Randomised Phase II clinical trial PIONEER- A Pre-operative wIndOw study of Letrozole plus PR agonist (Megestrol Acetate) versus Letrozole aloNE in post-menopausal patients with ER-positive breast cancer

Research summary

Breast cancer is the most common cancer in women worldwide, and the second most common cancer overall, with more than 1,676,000 people newly diagnosed in 2012 (25% of all female cancer cases and 12% of the total). Although advances in screening, surgical intervention, radiotherapy and systemic therapies have improved survival, worldwide approximately 522,000 women died as a result of their breast cancer in 2012.

Breast cancer is a heterogeneous disease and there are many ways to classify it, including using traditional histopathological features, immunohistological and molecular classifications. Around 75% of breast cancers are defined and driven by Oestrogen receptor alpha (ERa) transcriptional activity. A number of established endocrine treatments already exist, including Selective Oestrogen Receptor Modulators (SERMs) such as tamoxifen, Selective Oestrogen Receptor Downregulators (SERDs) such as fulvestrant, and Aromatase inhibitors (AIs) such as Letrozole, anastrozole (both non-steroidal) and exemestane (steroidal). However, clinical outcomes vary considerably, and a proportion of women with early breast cancer driven by ERa transcriptional activity develop drug resistance, and relapse with incurable, metastatic disease. There is an urgent need for better treatment strategies.

The potential clinical significance of exploiting this interaction between ER and PR signaling in breast cancer affords the possibility that the addition of a progesterone agonist might enhance the anti-proliferative effect of anti-oestrogen therapies and therefore prove a more effective combination therapy. A primary rationale for conducting PIONEER, in addition to seeking an increased anti-proliferative effect, is to help decide whether or not there is value in conducting a larger follow-on adjuvant trial investigating the longer-term benefit of the combination of an AI +/- Megestrol acetate, and if so, at what dose of Megestrol Acetate (40mg vs.160mg). A second important rationale for a larger adjuvant trial of combination therapy, is to potentially improve the quality of life of women taking anti-oestrogens, at a time in which the intensity and duration of adjuvant endocrine therapy is increasing. The use of low dose progesterone as a supportive therapy has been shown to completely and rapidly ameliorate anti-oestrogen therapy-related hot flushes in 75-85% of patients. This could hopefully prevent patients from prematurely ceasing their adjuvant endocrine therapy thereby improving clinical outcomes.

This is a three-arm, open-label, multicentre, randomized, window of opportunity, phase II trial which will evaluate the effects of 15 days (+ 4 days) preoperative therapy with Letrozole, or Letrozole plus low dose Megestrol acetate (40mg), or Letrozole plus high dose Megestrol acetate (160mg) in postmenopausal women with newly diagnosed, ER-positive, HER2-negative, invasive primary breast cancer of at least 1 cm size. Patients will be recruited from surgical or oncology clinics with approximately 8-10 participating UK centres. A total of 189 evaluable patients are required. Evaluable patients are defined as eligible patients who have completed at least 13 (or 80%) of the full 15 Day (+≤4 Days) trial dosing schedule. It is anticipated this will require approximately 10% more patients to be randomised, to account for patients that may not be evaluable. The estimated trial duration for each participant is approximately 8 weeks from first contact, including a 15 Day (+≤4 Days) treatment duration and a 2-week post-treatment follow-up visit.

Main inclusion criteria

To be included in the trial the patient must satisfy all of the following:

  1. Histologically confirmed breast adenocarcinoma

  2. Postmenopausal women, defined as having experienced at least one of the following:

    1. 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. ≥50 years, history of vasomotor symptoms) or

    2. six months of spontaneous amenorrhea with serum FSH and oestradiol levels consistent with postmenopause or

    3. surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.

  3. Core biopsy confirmation of invasive carcinoma on core biopsy, ≥T1c, either clinical NX or N0-N3

  4. ER positive (Allred≥3) and HER2 negative

  5. 2 groups of patients are potentially eligible:

    1. 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

    2. Cohort B: Patients with early or locoregionally advanced breast cancer planned for primary endocrine therapy either in lieu of surgery or as neoadjuvant therapy before surgery – such patients must begin PIONEER trial therapy prior to starting any other endocrine therapy.

  6. ECOG performance status of 0, 1 or 2

  7. Adequate Liver, Renal and Bone marrow function, defined as:

  8. Adequate liver function where bilirubin is ≤1.5 x ULN

  9. Adequate renal function with a serum creatinine ≤ 1.5 x ULN

  10. Adequate bone marrow function with ANC ≥1.0 x 109/L and Platelet count ≥100 x 109/L

  11. Written informed consent (IC) to participate in the trial and to donation of tissue

Main exclusion criteria

The presence of any of the following will preclude patient inclusion:

  1. History of hormone replacement therapy in the last 6 months

  2. Previous treatment with Tamoxifen or an aromatase inhibitor in the last six months

  3. Known hypersensitivity or contraindications to aromatase inhibitors or Megestrol acetate

  4. Known allergy to lactose

  5. Known to have a progestogen-containing intrauterine system in situ, unless removed prior to randomisation

  6. Known metastatic disease on presentation

  7. Recurrent breast cancer (patients with a new primary invasive breast cancer will be eligible to participate)

  8. 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

  9. Treatment with an investigational drug within 4 weeks before randomisation

  10. Inability to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication

  11. Inability to give informed consent

Chief investigator

Dr Richard Baird

Contact details

Cancer Theme Email: [email protected]