By The ASCO Put up Employees
Posted: 12/9/2021 12:51:00 PM
Final Up to date: 12/12/2021 3:37:06 PM
Amongst sufferers with hormone receptor–optimistic breast most cancers handled with an aromatase inhibitor plus palbociclib, those that displayed a rising ESR1 mutation detected of their blood earlier than illness development doubled their median progression-free survival following a change to fulvestrant plus palbociclib, in accordance with outcomes from the section III PADA-1 medical trial offered by François-Clément Bidard, MD, PhD, and colleagues on the 2021 San Antonio Breast Most cancers Symposium (Summary GS3-05).
“PADA-1 is the primary trial to show that, in most sufferers, resistance-associated mutations within the estrogen receptor gene might be detected and focused earlier than tumor development,” mentioned Dr. Bidard, Professor of Medical Oncology at Institut Curie and Paris-Saclay College. “The trial suggests a statistically and clinically vital profit when fulvestrant is used throughout this very new window of alternative.”
Monitoring ESR1 Mutations
Sufferers with breast tumors that categorical estrogen receptor alpha (ERα) are sometimes handled with aromatase inhibitors, which block the physique’s manufacturing of estradiol, the molecule that prompts ERα and drives tumor development. Lately, research have proven that these sufferers could derive extra profit from concurrent remedy with cell cycle inhibitors corresponding to palbociclib, resulting in the U.S. Meals and Drug Administration approval of the mixture as a first-line remedy in 2017.
Tumors can change into proof against aromatase inhibitors, nevertheless, by mutating ESR1, the gene that encodes ERα, in order that it now not requires estradiol to operate. On this case, PADA-1 reveals that some sufferers can profit from the change to a different medication—corresponding to fulvestrant, which degrades the estrogen receptor—whereas sustaining their remedy with palbociclib.
“Fulvestrant stays efficient towards receptors with these mutations, nevertheless it gives a restricted progression-free survival profit when used as a second-line remedy,” famous Dr. Bidard. “Our purpose was to trace the emergence of ESR1 mutations in sufferers’ blood throughout first-line remedy and act on them as quickly as they appeared, earlier than they led to an precise medical development of the illness.”
Blood-based detection of cancer-associated mutations gives a noninvasive technique of monitoring sufferers for illness development and should predict resistance to an ongoing remedy earlier than it's seen by different detection strategies. One methodology of detecting particular mutations in cell-free DNA harvested from blood is droplet digital PCR (ddPCR), a delicate assay which may determine comparatively small quantities of mutant DNA. Dr. Bidard and colleagues beforehand developed a ddPCR assay for the identification of ESR1 mutations, which they used on this research.
The PADA-1 trial recruited 1,017 sufferers with ERα-positive breast most cancers that had no overexpression of the expansion issue receptor HER2 who had been being handled within the first-line setting with an aromatase inhibitor plus palbociclib. The sufferers supplied blood samples for ESR1 mutation screening each 2 months.
Of the recruited sufferers, 407 skilled illness development within the absence of an ESR1 mutation, and a mutation was detected in 279 sufferers previous to (n = 219) or concurrent with (n = 60) illness development. Solely these with an recognized mutation who didn't expertise concurrent illness development had been randomly assigned both proceed remedy with an aromatase inhibitor plus palbociclib (n = 84) or switched to fulvestrant plus palbociclib (n = 88).
After a median follow-up of 26 months, the median progression-free survival of sufferers who switched to fulvestrant was over twice so long as those that remained on an aromatase inhibitor—11.9 months vs 5.7 months.
Sufferers whose illness progressed after persevering with aromatase inhibitor remedy got the choice to cross over to the fulvestrant arm of the research. Amongst sufferers within the crossover cohort, the median progression-free survival was 3.5 months. This supported earlier research exhibiting a comparatively quick good thing about fulvestrant when used as a second-line remedy, Dr. Bidard mentioned, and emphasised the significance of early detection.
“This focused strategy—after the beginning of the first-line endocrine remedy however earlier than the second line—yields a statistically and clinically vital acquire in progression-free survival,” he mentioned. “That profit may not catch up if you wait, which could justify the adoption of the PADA-1 remedy technique as a legitimate possibility in routine care.”
In line with Dr. Bidard, future instructions embrace studying extra concerning the medical options of ESR1-mutated tumors and making an attempt to foretell which sufferers will develop mutations. He talked about that two different medical trials investigating the efficacy of switching remedy after detection of an ESR1 mutation—the section II INTERACT trial and the section III SERENA-6 trial—are additionally ongoing.
Limitations of this research embrace the truth that the investigators who decided progression-free survival weren't blinded to which remedy arm a affected person was randomly assigned to, and the truth that the ddPCR assay used to detect ESR1 mutations just isn't licensed for medical use in the USA.
Disclosure: This research was funded by Pfizer. Dr. Bidard holds a patent for the ESR1 ddPCR assay used on this research; receives consulting charges from AstraZeneca, Eli Lilly and Firm, Novartis, Pfizer, Radius Well being, Roche Prescribed drugs, and Sanofi; receives charges for different companies from Pfizer and Seagen; and performs contracted analysis for Pfizer, ProLynx Inc., and Seagen.The content material on this put up has not been reviewed by the American Society of Medical Oncology, Inc. (ASCO®) and doesn't essentially mirror the concepts and opinions of ASCO®.