Breast cancer is one of the most prevalent cancers among females, with 29% of new diagnoses corresponding to it. While it is not the most lethal (lung cancer has a higher death rate), treatments for breast cancer are still not completely effective, especially when the tumor has metastasised.
One promising new drug treatment is trastuzumab deruxtecan. This combination of an antibody and a chemotherapy agent was approved by the FDA in late 2019. However, a recent study (DESTINY-Breast03) lead by the International Breast Cancer Center in Barcelona has revealed a 94,1% survival rate after 12 months among patients with HER2 positive metastatic breast cancer. This data opens the door for new therapy combinations both in breast cancer and beyond.
Keep on reading to find out more about breast cancer, what these drugs are and how they work!
How does breast cancer arise?
As most cancers, breast cancer is caused by mutations in the DNA of cells which lead to high levels of proliferation. In other words, one of the genes that normally regulated cell division (called oncogene) becomes suppressed, resulting in uncontrolled mitosis. There are several triggers for the mutations that cause breast cancer, including exposure to high levels of estrogen, inherited genetic diseases or inherited mutations, especially in the BRCA1/BRCA2 genes (responsible for controlling cell growth and death).
Another marker for this kind of cancer is the over expression of Human Epidermal Growth Factor Receptor 2 (HER2). This phenomenon is not exclusive to breast cancer, but it is estimated that 20% of patients with breast cancer are HER2 positive. Furthermore, gene amplification for HER2 is only reported in breast cancer, making anti-HER2 treatments specific for this disease. Sadly, if HER2 is over expressed, the cancers tend to replicate faster and thus are more likely to result in metastasis to the lymph nodes and beyond.
Breast cancer is typically diagnosed through mammograms or breast exams, which look for lumps in the mammary gland tissue.
What treatments are available?
Trastuzumab is a type of protein therapy which relies on antibodies to fight the cancer. Immunotherapy treatments also rely on using these drugs known as «biologics», instead of more traditional small molecule drugs, such as aspirin. Biologics refers to any kind of protein or nucleic acid based molecule which serves a therapeutic purpose.
These antibodies present in the treatment bind to a region of the HER2 extracellular domain. This prevents the protein from dimerizing or cleaving, which in turn activate the downstream pathway that stimulates growth and activation. Secondly, trastuzumab signals the cytotoxic T cells from the immune system to destroy the cell it is bounded to. Both of these processes are brought about by the action of only one antibody. The diagram below from the New England Journal of Medicine illustrates trastuzumab’s mechanism of action.
Deruxtecan is a type of chemotherapy agent. It belongs to the family of small molecule drugs, not the biologics, and it works to inhibit the enzyme topoisomerase I. By blocking this enzyme, it interrupts DNA replication, which is a necessary step to undergo cell division.
Topoisomerase I is critical for DNA replication because it removes the strain put on the double strands when they unwind. By breaking one of the chains and linking it back together after removing a twist, TOP-I manages to maintain a low strain on the rest of the genetic material. Because deruxtecan inhibits TOP-I, the genetic material is more likely to experience breakages due to the tension, impeding the polymerases from replicating the DNA.
In practice, only the second portion of the molecule is responsible for inhibiting the topoisomerase (past the last amide group).
How is the combined treatment more efficacious?
When these two drugs discussed previously are bound, their combined action results in a more effective cancer treatment. They are linked through one of the cysteine residues on the traztuzumab and the maleimide group on the deruxtecan, as shown below. The brand name of these treatments is Enhertu.
When this molecule now binds to the HER-2 antibody, it not only prevents the dimerisation and cleavage that was mentioned earlier, but it also undergoes phagocytosis into the cell. Once it is in an endocyte, the deruxtecan is cleaved and activated. After, it can enter the nucleus of the cell, damaging the DNA replication process, effectively killing that tumorous cell (apoptosis). Furthermore, the immune signalling function of trastuzumab is still present, so the cell now has two ways of being eliminated.
This released deruxtecan can also escape into neighbouring HER-2 positive tumor cells, speeding up the elimination of the cancer.
Around 20% of breast cancers exhibit over expression of HER-2 proteins, which make the tumor more aggressive. Recently, a new combination of trastuzumab and deruxtecan was found to improve survival of metastatic HER-2 positive breast cancer by 94,1%. This therapy, which is sold under the name of Enhertu, works by integrating traditional chemotherapy with specific antibody targeting to HER-2 proteins.
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