Pre-operative hormone treatment for ER+ breast cancer patients
Randomised Phase II Clinical Trial - A pre-operative window study of letrozole plus PR agonist (megestrol acetate) versus letrozole alone in post-menopausal patients with ER-positive breast cancer (PIONEER).
- Breast cancer
Why this trial?
Breast cancer is the most common cancer in women worldwide, and the second-most common cancer overall, with more than 1,676,000 people diagnosed in 2012. Although advances in screening, surgical intervention, radiotherapy and systemic therapies have improved survival, around 522,000 women died from breast cancer in 2012 worldwide.
Around 75% of breast cancers are defined and driven by estrogen receptor (ER) expression. However, clinical outcomes vary considerably, and a proportion of women with early ER+ breast develop drug resistance, and relapse with incurable, metastatic disease. There is an urgent need for better treatment strategies.
The rationale for this study comes from pre-clinical research from Cambridge University. They suggested a fundamental revision of our understanding of the relationship between progesterone receptor (PR) and estrogen receptor (ER) expression in breast cancer cells. In the past, it was assumed that PR expression was a passive by-product of increased ER expression in cancer cells. Now, research suggests that PR expression has a more direct role in controlling ER expression.
Results from studies in mice showed that progesterone, in combination with drugs that block ER, slowed the growth of estrogen-driven breast tumours.
Why this intervention?
A wealth of data already exists confirming the clinical benefit of the addition of megestrol acetate, a semi-synthetic derivative of progesterone, to letrozole in ER+ breast cancer. Overall, 9 trials have reported survival benefit from treatment with megestrol acetate in ER+ metastatic breast cancer. Recently, a study showed that megestrol acetate was effective in patients with ER-positive metastatic breast cancer.
In addition, megestrol acetate is also known to reduce some of the side-effects of hormonal treatments, such as ‘hot flashes’, and could also potentially reduce the number of women who drop out of hormonal treatments and thereby increase their risk of breast cancer recurrence.
The efficacy of letrozole as a single agent has been well established, supporting its current registered use in several stages and types of breast cancer.
This is a randomised phase II trial in early stage, operable ER+ breast cancer. This is a ‘window of opportunity’ trial in which three groups of post-menopausal women will receive two weeks of drug treatment prior to surgery. 189 women will be recruited and treated in 10 UK centres.
The trial will compare biopsy samples taken before and after treatment, to assess whether progesterone (using the repurposed drug megestrol acetate, known as Megace) increases the anti-cancer effect of the standard hormone treatment (letrozole). Two different doses of Megace, with letrozole, will be used and directly compared to letrozole alone.
Should this trial show that Megace has a significant impact on cancer cell growth, it will be followed up with a second trial to assess the longer-term outcomes of Megace as an addition to standard hormonal treatment of ER+ breast cancer.
Results are expect by end 2023.
- Dr Richard Baird, Addenbrooke’s Hospital, Cambridge, UK (Chief Investigator)
- Dr Jason Carroll, Cancer Research UK, London, UK (Co-Investigator)
- Dr Sanjeev Kumar, Addenbrooke's Hospital, Cambridge, UK (Coordinating Investigator until September 2019)
- Dr Rebecca Burrell, Addenbrooke's Hospital, Cambridge, UK (Coordination Investigator from October 2019 onwards)
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
More info on clinicaltrials.gov: NCT03306472
Bines, J., et al. (2014). Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial. Ann. Oncol. 25(4), 831-6. doi:10.1093/annonc/mdu015
Cancer Research UK, Breast cancer survival statistics, Retrieved from https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/survival.
Loprinzi, C.L., et al. (1994). Megestrol acetate for the prevention of hot flashes. N Engl J Med, 331(6), 347-52. doi:10.1056/NEJM199408113310602
Mohammed, H., et al. (2015). Progesterone receptor modulates ERα action in breast cancer. Nature, 523(7560), 313-7. doi:10.1038/nature14583
Morgan, L. R. (1985). Megestrol acetate v tamoxifen in advanced breast cancer in postmenopausal patients. Seminars in Oncology, 12, 43-7. Retrieved from https://www.journals.elsevier.com/seminars-in-oncology
Author: Kristine Beckers (Trial Manager)
Last updated: December 2022.