Circulating tumor DNA markers for early progression on fulvestrant with or without palbociclib in ER+ advanced breast cancer
Menée à partir d'échantillons plasmatiques prélevés avant traitement sur 459 patientes atteintes d'un cancer du sein HR+ de stade avancé et incluses dans un essai de phase III évaluant le fulvestrant en combinaison ou non avec le palbociclib, cette étude évalue l'association entre la quantité d'ADN tumoral circulant, des altérations génomiques identifiées dans cet ADN et la survie sans progression
Background : There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i.
Methods : PALOMA-3 was a phase III multicenter double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) versus placebo plus fulvestrant (n = 174) in patients with endocrine pre-treated ER+ breast cancer. Pre-treatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression free survival (PFS) was compared in patients with circulating tumor fraction above or below a pre-specified cut off of 10%, and with or without a specific genomic alteration. All statistical tests were two-sided.
Results : Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (HR = 1.62, 95%CI 1.17–2.24, p=.004) and placebo plus fulvestrant (HR = 1.77, 95%CI 1.21–2.59, p=.004. In multivariable analysis high circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95%CI 1.09–1.32, p<.001, as were TP53 mutation (HR = 1.84, 95%CI 1.27– 2.65, p=.001 and FGFR1 amplification (HR = 2.91, 95%CI 1.61–5.25, p<.001. No interaction with treatment randomization was observed.
Conclusions : Pre-treatment ctDNA identified patients identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.
Journal of the National Cancer Institute , article en libre accès, 2019