival reaches 88%. Early diagnosis and targeted therapies – it was recalled during an event today in Milan – contributed to this important result. Currently, approximately 52 thousand people live with metastatic disease which, with a 5-year survival rate of 25%, remains a condition characterized by strong unmet clinical needs. The newly approved therapy meets the needs of approximately two thirds of tumors positive for hormone receptors and negative for Her2 and those of a third of triple negative forms.
Specifically, the Italian Medicines Agency (Aifa) has given the green light to the reimbursement of trastuzumab deruxtecan as monotherapy for the treatment of adult patients with Her2 low breast cancer (Her2 low defined as: IHC 1+ or IHC 2+/ ISH-) unresectable or metastatic, who have received prior chemotherapy for metastatic disease or who have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. In January 2023, trastuzumab deruxtecan was approved by the European Commission, in this indication, based on the results of the phase 3 Destiny-Breast04 study, published in the 'New England Journal of Medicine' which recorded a median progression-free survival of 9. 9 months in treated patients compared to 5.1 months with chemotherapy. Furthermore, the antibody drug conjugate reduced the risk of death by 36%, with an improvement of more than 6 months in the median overall survival, which reached 23.4 months in the treated group compared to 16.8 months with chemotherapy.
“Trastuzumab deruxtecan – explains Giampaolo Bianchini, associate professor and head of the Breast Group of the Irccs San Raffaele hospital, Vita-Salute San Raffaele University of Milan – belongs to the category of drug-conjugated antibodies, that is, it is made up of an antibody directed against the receptor Her2, expressed on tumor cells, and by a very powerful chemotherapy drug linked to this antibody: the result is to ferry this chemotherapy drug into the cells which leads to cell death, limiting the exposure of normal tissues. In the Destiny-Breast04 study, which involved 557 patients – he continues – it reduced the risk of progression by 50% compared to chemotherapy and significantly increased overall survival”.
Breast cancer – it was recalled during the meeting – is classified into three main subtypes, fundamental for defining the prognosis and the therapeutic approach: tumors with positive human epidermal growth factor receptor 2 (Her2+); luminal tumors with hormone receptor (Hr) positive (estrogen or progesterone positive) and simultaneously Her2 negative (Hr+/Her2-) and the triple-negative subtype (Tnbc, negative for all three receptors). Her2 expression is defined as positive or negative. It is determined using an immunohistochemistry (IHC) test, which measures the levels of Her2 protein in a tumor cell (IHC test results are reported as 0, 1+, 2+, or 3+), and a fluorescent hybridization test in situ (Fish), which counts the copies of the Her2 gene in tumor cells (the latter is carried out only if a 2+ score is obtained from the Ihc test).
“Up to 55% of all breast tumors express low levels of Her2 – specifies Michelino De Laurentiis, director of the Department of Senological and Thoracic-Pulmonary Oncology, National Cancer Institute Irccs Fondazione 'G. Pascale' of Naples – and is, therefore , classifiable as Her2 low. Until now these tumors were simply classified as Her2 negative (i.e., with Her2 not overexpressed) and therefore fell among luminal tumors or triple-negative, depending on the presence or absence of hormone receptors Today, however, given that Her2 low tumors can take advantage of this new therapeutic opportunity given by trastuzumab deruxtecan, it becomes essential to identify them precisely. For this reason, the role of the multidisciplinary team in the evaluation of patients is more necessary than ever and, in particular, a close collaboration between the oncologist and the pathologist who carries out the diagnostic tests”.
For patients with Her2 low breast cancer “the therapeutic implications are important. – underlines Alessandra Fabi, head of Precision Medicine in Senology, Fondazione Policlinico Universitario A.Gemelli Irccs of Rome – Thanks to Aifa's reimbursement, we can treat patients previously considered Her2-negative, with a conjugated anti-Her2 monoclonal antibody, improving the time of disease control and overall survival in the metastatic stage”.
Trastuzumab deruxtecan has already been reimbursed by Aifa, in July 2023, in Her2 positive metastatic breast cancer. The approval also for Her2 low cases “makes us very happy – adds Rosanna D'Antona, president of Europa Donna Italia – This, together with dedicated management within the Breast Centers and the joint work of the multidisciplinary team , will not only increase the survival of these women, but also their quality of life in the treatment path that awaits them.”
According to Mauro Vitali, Head of Oncology at Daiichi Sankyo Italia, “the possibility of even nominating patients who express low levels of this protein for anti-Her2 treatment revolutionizes the current paradigm of diagnosis and treatment of metastatic breast cancer. Efficacy is independent of hormone receptor status, therefore both patients with hormone-positive breast cancer and those with triple-negative breast cancer are candidates for treatment with trastuzumab deruxtecan. The approval of reimbursement by Aifa – he continues – supports our objective of expanding to this population the benefit that therapy with trastuzumab deruxtecan can offer them”.
“Trastuzumab deruxtecan has opened the way to the treatment of new clinically significant segments of cancer patients whose disease did not provide targeted therapeutic options – concludes Alessandra Dorigo, Head of Oncology of AstraZeneca Italia -. These results are the result of the synergy between the medical-scientific and technological expertise of Daiichi Sankyo and the great experience in oncology and the global resources of AstraZeneca. We are proud of this approval, a further step that brings us closer to the goal of making cancer chronic and the ambition of one day eliminating it as a cause of death. Our commitment is to develop innovative therapies capable of improving not only survival but also the quality of life of patients.”
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