PIONEER: a randomised Phase II trial in early stage, operable ER+ breast cancer patients who will receive two weeks of drug treatment prior to surgery.

Info

Location: Cambridge University/Addenbrokes Hospital
Collaboration: Dr Richard Baird and Dr Jason Carroll.

 

PIONEER 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. The trial will compare biopsy samples, 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.

The rationale for the study comes from pre-clinical research from Cambridge University that suggested a fundamental revision of our understanding of the relationship between progesterone receptor (PR) and oestrogen receptor (ER) expression in breast cancer. In the past it was assumed that PR expression was a passive by-product of increased ER expression in cancer cells, whereas the work of the Carroll Laboratory suggested that in fact PR expression had a more direct role in controlling ER expression. Data from mice showed that progesterone, in combination with oestrogen receptor blocking, could slow the growth of oestrogen-driven breast tumours.

PIONEER is a multi-centre study in the UK, with Cambridge/Addenbrokes, Birmingham and Belfast centres recruiting patients.

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. In addition to its direct action on the growth of tumour cells , Megace is also known to reduce some of the side-effects of hormonal treatments, such as ‘hot flushes’, and therefore it could also potentially reduce the number of women who drop out of hormonal treatments and thereby increase their risk of breast cancer recurrence.

For more information on the rationale for the study: click here.

Professional info

Location: Cambridge University/Addenbrokes Hospital
Collaboration: Dr Richard Baird and Dr Jason Carroll.

 

It has long been known that PR+ expression is a positive prognostic factor in ER+ breast cancer. However, the mechanism underlying this clinically important finding has been unclear. Recent work from the Cambridge lab of Jason Carroll, and published in Nature, has substantially elucidated a mechanism by which the functional cross-talk between ER and PR alters the ER binding to chromatin and therefore substantially alters gene expression. In effect PR switches on genes associated with a better treatment response in ER+ breast cancer.

This new model of ER/PR cross-talk leads directly to the clinical question of whether exogenous progesterone may have an impact on breast cancer outcomes. The PIONEER trial is a randomised ‘window of opportunity’ to explore the effect of megestrol acetate (Megace) on breast cancer proliferation (as measured by Ki67).  Two doses of Megace will be compared, 40 mg and 160 mg, will be combined with standard letrozole treatment and compared with each other against a letrozole only cohort. The primary outcome will be the change of Ki67 staining between baseline and day 15 of treatment.

A positive result from the PIONEER trial will inform the design of a larger adjuvant trial to explore the use of Megace in addition with aromatase inhibitor treatment.

For more information on the rationale for the study: click here.

New publication in Nature Reviews Cancer 'Deciphering the divergent roles of progestogens in breast cancer’, Carroll et al (https://www.ncbi.nlm.nih.gov/pubmed/27885264 - abstract only)