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Acquired gene alterations in patients treated with ribociclib plus endocrine therapy or endocrine therapy alone using
F André1, N Solovieff2, F Su3
1Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
Background:
A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials.
Patients And Methods:
Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was carried out on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences.
Results:
The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT versus baseline (P = 0.08) was observed. Prevalence of alterations was higher at EOT versus baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar.
Conclusions:
This analysis identified acquired gene alterations in patients with hormone receptor-positive/human epidermal growth factor receptor-2 negative advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-cyclin-dependent kinase 4/6 inhibitor setting.
Insights
Analyzing circulating tumor DNA (ctDNA) in advanced breast cancer patients treated with ribociclib plus endocrine therapy (ET) revealed acquired gene alterations. These findings in RB1, SPEN, and ESR1 may inform future resistance mechanisms and treatments.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Previous research identified baseline markers for ribociclib plus endocrine therapy (ET) sensitivity/resistance.
- This study analyzes paired circulating tumor DNA (ctDNA) samples from baseline and end-of-treatment (EOT) in MONALEESA trials.
Purpose of the Study:
- To investigate acquired gene alterations in ctDNA after treatment with ribociclib plus ET or placebo plus ET.
- To identify potential mechanisms of acquired resistance to CDK4/6 inhibitors.
Main Methods:
- Sequencing of paired baseline and EOT ctDNA samples from 523 patients across MONALEESA trials.
- Analysis using a targeted next-generation sequencing panel and statistical modeling (McNemar test, Bayesian mixed-effects model).
- Focus on genes with >5% alteration prevalence at EOT, adjusting for ctDNA fraction and study differences.
Main Results:
- Increased prevalence of alterations observed at EOT versus baseline in RB1, SPEN, FGFR2 (ribociclib arm), PBRM1 (placebo arm), and ESR1 (both arms).
- RB1 and SPEN alteration increases were specific to the ribociclib plus ET arm.
- Common acquired ESR1 mutations included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC.
Conclusions:
- Acquired gene alterations were identified in patients with advanced HR+/HER2- breast cancer treated with ribociclib plus ET.
- These findings provide insights into acquired resistance mechanisms.
- Data may guide future systemic interventions in the post-CDK4/6 inhibitor setting.
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