Acquired gene alterations in patients treated with ribociclib plus endocrine therapy or endocrine therapy alone using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials

Messaggi chiave

• Vengono presentati i risultati di un’analisi condotta su campioni appaiati di DNA tumorale circolante (ctDNA) acquisiti al basale e a fine trattamento (EOT) nell’ambito degli studi MONALEESA-2, -3 e -7.
• L’analisi ha incluso un totale di 523 campioni. All’EOT, 21 geni presentavano una prevalenza di alterazioni >5%, con un aumento della prevalenza rispetto al basale osservabile per RB1, SPEN, TPR, PCDH15 e FGFR2 nel braccio ribociclib, PBRM1 nel braccio placebo e ESR1 in entrambi i bracci. Dopo correzione per la frazione di ctDNA, l’aumento della frequenza di alterazioni a carico di RB1 e SPEN all’EOT è apparso specifico per il braccio ribociclib + endocrinoterapia. D538G, Y537S/N/C/D, E380Q e L536H/P/R/LC sono state le alterazioni di ESR1 più comuni in entrambi i bracci. Non sono state osservate differenze nella prevalenza di mutazioni hotspot di PIK3CA tra il basale e l’EOT.
• I dati presentati contribuiscono alla comprensione dei meccanismi di resistenza acquisita al trattamento con CDK4/6 inibitori (CDK4/6i) in pazienti con carcinoma mammario avanzato HR+/HER2- e rimarcano l’importanza dell’analisi seriale del ctDNA per acquisire informazioni potenzialmente utili a guidare le decisioni di trattamento nel setting post-CDK4/6i.

Abstract

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 performed 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 vs baseline (p = 0.08) was observed.
• Prevalence of alterations was higher at EOT vs 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 HR+/HER2- 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-CDK4/6 inhibitor setting.