PIONEER trial of new treatment for breast cancer patients

A Cambridge-led trial testing a potential new treatment combination for post-menopausal women with hormone driven breast cancer reports positive findings at the international San Antonio Breast Cancer Symposium.

The PIONEER trial involved nearly 200 post-menopausal women diagnosed with early-stage oestrogen receptor (ER) positive breast cancer.

Exemplifying the close links between researchers and clinicians on the Cambridge Biomedical Campus, the trial – overseen by Chief Investigator Dr Richard Baird at Addenbrooke’s Hospital – was borne out of research from the Carroll Group at Cancer Research UK Cambridge Institute. Further, over 100 of its patient participants were treated for their cancer at Addenbrooke’s Hospital.

The study compared two treatment pathways: i) giving a mimic of the hormone progesterone, called megestrol acetate, in combination with standard hormone therapy, called letrozole and ii) standard hormone therapy alone.

The results show that either a high or low dose of megestrol when given with the standard hormone therapy, letrozole, could be more effective in stopping tumour growth than letrozole alone.

These results will need to be confirmed in larger trials before the treatment is made routinely available.

Megestrol is a readily available treatment taken as a daily tablet and has already been shown to reduce side effects of standard hormone therapy such as severe hot flushes and sweats, when given at low dose.

Dr Rebecca Burrell, who is the lead oncology trainee for PIONEER at Addenbrooke’s Hospital, presented the first results of the trial at the 2023 San Antonio Breast Cancer Conference, the largest global gathering of breast cancer researchers and clinicians.

Dr Richard Baird, consultant oncologist at Addenbrooke’s Hospital and a member of the Cancer Research UK Cambridge Centre’s Precision Breast Cancer Institute, said: “We are excited that the PIONEER trial results suggest that adding low-cost megestrol to standard hormone therapy could make it work better and help with side effects.”

Bench to bedside

The idea for the trial originated from research led by Prof Jason Carroll, Senior Group Leader at the CRUK Cambridge Institute and co-lead of the Precision Breast Cancer Institute.

When breast cancer cells have high levels of the molecule known as ER, it means that the hormone oestrogen fuels the cancer cells to keep growing and dividing. This type of cancer is called ER positive breast cancer.

About 75% of breast cancer cases are ER positive. It is treated with an anti-oestrogen hormone therapy, such as letrozole, to prevent cancer cells responding to oestrogen, thereby slowing tumour growth.

Some breast cancer patients also have high levels of another molecule, known as progesterone receptor (PR), and this group of patients also respond better to the anti-oestrogen hormone therapy.

In order to find out why, the Carroll Group carried out experiments on cancer cells in the lab and discovered that the hormone progesterone stops ER positive cancer cells dividing, by indirectly blocking ER, resulting in slower growth of the tumour. And when mice treated with anti-oestrogen hormone therapy were also given progesterone, the tumours grew even more slowly.

Prof Carroll and Dr Baird went about testing whether the results seen in the lab, published in Nature in 2015, could be replicated in the clinic with breast cancer patients.

PIONEER trial

Together with Dr Sanjeev Kumar, a clinical PhD student, Dr Baird and Prof Carroll devised the PIONEER trial to look at whether giving progesterone to post-menopausal women with early-stage ER positive breast cancer in addition to standard hormone therapy slows the growth of their tumour more than the standard hormone therapy alone. It was a ‘window of opportunity’ trial which means that patients received the trial treatment in the ‘window’ of time – usually 2–3 weeks – between their diagnosis and surgery to remove their tumour.

Patient representatives played an important role in contributing to the trial design and protocol as members of the Trial Steering Committee.

Dr Adrienne Morgan, a breast cancer patient advocate and chair of trustees for the organisation Independent Cancer Patients’ Voice, particularly emphasised the importance of including the lower dose of megestrol in the trial, given its ability to reduce side effects of standard hormone therapy, which is an area of unmet need for breast cancer patients.

She said: “The PIONEER trial is very good news for breast cancer patients. Not only is megestrol safe and can reduce hot flushes, but it also had an anti-cancer effect.”

Julia Loudon, who was treated for ER positive breast cancer at Addenbrooke’s Hospital in 2003 and is a patient governor at Addenbrooke’s, said: “It is so encouraging that the primary endpoint for this study has been met. Anything that has the potential to improve response to treatment in the future is reassuring and of great value to patients.”

With funding from the Anticancer Fund and support from the NIHR Cambridge Biomedical Research Centre, the trial opened in 2017 and continued to recruit during the COVID pandemic, completing recruitment in October 2022.

Dr Gauthier Bouche, director of clinical research at the Anticancer Fund, Belgium, said: “When we read about the results from Prof Carroll’s lab about a low-cost, possibly effective therapy, we realised that philanthropic support was needed to move this research forward. We reached out to Dr Baird and Prof Carroll to express our interest in supporting a clinical trial stemming from this work.”

In addition to the more than 100 patients who took part in the trial at Addenbrooke’s Hospital, there were also participants from Belfast City Hospital, Ninewells Hospital in Dundee, Aberdeen Royal Infirmary and The Royal Cornwall Hospital in Truro.

Although the conference presentation is the first time the PIONEER results have been shared with the breast cancer research community, a full paper is being submitted to a peer-reviewed journal and will be published early next year.

It is hoped that these findings will pave the way for further studies leading to a potential new strategy for improving and personalising treatment for high-risk ER positive breast cancer patients.