"Degrading Estrogen" — A New Approach To Treatment
- Hormone or hormone receptor (estrogen, progesterone) therapies are critical players in treating advanced and metastatic breast cancers. Hormones drive the growth of many breast cancers.
- Despite their importance, only a few new agents have been discovered in the past.
- Camizestrant is a degrader of estrogen receptors, which leads to a cessation of cancer growth and proliferation. It delays breast cancer progression in people with advanced or metastatic disease. This class of drug has theoretical promise, and now some good data to potentially back up the continued trials. It is well-tolerated in clinical trials.
- It, however, needs to be tested in larger, phase III clinical trials before it can be made available to the public.
Breast Cancer And Its TreatmentBreast cancer is one of the most common diagnoses. An average woman has a 13% chance of developing this cancer during her lifetime. In 2022, around 290,000 new cases of breast cancer will be diagnosed in women, resulting in more than 40,000 deaths. This makes it the second leading cause of cancer-related death among women in the US. The rates of breast cancer have increased by 0.5% over recent years. However, the rates of death caused by this cancer have steadily decreased, which can be attributed to better screening and improved, targeted therapies. RELATED: Guide to Breast Cancer
Breast cancer cells carry many proteins on their surfaces, some of which contribute to their growth and progression. Estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor-2 (HER2) are three such proteins. ER and PR bind estrogen and progesterone, two hormones that play a role in breast cancer development. If the cancer cells carry both these proteins, it is collectively called hormone receptor-positive (HR+). The growth of such cancers can be controlled with hormone or endocrine therapies (ET), such as Tamoxifen. Tamoxifen binds to ERs, preventing it from interacting with estrogen. This prevents the breast tumor cells from growing and multiplying.
Increased expression of the HER2 protein is associated with rapid cancer growth. Such cancers tend to be aggressive, however, they can be targeted very effectively by chemotherapy drugs like Herceptin.
How Does Camizestrant Work?
Camizestrant belongs to a class of drugs called selective estrogen receptor degraders (SERDs). SERDs bind to the ER, causing the receptor to become unstable. The receptor is then degraded, and the cell can no longer bind to estrogen, which is needed for growth. Lacking the estrogen stimulus, the tumor cells cannot grow or divide.
SERENA-2 trial is a phase II clinical trial, designed to test whether camizestrant has a therapeutic benefit or not. This trial enrolled 240 postmenopausal women with ER+, HER2- breast cancers who had received one prior endocrine therapy and one chemotherapy for their advanced, metastatic tumors. These women were split into three groups. Two groups received camizestrant at doses of 75 mg and 150 mg respectively. The third group received fulvestrant, which is another SERD that has been in clinical use for a few years.
The investigators studied measured progression-free survival (PFS), which represents the time a patient is alive without a worsening of their disease. The PFS was 7.2 months and 7.7 months for patients who received camizestrant at 75 mg and 150 mg respectively. PFS for those who received fulvestrant was 3.7 months.
Patients were further divided into two groups for analysis, those with detectable estrogen receptor (ESR1) mutations and those without. Those with the mutation, a total of 83 patients, had a PFS of 6.3 months, 9.2 months, and 2.2 months with 75 mg camizestrant, 150 mg camizestrant, and fulvestrant respectively. Those without the mutation benefitted less from camizestrant, but their PFS was still better with camizestrant than fulvestrant.
Not Without Side Effects
Camizestrant is overall well-tolerated by patients. However, it does carry some side effects. Common side effects include nausea, visual disturbances, and decreased heart rate.
Overall, 52.7% of patients in the 75 mg group, 67.1% of the patients in the 150 mg group, and 17.8%% of the patients in the fulvestrant group experienced at least some side effects. 1.4% and 2.7% of the patients receiving camizestrant at doses of 75 mg and 150 mg experienced significant side effects. Similarly, 1.4% of the patients receiving fulvestrant experienced significant side effects.
What Does The Future Hold
While the data are encouraging, camizestrant has not yet proven its mettle in phase III clinical trials, which constitute the highest level of evidence for the efficacy of a treatment. AstraZeneca has a few phase III trials underway, including the SERENA-6 trial which will pit camizestrant and cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors against aromatase inhibitors (a form of endocrine therapy), such as anastrozole, in patients with HR+ metastatic breast cancers with detectable ESR1 mutations. CDK 4/6 proteins control the growth of breast tumors and inhibiting them can have potent anticancer effects.
Once the results of the phase III trials become available, camizestrant will likely gain fast-track approval from the U.S. Food and Drug Administration and be available for all patients across the country.