Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial

Pierga, Jean‐Yves; Ferrero, Jean Marc; Garnier-Tixidré, Claire; Canon, Jean-Luc; André, Fabrice; Arnould́, Laurent; Pradines, Anne; Bièche, Ivan; Callens, Céline; Lemonnier, Jérôme; Berger, Frédérique; Delaloge, Suzette; Bidard, François‐Clément; Pistilli, Barbara; Dalenc, Florence; Bachelot, Thomas; Rouge, Thibault De La Motte; Sabatier, Renaud; Dubot, Coraline; Frenel, Jean‐Sébastien; Ferrero, Jean-­Marc; Ladoire, Sylvain; Lévy, Christelle; Mouret-Reynier, Marie-Ange; Hardy‐Bessard, Anne‐Claire; Lortholary, Alain; Grenier, Julien; Chakiba, Camille; Stefani, Laetitia; Soulié, P; Jacquin, Jean‐Philippe; Plaza, Jérôme Edouard; Clatot, Florian; Teixeira, Luís; D’Hondt, Véronique; Vegas, Hélène; Derbel, Olfa; TIXIDRE, Claire GARNIER; DELBALDO, Catherine; MOREAU, Lionel; CHENEAU, Caroline; PAITEL, Jean-François; SPAETH, Dominique; GENET, Dominique; MOULLET, Isabelle; BONICHON-LAMICHHANE, Nathalie; DEIANA, Laura; GREILSAMER, Charlotte; Vénat-Bouvet, Laurence; DELECROIX, Valérie; MELIS, Adrien; ORFEUVRE, Hubert; Nguyen, Suzanne; Legouffe, Eric; Zannetti, A; SCODAN, Romuald LE; DOHOLLOU, Nadine; DALIVOUST, Philippe; ARSENE, Olivier; MARQUES, Nathalie; Petit, Thierry; MOLLON, Delphine; DAUBA, Jérôme; BONNIN, Nathalie; MORVAN, François; GARDNER, Miriam; MARTI, Adina; Levaché, Charles-Briac; LACHAIER, Emma; ACHILLE, Mihaela; VALMAR, Christophe; BOUAITA, Ryan; Médioni, Jacques; FOA, Cyril; BERNARD-MARTY, Chantal; Piano, Francesco Del; GOZY, Michel; ESCANDE, Anne; LEDUC, Nicolas; LUCAS, Brigitte; MILLE, Dominique; AMMARGUELLAT, Hanifa; NAJEM, Abeer; TROUBOUL, Fanny; Barthélémy, Philippe; DESCLOS, Hervé; Mayeur, Didier; LORCHEL, Fabrice; GUINET, François; LAURENTY, Anne-Pascale; BOUDRANT, Axelle; GISSEROT, Olivier; ALLEAUME, Corinne; GRAMONT, Aimery DE

doi:10.1016/s1470-2045(22)00555-1

Cited by 130 publications

(87 citation statements)

References 16 publications

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“…The first results of this trial have recently been published showing that the early therapeutic targeting of ESR1 mutations in blood results in significant clinical benefit 56 . It is an important study as the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials 56 . In our study, PIK3CA mutations were detected in all patients that later developed metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…This trial has also shown that ESR1 mutations are rarely detected in plasma-cfDNA of ER+ HER2− MBC patients with no overt resistance to aromatase inhibitor and that the detection of ESR1 mutations was associated with a significantly shorter PFS, suggesting that the existence of ESR1 mutation at baseline could accelerate the outset of resistance to AI-palbociclib 55 . The first results of this trial have recently been published showing that the early therapeutic targeting of ESR1 mutations in blood results in significant clinical benefit 56 . It is an important study as the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials 56 .…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive liquid biopsy analysis as a tool for the early detection of minimal residual disease in breast cancer

