Fulvestrant

Mechanism of Action

Fulvestrant is a novel drug that has shown to be of some use in the management of advanced breast cancer. It acts by binding, blocking, and degradation of estrogen receptors, which in turn leads to the complete cessation of estrogen signaling through the estrogen receptors in the body.[6] Fulvestrant acts as a complete antagonist at the estrogen receptor, compared with the previously used drugs, namely the selective estrogen receptor modulators (SERMs), for example, tamoxifen, which had partial agonist activity. SERMs blocked the cellular E2 mediated activity of AF-2, which lead to inhibition of transcription downstream. However, they did not have enough AF-1 activity, which possibly leads to their partial agonist activity. Fulvestrant blocks both AF-1 and AF-2, blocking the transcriptional activities of both downstream, and leaves no room for estrogen to exert its effects. Therefore, it is a complete antagonist at the estrogen receptor.[6] 

The novel drug has a high binding affinity for the estrogen receptor, almost 89% of estradiol.[6] It binds tightly with the estrogen receptor and inhibits the dimerization of the receptor, thus inhibiting its nuclear localization. This process forms an unstable nuclear complex, which degrades at a rapid pace and causes disintegration of the estrogen receptor itself. Consequently, in addition to its exclusively antagonistic actions at the estrogen receptor, Fulvestrant also causes accelerated degradation of the estrogen receptors throughout the body, leading to a decrease in cellular estrogen receptor alpha levels and inhibiting estrogen signaling the estrogen receptor itself.[6]

Administration

Fulvestrant is available in a pre-filled syringe of 250 mg per 5 mL.[7]

Dosing

For advanced, hormone receptor-positive breast cancer or hormone receptor-positive HER2-negative breast cancer: 500 mg IM, administered as two 5 mL injections, one in each buttock on days 1, 15, and 29, and subsequently once monthly.[7]

For advanced or metastatic disease: Same dosing as above, in combination with ribociclib. If giving with palbociclib or ademaciclib, administer with an LHRH agonist in pre or perimenopausal patients.[7]

In cases of moderate liver impairment, the recommendation is to reduce the dose to 250 mg.

Adverse Effects

Fulvestrant is well-tolerated in most cases, according to multiple clinical trials. The most commonly encountered adverse effects were pain at the injection site and hot flashes. Other common side effects include headache, nausea, vomiting, loss of appetite, constipation, diarrhea, fatigue, abnormal liver function tests, urinary tract infections, and rashes.[8] In one case study, toxic epidermal necrolysis was observed in a woman with ductal carcinoma of the breast five days after the initiation of fulvestrant.[9]

Another study reported vaginitis, weight gain, joint problems, and thromboembolic problems.[10] In a study investigating the role of palbociclib–fulvestrant in hormone-positive advanced breast carcinoma, various hematological side effects were reported, including neutropenia, thrombocytopenia, anemia, and leukemia.[5] Vulvovaginal dryness, pelvic pain, and vasomotor symptoms were observations in yet another study.[11] All of these side effects are comparable to the previously used endocrine medications such as anastrozole fused to treat breast cancer. 

Contraindications

Fulvestrant is contraindicated in women who are pregnant or are breastfeeding. It is also associated with an increased bleeding risk in patients who have a clotting disorder and hence is not indicated in these patients. Low platelet count and liver diseases are also contraindications if present in any patient.[12]

Monitoring

The monitoring of blood levels of fulvestrant is not indicated in most patients because, in its usual dosage, it is not known to cause significant adverse effects. No dose adjustment in renal or hepatic impairment is required, and it does not interact with cytochrome 3A4.[13] Regardless, efforts need to be put in this subject to find out the exact therapeutic index and the toxic dose of the medicine so that clinicians may have a sound protocol to administer the drug, even on a trial basis.

Toxicity

An overdose of fulvestrant is not overly likely as its administration must be by healthcare practitioners in a controlled environment. Thus the toxicity that results from the overdose of fulvestrant has not been reported in studies. However, more research is necessary regarding the development of a protocol in case such an event occurs.

Enhancing Healthcare Team Outcomes

Breast cancer is the most common type of carcinoma in women (aside from skin cancers). Fulvestrant is one of the many medications employed in the treatment of breast carcinoma. All patients with breast cancer should be tested for hormone positivity to determine the role of endocrine therapy in their management. A team of healthcare professionals, which includes nurses, lab technologists, pharmacists, and physicians belonging to all related specialties, should coordinate and formulate the best treatment course appropriate for the stage of this type of cancer. 

Interprofessional communication and care coordination will ensure improved patient outcomes and hence should be encouraged and optimized. An essential aspect of the management of breast cancer is the selection of appropriate treatment modalities; this can be done by clinicians working with other healthcare providers to determine the receptor positivities of the particular tumor. Administration and management/monitoring should use nurses and pharmacists with specialized oncology training. In any case, all patients should receive counseling regarding the clinical benefit and possible toxicities of any medication that the interprofessional healthcare team deems suitable. This will optimize patient results with fewer adverse events. [Level 5]

Multiple trials investigating the effect of fulvestrant in combination with other drugs in patients with hormone-positive breast carcinoma have shown promising results. There is evidence that the 500 mg dose is superior to the 250 mg dose used previously. However, more research is necessary to clarify these dosing parameters. The adverse effects reported are consistent with the side effects observed previously with other endocrine medications. Thus, the efficacy and safety of fulvestrant are well established.[14] [Level 1]