Working on chronification of Her2-positive advanced breast cancer

Therapeutic options using nanotechnology

James Fleck, MD, PhD and Emily Tonin da Costa, MD: Anticancerweb 9 (05), 202

According to the Global Cancer Observatory, breast cancer is the leading malignancy in women, reaching a global incidence of nearly 2.3 million (ASR = 47.8) in the most recent annual report of the International Agency for Research on Cancer ( IARC). Currently, breast cancer is the leading cause of mortality from malignant disease in women worldwide, leading to approximately 685,000 deaths, annually. These global epidemiological data give breast cancer a fatality risk of 29.8%. In Brazil and the USA, the breast cancer case fatality rate drops to 23.4% and 16.8%, respectively. In the United States, up to 5% of women diagnosed with breast cancer have metastatic disease at presentation, and up to 30% of patients with early-stage breast cancer will develop metastatic disease. In Brazil, these numbers are worse, which is responsible for the difference in the fatality rate observed between the two countries. Worldwide, approximately 20% of breast cancer overexpress human epidermal growth factor receptor 2 (Her2), a transmembrane glycoprotein eliciting tyrosine kinase activity. For a better understanding of activation and dimerization of Her2 receptor go to the link showed below. Her2-overexpression is associated with an increased risk of disease recurrence and a worse prognosis. Although Her2-positive metastatic breast cancer is an incurable disease, long-term survival has been achieved with Her2-double blockade. First, trastuzumab was developed, binding to the extracellular domain of the Her-2 receptor, promoting cytotoxicity and independent decrease in cell proliferation. Subsequently, pertuzumab was identified, binding to a distinct epitope (subdomain II) of the extracellular domain of Her-2 receptor. The action prevented receptor dimerization, leading to impaired tumor cell function. The combined use of two MoAb was assessed by a phase III prospective randomized trial called CLEOPATRA. The median OS difference, favoring the double blockade (pertuzumab + trastuzumab + docetaxel) was 16.3 months, when compared to the control arm (placebo + trastuzumab + docetaxel). After 8 years of follow-up, the landmark analysis of double-blockade Her-2 positive advanced breast cancer in the ITT population showed an unprecedented 37% overall survival, leading to the concept of disease chronification. Despite the encouraging results of the CLEOPATRA trial, most patients with Her2-positive metastatic breast cancer will progress after double blockade.

The next question is: which treatment should be used after progression with double blockade? Nanotechnology, using antibody-drug conjugate (ADC), came as a very promise alternative. Here, the anti-Her2 MoAb trastuzumab is combined to a cytotoxic drug, named proprietary payload through a cleavage proprietary drug linkerTrastuzumab helps by being very specific in identifying Her2-positive breast cancer cells. The complex remains stable in the systemic circulation, preventing extensive, nonspecific and undesirable release of chemotherapy. Finally, the complex is endocytosed and fused with a lysosome, where it undergoes proteolytic degradation, finally releasing its proprietary payload (chemotherapy). Eventually, there is also a bystander effect as neighboring Her2-negative cells are also exposed to cytotoxicity, presumably due to increased membrane permeability and therefore transcellular diffusion of the payload. Sequentially, two initiatives competed in this therapeutic scenario. First, appeared trastuzumab emtansine (TDM-1), which is an antibody-drug conjugate made up of trastuzumab, stable linked to DM1 (proprietary payload). T-DM1 carries an average of 3.5 DM1 molecules per one molecule of trastuzumab. Each DM1 molecule is conjugated to trastuzumab through MCC (proprietary drug linker), which is a non-reducible thioether linker N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate. DM1 has a mechanism of action that is similar to vinca alkaloids, but 100 times more potent.  Another promise drug is trastuzumab deruxtecan. This antibody-drug conjugate combines trastuzumab with DXd, a cytotoxic topoisomerase I inhibitor (proprietary payload), using a cleavable tetrapeptide-based linker (proprietary drug linker). After binding to Her2-positive breast cancer cells, trastuzumab deruxtecan undergoes internalization and intracellular cleavage by lysosomal enzymes. After being released, DXd causes DNA damage and cell death by apoptosis. Cytoplasmic DXd is membrane permeable, being also effective in killing neighbor Her2-negative breast cancer cells (bystander effect).

In March 2022, the New England Journal of Medicine published the DESTINY-Breast03 study, a phase III, multicenter, open-label, randomized trial comparing the efficacy and safety of the two advanced ADC breast cancer treatments currently available. A total of 524 patients with advanced Her2-positive breast cancer who progressed during or after trastuzumab + taxane were randomly assigned 1:1 to receive trastuzumab emtansine or trastuzumab deruxtecan. The primary outcome was progression-free survival (PFS) and the secondary end points included overall survival, objective response and safety. The PFS at 12 months, was significantly higher (HR = 0.28, P < 0.001) using trastuzumab deruxtecan (75.8%) versus trastuzumab emtansine (34.1%). Despite a prespecified significant boundary not reached, the percentage of patients alive at 12 months were also higher in the trastuzumab deruxtecan (94.1%) arm than in the trastuzumab emtansine (85.9%). A longer follow-up will be necessary to better evaluate median overall survival. There was a higher grade 3 or 4 associated to trastuzumab deruxtecan (45.1%) than it was observed with trastuzumab emtansine (39.8%). Some concern poses over adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the women treated with trastuzumab deruxtecan

In May 2022, the US Food and Drug Administration (FDA) approved trastuzumab deruxtecan for pretreated advanced Her2-positive breast cancer patients who have progressed in the metastatic setting or within 6 months after neoadjuvant treatment. The review was conducted under the Project Orbis, which provides a framework for concurrent submission and review of oncology drugs among international partners. However, application reviews maybe ongoing at other regulatory agencies. The application was granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation.

Link: (
ASR = Age-standardized Rate, OS = Overall survival, ITT = Intention-to-treat, MoAb = Monoclonal antibody



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