Ben O'Leary1,2, Rosalind J Cutts1, Xin Huang3, Sarah Hrebien1, Yuan Liu3, Fabrice André4, Sibylle Loibl5, Sherene Loi6, Isaac Garcia-Murillas1, Massimo Cristofanilli7, Cynthia Huang Bartlett3, Nicholas C Turner1,2. 1. Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. 2. Breast Unit, Royal Marsden Hospital, London, UK. 3. Pfizer, New York, NY, USA. 4. Department of Medical Oncology, Institut Gustave Roussy, Université Paris Sud, Villejuif, France. 5. German Breast Group, Martin Behaim-Strasse 12, Neu-Isenburg, Germany. 6. Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia. 7. Robert H Lurie Comprehensive Cancer Centre, Feinberg School of Medicine, Chicago, IL, USA.
Abstract
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.
RCT Entities:
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 plusfulvestrant (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 plusfulvestrant (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.
Authors: M Cisneros-Villanueva; L Hidalgo-Pérez; M Rios-Romero; A Cedro-Tanda; C A Ruiz-Villavicencio; K Page; R Hastings; D Fernandez-Garcia; R Allsopp; M A Fonseca-Montaño; S Jimenez-Morales; V Padilla-Palma; J A Shaw; A Hidalgo-Miranda Journal: Br J Cancer Date: 2022-01-13 Impact factor: 7.640
Authors: Diana Lüftner; Florian Schütz; Elmar Stickeler; Peter A Fasching; Wolfgang Janni; Cornelia Kolberg-Liedtke; Hans-Christian Kolberg; Christoph Thomssen; Volkmar Müller; Tanja N Fehm; Erik Belleville; Simon Bader; Michael Untch; Manfred Welslau; Marc Thill; Hans Tesch; Nina Ditsch; Michael P Lux; Achim Wöckel; Bahriye Aktas; Andreas Schneeweiss; Rachel Würstlein; Andreas D Hartkopf Journal: Geburtshilfe Frauenheilkd Date: 2022-02-11 Impact factor: 2.915