Resistance to HER2-targeted breast cancer therapies can be a problem when treating patients with breast cancer HER2-positive (HER2+). Therefore, the identification of new therapies for this patient group is important.
Researchers at the Leibniz Research Center for Working Environments and Human Factors in Dortmund (IfADo) have already shown that the EDI3 enzyme is associated with changes in the metabolism of cancer cells. Their most recent results reveal that EDI3 inhibition may be a novel therapeutic target in patients with therapy-resistant ER-HER2+ breast cancer.
The results of the study have been published in the Journal of Experimental & Clinical Cancer Research.
HER2 positive breast cancer: some details on the new therapeutic approach
Cancer cells alter their metabolism to maintain growth, thus ensuring their survival. Enzymes regulate metabolism and are therefore good candidates for targeted anticancer therapies. IfADo researchers have already identified one such enzyme: EDI3.
Glycerophosphodiesterase EDI3, which cleaves glycerophosphocholine into choline and glycerol-3-phosphate, affects choline and phospholipid metabolism and has been linked to cancer-relevant functions in vitro. While the importance of choline metabolism in breast cancer has been studied, the role of EDI3 in this type of cancer has not yet been explored.
The researchers demonstrated that EDI3 expression is higher in human HER2+ breast cancer and that both expression and enzyme activity were higher in ER-HER2+ breast cancer cell lines. HER2 silencing and inhibition of HER2 signaling reduced EDI3 expression. Inhibition of EDI3, in turn, mainly reduced the viability of ER-HER2+ cells. Furthermore, inhibition of EDI3 in HER2-targeted therapy-resistant ER-HER2+ cells decreased in vitro cell viability and in vivo tumor growth in mice.
Based on these results, the researchers conclude that EDI3 expression is upregulated in ER-HER2+ breast cancer compared with other subtypes. Furthermore, inhibition of EDI3 leads to a significant reduction in tumor viability and growth, especially in ER-HER2+ breast cancer cells that are resistant to conventional HER2-targeted therapies. Targeting EDI3 can therefore be a therapeutic approach to enhance the effect of standard therapies or an alternative in case of resistance to standard therapies.
HER2 is the name of a growth factor receptor. Its job is to collect signals from outside the cell, conduct them inside the cell, leading to the stimulation of cell division. If a patient has too much growth factor receptor HER2, the cancer is called HER2+, a subtype of breast cancer. As a result of the numerous growth signals, the tumor can divide uncontrollably.
Determining HER2 breast cancer status is important since there are drugs that specifically target HER2. Most HER2+ patients respond successfully to these drugs, but resistance to therapy is a problem for some. Therefore, alternative treatments are needed for this tumor subtype.
In addition to HER2 breast cancer signaling, the hormone estrogen may also affect the growth of breast cancer cells. Estrogen binds to binding sites (hormone receptors) in the cell, which then activates the expression of genes that promote cell growth. To determine whether a tumor is growing hormone-dependent, the proportion of cells and the amount of the corresponding hormone receptors are often examined. The result is expressed by the indication ER+ (positive estrogen receptor) or ER- (negative estrogen receptor).
HER2-positive breast cancer is breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2). This protein promotes the growth of cancer cells.
In about 1 in 5 breast cancers, the cancer cells have extra copies of the gene that makes the HER2 protein. HER2-positive breast cancer tends to be more aggressive than other types of breast cancer.
Treatments specifically targeting HER2 are very effective. These treatments are so effective that the prognosis for HER2-positive breast cancer is actually quite good.
Some standard chemotherapy drugs may also be effective in treating HER2-positive breast cancer, although these drugs do not specifically target the HER2 protein.
Experts recommend that any invasive breast cancer be tested for the presence of HER2 because the results significantly impact treatment recommendations and decisions. HER2 testing is not routinely done for DCIS, except as part of a clinical trial.
Whenever breast cancer comes back or spreads, the cancer cells should be retested for HER2 and hormone receptor status, as these can change from the original diagnosis.
About 15-20% of breast cancers have higher levels of a protein known as HER2. These cancers are called HER2-positive breast cancers. All invasive breast cancers should be tested for HER2 on the biopsy specimen or when the tumor is removed with surgery.
A test called an immunohistochemistry (IHC) test or fluorescent in situ hybridization (F ISH) test is used to find out if cancer cells have an elevated level of the HER2 protein. It’s not clear whether one test is more accurate than the other, but FISH is more expensive and takes longer to get results. Often the IHC test is done first.
If the IHC result is 0, the cancer is considered HER2 negative. These tumors do not respond to treatment with drugs that target HER2.
If the IHC result is 1+, the cancer is considered HER2 negative. These tumors usually don’t respond to treatment with drugs that target HER2, but new research shows that some HER2 drugs might help in some cases (see below).
If the IHC result is 2+, the HER2 status of the tumor is unclear and is referred to as “equivocal”. This means that HER2 status should be tested with FISH to clarify the result.
If the IHC result is 3+, the tumor is HER2 positive. These tumors are usually treated with drugs that target HER2.
Some breast cancers that have an IHC result of 1+ or an IHC result of 2+ along with a negative FISH test might be called HER2-low cancers. These breast cancers are still being studied, but appear to benefit from certain HER2-targeting drugs.
Some breast cancers that have an IHC result of 1+ or an IHC result of 2+ along with a negative FISH test might be called HER2-low cancers. These breast cancers are still being studied, but appear to benefit from certain HER2-targeting drugs.
Triple-negative breast cancers don’t have too much HER2 and also don’t have estrogen or progesterone receptors. They are HER2-, ER- and PR-negative. Hormone therapy and drugs that target HER2 are not helpful in treating these cancers. See Triple Negative Breast Cancer to learn more.
Triple positive breast cancer is divided into HER2-positive, ER-positive and PR-positive. These tumors are treated with hormone medications and drugs that target HER2
Sara Hurvitz, MD, associate professor at the David Geffen School of Medicine, medical director of the Johnson Comprehensive Cancer Center Clinical Research Unit, co-director of outpatient oncology practices at Santa-Monica- University of California Los Angeles (UCLA), and director of the Breast Cancer Clinical Trials Program at the University of California, Los Angeles, spoke with CancerNetwork® about improvements in the treatment of HER2-positive breast cancer.
The scientist said: “Although HER2-positive breast cancer is now able to be treated with a number of HER2-targeted therapies, T-DXd is one agent that has demonstrated remarkable antitumor activity. HER2-positive breast cancer is a more biologically aggressive type of disease [è] associated with worse outcomes, including survival without HER2-targeted therapies.
While our HER2-targeted therapies are very important and have improved patient outcomes, [quelli] diagnosed with metastatic disease that is HER2-positive are still not generally considered curable.
T-DXd achieved impressive objective response, prolonged progression-free survival, and [ha prodotto] a strong trend towards overall survival. All of these are improving patient outcomes compared to the standard agents we have available for this disease.”
In Italy, according to the Ministry of Health: “Il 2022 report estimates in Italy for the year 2022 about 55,700 new cancer diagnoses in women, with an increase of 0.5% compared to 2020.
Mortality for the 2021 is estimated at 12,500 deaths. The 5-year net survival after diagnosis is estimated by the report to be 88%. The probability of living another 4 years, conditioned on having passed the first year after diagnosis, is indicated as 91%.
According to ISTAT data in 2018 the breast cancer represented, with 13,076 deaths, the leading cause of death from cancer in women.
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