Switching From Aromatase Inhibitor to Faslodex May Overcome Treatment Resistance
Having women switch from the combination of an aromatase inhibitor and Ibrance (chemical name: palbociclib) to Faslodex (chemical name: fulvestrant) and Ibrance as the first treatment for advanced-stage, estrogen receptor-positive breast cancer seemed to overcome treatment resistance caused by ESR1 mutations, according to a French study.
The research was published online on Sept. 29, 2022, by the journal The Lancet Oncology. Read the abstract of “Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial.”
Advanced-stage breast cancer is either locally advanced breast cancer or metastatic breast cancer. Locally advanced breast cancer is breast cancer that has spread to tissue near the breast, but not to parts of the body away from the breast. Metastatic breast cancer is breast cancer that has spread to parts of the body away from the breast, such as the bones or liver.
Estrogen receptor-positive breast cancer and ESR1 mutations
Estrogen receptor-positive, HER2-negative disease is the most common type of advanced-stage breast cancer.
Estrogen receptor-positive cancer cells have estrogen receptors on their surfaces that pick up signals from the hormone estrogen telling the cells to grow.
The ESR1 gene makes a protein that is an estrogen receptor.
Aromatase inhibitors work against estrogen receptor-positive breast cancer by stopping the enzyme aromatase from changing other hormones into estrogen.
There are three aromatase inhibitors used to treat breast cancer:
Arimidex (chemical name: anastrozole)
Aromasin (chemical name: exemestane)
Femara (chemical name: letrozole)
The first treatment for advanced-stage, estrogen receptor-positive breast cancer is usually an aromatase inhibitor and a CDK4/6 inhibitor, such as Ibrance. Kisqali (chemical name: ribociclib) and Verzenio (chemical name: abemaciclib) are the other two CDK4/6 inhibitors used to treat certain hormone receptor-positive, HER2-negative breast cancers.
Research shows that the combination of an aromatase inhibitor and a CDK4/6 inhibitor can help control advanced-stage, hormone receptor-positive, HER2-negative breast cancer long term in many cases.
Still, a number of cancers develop resistance to this treatment. Research suggests that a mutation in the ESR1 gene causes resistance to aromatase inhibitors.
About the study
In this study, called PADA-1, the researchers wanted to see if switching treatment from an aromatase inhibitor and Ibrance to Faslodex and Ibrance, based on increasing blood levels of ESR1 mutations, would offer benefits for people diagnosed with advanced-stage, estrogen receptor-positive, HER2-negative breast cancer.
Faslodex is a type of hormonal therapy called an estrogen receptor downregulator. Faslodex blocks the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. It also reduces the number of estrogen receptors and changes the shape of breast cell estrogen receptors so they don’t work as well. Previous studies have suggested that estrogen receptors produced by a mutated ESR1 gene would be sensitive to Faslodex.
The study was conducted at 83 hospitals in France between March 2017 and January 2019. The study included 1,017 women diagnosed with advanced-stage, estrogen receptor-positive, HER2-negative breast cancer. None of the women had received systemic therapy for advanced-stage disease. The women also had never received an aromatase inhibitor after surgery or had stopped taking an aromatase inhibitor for more than a year before joining the study.
Systemic treatments are treatments that affect the whole body by going through the bloodstream. Chemotherapy medicines, hormonal therapy medicines, targeted therapy medicines, and immunotherapy medicines are examples of systemic treatments.
All the women started treatment with an aromatase inhibitor plus Ibrance.
The researchers monitored ESR1 mutation levels in the women’s blood. They randomly assigned 172 women who had increasing levels of ESR1 mutations without the cancer growing to one of two treatment groups:
84 women continued taking an aromatase inhibitor and Ibrance
88 women switched to Faslodex and Ibrance
After following the women for about 35 months, the researchers checked which treatment combination offered better progression-free survival. Progression-free survival is how long a person lives without the cancer growing.
Among the women receiving Faslodex and taking Ibrance:
cancer grew in 63 of them
one woman died
progression-free survival was about 11.9 months
Among the women taking an aromatase inhibitor and Ibrance:
cancer grew in 69 of them
one woman died
progression-free survival was about 5.7 months
This difference in progression-free survival was statistically significant, which means that it was likely due to the difference in treatment and not just because of chance.
The researchers said the side effects were similar in both treatment groups. Three of the 172 women (1.7%) had a serious side effect.
Among the women taking an aromatase inhibitor and Ibrance:
one woman developed grade 4 neutropenia
one woman developed grade 3 fatigue
Among women receiving Faslodex and taking an aromatase inhibitor:
one woman developed grade 4 neutropenia
Neutrophils are a type of white blood cell. Neutropenia is when you have too few neutrophils. If you have neutropenia, it’s harder for your body to fight bacteria, viruses, and other organisms that can make you sick. If you have grade 4 neutropenia, which is severe, even bacteria that a healthy body tolerates, such as the bacteria in your mouth and intestines, can make you sick.
The follow-up time was not long enough to see if switching from an aromatase inhibitor to Faslodex improved overall survival. The researchers plan to report on that outcome at a later time.
“We found that a switch of the endocrine therapy backbone, after the onset of rising [ESR1 mutation levels] and before clinical tumour progression, significantly improves the progression-free survival among patients with oestrogen receptor-positive HER2-negative advanced breast cancer receiving a first-line therapy with aromatase inhibitor and palbociclib,” the researchers wrote.
What this means for you
If you’ve been diagnosed with advanced-stage, estrogen receptor-positive, HER2-negative breast cancer that has stopped responding to an aromatase inhibitor plus Ibrance, this study offers some promising news.
You may want to talk to your doctor about the results and ask if switching from an aromatase inhibitor to Faslodex makes sense for you and your unique situation.
Learn more about Faslodex.
— Last updated on May 26, 2023 at 4:59 PM