Charlotte Proudhon1,2, François-Clément Bidard3,4,5, Lauren Darrigues6,7,8, Jean-Yves Pierga6,8,9, Alice Bernard-Tessier6, Ivan Bièche8,10, Amanda Bartolini Silveira6, Marc Michel6, Delphine Loirat9, Paul Cottu9, Luc Cabel9,11, Coraline Dubot9, Romain Geiss9, Francesco Ricci9, Anne Vincent-Salomon10. 1. Circulating Tumor Biomarkers Laboratory, Inserm CIC-BT 1428, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France. charlotte.proudhon@curie.fr. 2. INSERM U934 CNRS UMR3215, Paris, France. charlotte.proudhon@curie.fr. 3. Circulating Tumor Biomarkers Laboratory, Inserm CIC-BT 1428, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France. francois-clement.bidard@curie.fr. 4. Department of Medical Oncology, Institut Curie, 35 rue Dailly, 92210, Saint Cloud, France. francois-clement.bidard@curie.fr. 5. UVSQ Paris-Saclay University, Saint Cloud, France. francois-clement.bidard@curie.fr. 6. Circulating Tumor Biomarkers Laboratory, Inserm CIC-BT 1428, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France. 7. Department of Surgical Oncology, Institut Curie, Paris, France. 8. Université de Paris, Paris, France. 9. Department of Medical Oncology, Institut Curie, 35 rue Dailly, 92210, Saint Cloud, France. 10. Department of Biopathology, Institut Curie, Paris, France. 11. INSERM U934 CNRS UMR3215, Paris, France.
Abstract
BACKGROUND: Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. METHODS: ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. RESULTS: Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. CONCLUSION: Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
BACKGROUND: Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. METHODS: ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. RESULTS: Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. CONCLUSION: Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
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