Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER plus Advanced Breast Cancer

被引：72

作者：

O'Leary, Ben ^{[1
,2
]}

Cutts, Rosalind J. ^{[1
]}

Huang, Xin ^{[3
]}

Hrebien, Sarah ^{[1
]}

Liu, Yuan ^{[3
]}

Andre, Fabrice ^{[4
]}

Loibl, Sibylle ^{[5
]}

Loi, Sherene ^{[6
]}

Garcia-Murillas, Isaac ^{[1
]}

Cristofanilli, Massimo ^{[7
]}

Bartlett, Cynthia Huang ^{[3
]}

Turner, Nicholas C. ^{[1
,2
]}

机构：

[1] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England

[2] Royal Marsden Hosp, Breast Unit, London, England

[3] Pfizer, New York, NY USA

[4] Univ Paris Sud, Inst Gustave Roussy, Dept Med Oncol, Villejuif, France

[5] German Breast Grp, Martin Behaim Str 12, Neu Isenburg, Germany

[6] Univ Melbourne, Peter MacCallum Canc Ctr, Div Res & Canc Med, Melbourne, Vic, Australia

[7] Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA

来源：

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2021年 / 113卷 / 03期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1093/jnci/djaa087

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment 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 prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided. Results: Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 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 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed. Conclusions: Pretreatment ctDNA 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.

引用

页码：309 / 317

页数：9

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