Miguel Bronchud, Co-Founder and Advisory Board at Regenerative Medicine Solutions, shared a post on LinkedIn:
“What role in breast cancer therapy for ‘oral selective estrogen receptor degraders’ (SERD)? Adjuvant in pre- or post-menopausal? Monotherapy in early stages and combined with CDK- inhibitors in RE+ metastatic disease? How long and what dose? When are stage IV patients? First line or second lines? Only for ESR-1 mutations?
These are some of the questions that require meaningful answers in recent or current clinical trials. The truth is that new molecular versions of these SERD drugs are very promising.
Some 2 decades ago I asked my friend and colleague Craig Jordan (English born ‘father of Tamoxifen’ in breast cancer – while in Manchester, UK and then professor of oncology in several prestigious institutions in the USA) to write a short review for my book ‘Principles of Molecular Oncology’, 3rd edition 2008, published by Humana Press NJ and distributed eventually by Springer NY.
It has been known for over a century that the steroid hormone estrogen is the primary promotional factor in breast cancer.
Epidemiologic evidence has shown that a woman’s overall lifetime exposure to endogenous estrogen, increased by early menarche, late menopause, and nulliparity, is a primary risk factor for developing breast cancer
In 1896, George Beatson demonstrated that removal of the ovaries from a premenopausal woman with breast cancer could lead to a dramatic improvement in the course of her metastatic disease.
However, by 1900, Stanley Boyd had demonstrated, in perhaps the first clinical trial, that only one in three premenopausal women could anticipate disease control after oophorectomy. The reason for this conundrum, now known to be the selective hormonal sensitivity of breast cancer, would not be discovered until 60 years later, when Jensen and Jacobson described the target-site specificity of estradiol in the immature rat.
Their classic experiment showed that after an injection of [3H]estradiol, the radioactive steroid was bound to and retained by known estrogen target tissues, such as the uterus, vagina, and pituitary gland. I still remember, as a student, the excitement when this breakthrough happened.
By contrast, estradiol was not retained by nontarget tissues, such as skeletal muscle. These observations led Jensen to postulate that an estrogen receptor (ER) present in estrogen target tissues must sequester the steroid specifically and initiate the cascade of biochemical events associated with estrogen action in that tissue. Increased estrogen exposure is the most important risk factor for the initiation and progression of breast cancer.
Therefore, ER-α and ERβ, which mediate estrogen action, have been well studied as both predictors of hormone sensitivity in breast cancer and crucial targets for anticancer drugs.
SERD history began with early failures in the 1990s, leading to the breakthrough FDA approval of the first-gen injectable fulvestrant (Faslodex) in 2002 for advanced breast cancer, a pure estrogen receptor (ER) blocker that destabilizes and degrades the receptor. This drug I found particularly useful in first-line therapy of metastatic breast cancer patients with cognitive impairment (unable to remember their daily tablets) or to ensure compliance in Alzheimer’s disease. It was also useful as 2nd or 3rd line in other breast cancer patients (male and female), but had the inconvenience of IM injections.
Subsequent research focused on :
- AZD9496, GDC-0810: First-gen oral SERDs with acrylic acid side chains, mostly discontinued for lack of efficacy compared to fulvestrant.
- Elacestrant (Orserdu): Became the first FDA-approved oral SERD in 2023, particularly effective in patients with ESR1mutations.
- Imlunestrant: Another promising oral SERD showing strong activity against mutated ER, improving on fulvestrant’s degradation of mutant receptors.
- Camizestrant, Giredestrant: Next-gen oral SERDs in advanced trials, showing broad efficacy and potential to overcome resistance.
Though SERDs are often said to be associated with better tolerance and fewer side effects, Bradycardia—a known class effect of oral SERDs, according to Dr. Bardia—was higher in the giredestrant arm, at 11.3%, than in the standard-of-care arm, at 3.2%.
Most cases were grade 1, asymptomatic, and nonserious, not requiring treatment interruption/discontinuation.
Grade 2 adverse events (< 1%) were confounded by concurrent conditions/antihypertensives, and all resolved. Treatment discontinuations due to treatment-emergent adverse events were numerically lower in the giredestrant arm, at 5.3%, than in the standard-of-care endocrine therapy arm, at 8.2%.
‘For more than a quarter of a century, tamoxifen and aromatase inhibitors have remained the standard endocrine therapy option for patients with early breast cancer,’ said Dr. Bardia. ‘Results from lidERA demonstrate clinical superiority of giredestrant to tamoxifen and aromatase inhibitors, placing giredestrant as a new standard in endocrine therapy for patients with early-stage, hormone receptor–positive, HER2-negative breast cancer.’
The study’s limitations include limited follow-up and immature overall survival data.
Disclosure: The study was funded by F. Hoffmann-La Roche Ltd.”
Title: Estrogen receptor pathways and breast cancer
Authors: Jing Peng, V. Craig Jordan
You can read the Full Article in the Principles of Molecular Oncology.
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