Stergiopoulou

Markou

Strati

et al. 2023

Sci Rep

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Liquid biopsy (LB) provides a unique minimally invasive tool to follow-up cancer patients over time, to detect minimal residual disease (MRD), to study metastasis-biology and mechanisms of therapy-resistance. Molecular characterization of CTCs offers additionally the potential to understand resistance to therapy and implement individualized targeted treatments which can be modified during the disease evolution and follow-up period of a patient. In this study, we present a long-term follow-up of operable breast cancer patients based on a comprehensive liquid biopsy analysis. We performed a comprehensive liquid biopsy analysis in peripheral blood of 13 patients with early-stage operable breast cancer at several time points for a period of ten years, consisting of: (a) CTC enumeration using the CellSearch system, (b) phenotypic analysis of CTCs using Immunofluorescence, (c) gene expression analysis, in EpCAM(+) CTCs for CK-19, CD24,CD44, ALDH1, and TWIST1, (d) analysis of PIK3CA and ESR1 mutations in EpCAM(+) CTCs and corresponding plasma ctDNA and (e) DNA methylation of ESR1 in CTCs. 10/13 (77%) patients were found negative for LB markers in PB during the whole follow-up period, and these patients did not relapse during the follow-up. However, 3/13(18%) patients that were positive for at least one LB marker relapsed within the follow-up period. The molecular characteristics of CTCs were highly different even for the same patient at different time points, and always increased before the clinical relapse. Our results indicate that liquid biopsy can reveal the presence of MRD at least 4 years before the appearance of clinically detectable metastatic disease demonstrating that a comprehensive liquid biopsy analysis provides highly important information for the therapeutic management of breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive liquid biopsy analysis as a tool for the early detection of minimal residual disease in breast cancer

Stergiopoulou

Markou

Strati

et al. 2023

Sci Rep

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“…There is however a signi cant gap in our current understanding of the connection between adiposity and BC biology in patients, since most of the molecular evidence comes from experimental models 14 . Genomic alterations representing treatment targets or markers of treatment resistance are increasingly used in clinics, such as PIK3CA, ERBB2 and ESR1 mutations, respectively [15][16][17][18] . Still, it is not well understood whether the genomic pro le of a tumor could differ according to the adiposity of the patient.…”

Section: Introductionmentioning

confidence: 99%

Obesity-associated changes in molecular biology of primary breast cancer

Desmedt

Nguyen

Geukens

et al. 2023

Preprint

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Worldwide, there is a growing proportion of women who are overweight or obese. While obesity has been associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet the impact of adiposity (abnormal or excess body fat) on BC biology remains understudied in humans. This retrospective study aimed to investigate how the biology of primary BC would differ according to patients’ body mass index (BMI). We examined clinicopathological data (including BMI at the time of diagnosis) and molecular data (including genomic, bulk and single-cell transcriptomic data) of treatment-naïve (early stage) BC patients from five cohorts (N = 2071). We identified several genomic alterations considered actionable or of potential clinical relevance which had a different prevalence in overweight or obese patients compared to lean patients, for instances, less PIK3CA gene mutations, and more CCND1, CCNE1 and IGFR1 amplifications. Moreover, we found evidence supporting an ageing accelerating effect of obesity at the genetic level, through its association with an age-associated mutational signature. We showed that BMI-associated differences in transcriptomic profile were subtle at the bulk resolution while single cell profiling allowed detection of more pronounced changes in different cell compartments. Investigation at the single cell resolution revealed an elevated and unresolved inflammation of the BC tumor microenvironment (TME) associated with obesity, which had distinct characteristics contingent on the estrogen receptor status. Collectively, analyses at both genomic and transcriptomic levels implied that obesity is associated with an inflammaging-like phenotype of the TME. Our results indicate that patient adiposity might play a significant role in the heterogeneity of BC and should be considered in the context of precision medicine.

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“…PADA-1 assessed the safety and efficacy of combination therapy (endocrine treatment plus a CDK4/6i) among patients who developed ESR1 mutations while receiving aromatase inhibitors in combination with a CDK4/6i. 5 MAINTAIN evaluated the safety and efficacy of ribociclib in combination with endocrine therapy among patients who progressed while receiving the combination of a CDK4/6i and endocrine therapy. 6 Since EMERALD showed head-to-head superiority of elacestrant over fulvestrant used in both PADA-1 and MAIN-TAIN, we hypothesize these new concepts might be successfully addressed using elacestrant as backbone endocrine therapy in combination with other targeted therapies, including CDK 4/6i, phosphatidylinositol 3-kinase inhibitor, and mammalian target of rapamycin inhibitor, and is thesubject of investigation in future planned study.…”

mentioning

confidence: 99%