A Pre-operative Window Study of Letrozole Plus PR Agonist (Megestrol Acetate) Versus Letrozole Alone in Post-menopausal Patients With ER-positive Breast Cancer

  • STATUS
    Recruiting
  • End date
    Nov 30, 2022
  • participants needed
    189
  • sponsor
    Cambridge University Hospitals NHS Foundation Trust
Updated on 28 January 2021
estrogen
carcinoma
endocrine therapy
progesterone
metastasis
hormone therapy
advanced breast cancer
HER2
progesterone receptor
erbb2
aromatase inhibitor
estrogen receptor
breast adenocarcinoma
letrozole
mammogram
core needle biopsy
invasive carcinoma

Summary

Around 75% of breast cancers are defined and driven by Oestrogen receptor alpha (ER) transcriptional activity. Standard treatment is endocrine therapy however clinical outcomes vary considerably, and a proportion of women with early breast cancer driven by ER transcriptional activity develop drug resistance, and relapse with incurable, metastatic disease.

Historically, PR-positivity was viewed as just a passive consequence of a functional oestrogen receptor, and PR was established as a biomarker of ER functionality in breast cancer. However, recent preclinical discoveries have provided an alternative explanation to the previous over-simplistic assumption, providing new insights into progestogen action and functional 'cross-talk' between ER and PR in breast cancer. In the presence of agonist ligands, progesterone-activated PR causes rapid sequestration of ERa chromatin binding sites in breast cancer cells, resulting in a unique gene expression program that is associated with a good clinical outcomes. This highlights a potential therapeutic opportunity.

The PIONEER trial will investigate the effect of combining megestrol acetate (a progesterone receptor agonist) and letrozole (an aromatase inhibitor) in post menopausal women with early breast cancer. This is a 'window of opportunity' study treating and observing patients in the two weeks prior to definitive surgery. Patients are randomised into one of three arms; one in which the patients receive Letrozole alone; one in which they will receive a combination of Letrozole and low dose Megestrol acetate and the third arm will receive Letrozole and high dose Megestrol acetate. This trial will be open to postmenopausal women with newly diagnosed, untreated ER-positive, HER2-negative, invasive primary breast cancer.

Details
Condition Breast Cancer, Breast Cancer, Breast Cancer Diagnosis, breast carcinoma, cancer, breast
Treatment Letrozole, Megestrol Acetate 40 MG, Megestrol Acetate 160 MG
Clinical Study IdentifierNCT03306472
SponsorCambridge University Hospitals NHS Foundation Trust
Last Modified on28 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Histologically confirmed breast adenocarcinoma
Postmenopausal women
Core biopsy confirmation of invasive carcinoma on core biopsy, T1c, either clinical NX or N0-N3
ER positive (Allred3) and HER2 negative
groups of patients are potentially eligible
Cohort A: Patients whose cancers have been deemed to be operable by the Multi-Disciplinary Team (MDT), with surgery planned for the next 2-6 weeks
Cohort B: Patients with early or locoregionally advanced breast cancer planned for primary endocrine therapy, either in lieu of surgery or as neoadjuvant therapy prior to surgery- such patients must begin PIONEER trial therapy prior to starting any other endocrine therapy
ECOG performance status of 0, 1 or 2
Adequate Liver, Renal and Bone marrow function, defined as
Adequate liver function where bilirubin is 1.5 x ULN
Adequate renal function with serum creatinine 1.5 x ULN
Adequate bone marrow function with ANC 1.0 x 10 _9/L and Platelet count 100 x 10_ 9/L
Written informed consent to participate in the trial and to donation of tissue

Exclusion Criteria

History of hormone replacement therapy in the last 6 months
Previous treatment with Tamoxifen or an aromatase inhibitor in the last six months
Known hypersensitivity or contraindications to aromatase inhibitors or Megestrol acetate
Known allergy to lactose
Known to have a progestogen-containing intrauterine system in situ, unless removed prior to randomisation
Known metastatic disease on presentation
Recurrent breast cancer (patients with a new primary invasive breast cancer will be eligible to participate)
Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the trial, at the discretion of the investigator
Treatment with an investigational drug within 4 weeks before randomisation
Inability to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication
Inability to give informed consent
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