A recent clinical trial, known as PIONEER, has indicated that megestrol acetate, a synthetic form of progesterone, may enhance the effectiveness of anti-oestrogen therapy in post-menopausal women with estrogen receptor-positive (ER-positive) early-stage breast cancer. The study found that adding low-dose megestrol acetate to standard anti-oestrogen treatment led to a greater reduction in tumor growth rates over a two-week period compared to anti-oestrogen therapy alone.
Context of ER-Positive Breast Cancer Treatment
Approximately three-quarters of all breast cancers are classified as ER-positive, meaning their growth is stimulated by the hormone oestrogen. Standard treatment for these cancers typically involves anti-oestrogen medications, which work by reducing oestrogen levels to inhibit tumor growth. However, these therapies can induce menopause-like side effects, such as hot flushes, joint pain, and potential bone loss. These side effects sometimes lead patients to discontinue treatment. Megestrol acetate is an off-patent drug already used to manage hot flushes associated with anti-oestrogen therapies.
Pre-Clinical Research
Prior to the PIONEER trial, laboratory studies conducted by Professor Jason Carroll's team at the Cancer Research UK Cambridge Institute demonstrated a mechanism by which progesterone could inhibit the division of ER-positive cancer cells. This research indicated that progesterone indirectly blocks the oestrogen receptor, resulting in slower tumor growth in cell cultures and mouse models. The combination of progesterone and anti-oestrogen therapy showed further reduced growth in these models.
The PIONEER Trial Design
The PIONEER trial, led by the University of Cambridge, was designed as a window-of-opportunity, randomized, phase 2b study. It involved 198 post-menopausal women with ER-positive breast cancers, recruited across ten hospitals in the UK, including Addenbrooke's Hospital in Cambridge. Participants were randomized into one of three treatment groups for a two-week period immediately preceding surgery:
- Letrozole (an anti-oestrogen) only.
- Letrozole combined with 40mg of megestrol acetate daily.
- Letrozole combined with 160mg of megestrol acetate daily.
Tumor cell growth rates were assessed at the beginning of the trial and before surgical removal of the tumor. The trial was designed by Dr. Richard Baird and Professor Carroll.
Key Findings
The results, published in Nature Cancer, indicated that both the 40mg and 160mg daily doses of megestrol acetate comparably improved letrozole's ability to inhibit tumor growth. Patients receiving the combination treatment showed a greater reduction in tumor growth rates compared to those treated with letrozole alone. The findings suggested that megestrol acetate may exert a direct anti-cancer effect when used in conjunction with anti-oestrogen therapy.
Dr. Rebecca Burrell, a joint first author on the study, noted that the lower 40mg dose of megestrol acetate achieved similar effects to the higher dose within the two-week observation period. This is considered significant because while a 160mg dose of progesterone is an approved anti-cancer treatment, it is associated with potential long-term side effects such as weight gain and elevated blood pressure. The comparable efficacy of the lower dose suggests a potential for fewer side effects over extended treatment durations.
Implications and Future Research
The PIONEER trial suggests that megestrol acetate could potentially improve the efficacy of anti-oestrogen treatments for ER-positive breast cancer. Given that low-dose megestrol acetate is already used to manage hot flushes, its addition to anti-oestrogen therapy could offer a dual benefit: mitigating treatment side effects and enhancing anti-cancer activity. This dual function could potentially improve patient adherence to therapy and ultimately contribute to better breast cancer outcomes.
Researchers emphasize that these findings require further confirmation through larger clinical trials involving more patients and longer observation periods to ascertain sustained beneficial effects and reduced side-effect profiles over extended treatment durations.
Funding and Support
The research received primary funding from the Anticancer Fund, with additional support provided by Cancer Research UK, Addenbrooke's Charitable Trust, and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.