Dynamics and type of ESR1 mutations under aromatase inhibitor or fulvestrant combined with palbociclib after randomization in the PADA-1 trial.

person Luc Cabel Curie Institute, Saint-Cloud, France info_outline Luc Cabel, Suzette Delaloge, Anne-Claire Hardy-Bessard, Fabrice Andre, Thomas Bachelot, Ivan Bieche, Celine Callens, Anne Pradines, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Re Canon, Laurent Arnould, Barbara Pistilli, Florence Dalenc, Renaud Sabatier, Jean-Marc Ferrero, Alain Lortholary, Jerome Lemonnier, Frederique Berger, Francois Clement Bidard

Authors person Luc Cabel Curie Institute, Saint-Cloud, France info_outline Luc Cabel, Suzette Delaloge, Anne-Claire Hardy-Bessard, Fabrice Andre, Thomas Bachelot, Ivan Bieche, Celine Callens, Anne Pradines, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Re Canon, Laurent Arnould, Barbara Pistilli, Florence Dalenc, Renaud Sabatier, Jean-Marc Ferrero, Alain Lortholary, Jerome Lemonnier, Frederique Berger, Francois Clement Bidard Organizations Curie Institute, Saint-Cloud, France, Gustave Roussy, Villejuif, France, Medical Oncology, CARIO - HPCA, Plerin-Sur-Mer, France, Medical Oncology, Centre Léon Bérard, Lyon, France, Department of Genetics, Institut Curie and University of Paris, Paris, France, Curie Institute, Paris, France, Claudius Regaud Institute, Toulouse, France, Department of Medical Oncology, Centre Henri Becquerel, Rouen, France, Eugène Marquis Comprehensive Cancer Center, Rennes, France, Grand Hopital De Charleroi, Charleroi, Belgium, Department of Pathology, Center GF Leclerc, Dijon, France, Breast Cancer Unit, Gustave Roussy, Villejuif, France, Institut Claudius Regaud, Institut Universitaire du Cancer – Oncopole, Toulouse, France, Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France, Centre Antoine Lacassagne, Nice, France, Centre Catherine de Sienne, Hôpital Privé du Confluent, Nantes, France, R&D Unicancer, Paris, France, Institut Curie, Biostatistics Unit, Paris, France, Institut Curie, Paris and Saint Cloud, France Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Pfizer, INCA PRT-K (Grant nb PRT-K19-110) Background: In PADA-1, ER+ HER2- metastatic breast cancer patients who displayed a rising ESR1 mutation in blood (bESR1mut) during a first-line therapy with aromatase inhibitor (AI) and palbociclib were randomized between keeping the same treatment or switching to fulvestrant (FUL) and palbociclib (PAL) (Bidard, Lancet Oncol 2022). In this analysis, we investigated the kinetics of bESR1mut after randomization, under AI+PAL or FUL+PAL. Methods: Patients who had a rising bESR1mut detected and no synchronous disease progression underwent further serial ctDNA analyses at randomization and then every 2 months until disease progression. ctDNA analysis at randomization, i.e. before any change in endocrine therapy, was intended to study the impact of sampling fluctuations – since rising bESR1mut levels were often close to the limit of detection of the assay. bESR1mut detection was performed with droplet digital PCR (Jeannot, Oncogene 2020), while left over samples were subjected to next-generation sequencing, which allowed for bESR1mut typing and clonality assessment (Callens, Anal Chem 2022). Results: 172 patients were randomized in PADA-1 after having a rising bESR1mut and no synchronous disease progression. In these patients, bESR1mut had a median mutant allelic frequency of 0.8 % (range 0.1-25.8%) and a median copy number of 14 copies/ml of plasma (4-1033) on the “rising” sample, with no imbalance between randomization arms. Among them, N=75 (46.6%) had no bESR1mut detected at the repeat blood sample at randomization. Of note, these patients had a lower level of bESR1mut at “rising” compared to those who remained bESR1mut+ at randomization (p=0.01). After treatment start, patients who were switched to FUL+PAL experienced a higher rate of bESR1mut clearance at 2 months, compared to those remaining on AI (70.9% vs 32.8%, p<0.001). bESR1mut clearance at 2 months was associated with longer PFS (HR=0.36 95%CI=[0.25;0.52], p<0.001). The length of bESR1mut clearance was also longer in patients randomized to FUL (median: 7.3 mo 95%CI=[3.7;11.2] vs 1.9 mo 95%CI=[1.8;2.3]; p<0.001). At clinical disease progression, N=62 (83%) and N=49 (73%) patients tested positive for bESR1mut in the AI and FUL arms, respectively. Mutation typing in 95 patients with available material revealed that the Y537S mutation was the most prevalent (N=36, 37.9%), while N=25 (26.3%) and N=18 (69.2%) had polyclonal bESR1mut at time of rising bESR1mut and progression, respectively. The mutation type -including Y537S- and the presence of polyclonal bESR1mut at time of rising bESR1mut did not influence patients’ survival and hazard ratio between arms. Conclusions: bESR1mut ctDNA kinetics support the clinical benefit observed in the FUL+PAL arm over the AI+PAL arm. ESR1 mutation type and clonality did not impact the benefit of the treatment switch. Clinical trial information: NCT03079011.