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    Association details:
    Biomarker:ER mutation
    Cancer:Breast Cancer
    Drug:Ibrance (palbociclib) (CDK4 inhibitor, CDK6 inhibitor)
    Direction:Resistant
    Evidence:
    Evidence Level:
    Resistant: B - Late Trials
    Source:
    Ann Oncol
    Title:

    Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL

    Published date:
    12/29/2020
    Excerpt:
    NON-SUPPORTIVE EVIDENCE: In cohort 1 (C1), patients were randomised 1:1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about oestrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2 (C2), in which patients were randomised 1:1 between palbociclib plus fulvestrant and capecitabine....Palbociclib plus ET was not superior to capecitabine in both C2 (median PFS: 7.5 vs. 10.0 months; adjusted hazard ratio [aHR]: 1.13; 95% confidence Interval [CI]: 0.85-1.50) and wild-type ESR1 patients (median PFS: 8.0 vs. 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41)....There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs.
    Secondary therapy:
    exemestane; fulvestrant
    DOI:
    10.1016/j.annonc.2020.12.013
    Trial ID:
    PEARL
    Evidence Level:
    Resistant: B - Late Trials
    Source:
    ASCO 2020
    Title:

    Prognostic and predictive value of ESR1 mutations in postmenopausal metastatic breast cancer (MBC) patients (pts) resistant to aromatase inhibitors (AI), treated with palbociclib (PAL) in combination with endocrine therapy (ET) or capecitabine (CAP) in the PEARL study.

    Published date:
    05/13/2020
    Excerpt:
    PEARL is a phase 3 study with 2 subsequent cohorts: cohort 1 with 296 pts randomized to PAL+Exemestane (EXE) vs CAP and cohort 2 with 305 pts randomized to PAL+ Fulvestran (FUL) vs CAP....No interaction was seen between treatment arm and ESR1 status either for PFS (p = 0.538) or OS (p = 0.957)….In luminal MBC, ESR1-mutated pts had poorer OS than ESR1-WT pts regardless of treatment received.
    Secondary therapy:
    exemestane; fulvestrant
    DOI:
    10.1200/JCO.2020.38.15_suppl.1022
    Trial ID:
    PEARL
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection

    Excerpt:
    ...Incidence of treatment-emergent Adverse Events`To assess whether a change of the hormone therapy associated with palbociclib will benefit patients for whom rising ESR1 mutations are detected during treatment with palbociclib and aromatase inhibitor. ...
    Trial ID:
    PADA-1
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrialsregister.eu
    Title:

    PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection

    Excerpt:
    ...- Hematological safety of patients with bone metastases will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.- Progression-Free Survival (PFS) will be measured from the time of randomization (following rising ESR1 mutation detection) to the time of tumor progression (as assessed by the investigator per RECIST v1.1) or death (whichever comes first) – in randomized patients....
    Trial ID:
    2016-004360-18
    More C2 evidence
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib

    Excerpt:
    ...Assessment of longitudinal changes in allele frequency of ESR1 mutation (mt) in plasma in treated patients. ...
    Trial ID:
    NCT02913430
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Go to data
    Source:
    clinicaltrials.gov
    Title:

    Phase III Palbociclib With Endocrine Therapy vs. Capecitabine in HR+/HER2- MBC With Resistance to Aromatase Inhibitors

    Excerpt:
    ...ESR1 mutational status will be blinded to the patients, investigators and study team.`...
    Trial ID:
    PEARL
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    A Phase I Clinical Trial of FWD1802 in Patients With ER+/HER2- BC.

    Excerpt:
    ...Provision of blood sample to test ESR1 mutation status and for other biomarker assessment....
    Trial ID:
    NCT06064812
    Less C2 evidence
    Evidence Level:
    Resistant: C3 – Early Trials
    Source:
    AACR 2022
    Title:

    4123 / 7 - Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients

    Published date:
    03/09/2022
    Excerpt:
    We obtained Flatiron CGDB Breast Cancer (as of Q3 2020 release) data set. This data set includes clinical and genomic data from 6,918 breast cancer patients. Time to treatment discontinuation (TTD) was used as real world outcome. We performed two types of genomic-outcome association analysis...We found TP53 mutation is associated with shorter TTD for Palbociclib + Aromatase inhibitor (AI); Palbociclib + Fulvestrant; and endocrine monotherapy. 
    Secondary therapy:
    Aromatase inhibitor