Breast cancer is one of the most common forms of cancer in women across the world. The World Health Organization (WHO) says that it is the most common cancer in women in 157 out of 185 countries. In 2022, nearly 2.3 million women were diagnosed with breast cancer and 6,70,000 died of the condition. Breast cancer occurs when cancerous cells in your breasts multiply and become tumours. About 80% of breast cancer cases are invasive, which means a tumour may spread from your breast to other areas of your body.
For treatments for breast cancer, doctors use anti-estrogen medication since most breast cancers are estrogen-receptor (ER) positive. However, these medications tend to cause some side effects which include hot flashes, joint and muscle pain, and potential bone loss. Researchers for the PIONEER trial, led by those from Cambridge, United Kingdom, found that artificial progesterones, such as megestrol acetate, which help to fight these side effects, can slow the growth of ER-positive breast tumours. The study was published in Nature Cancer.
The researchers found that when megestrol was given along with estrogen-inhibitor letrozole, the rapid growth of cells in the tumors was slowed, even at low doses of megestrol.
Anti-estrogen therapy such as letrozole is a common secondary treatment option for ER-positive breast cancer. This therapy is predominantly prescribed to post-menopausal women following their initial breast cancer treatment, such as surgery, chemotherapy, or radiation. Letrozole works by potently inhibiting the aromatase enzyme, which lowers the levels of estrogen produced in fatty tissues and other peripheral sites within the body. Earlier studies have demonstrated its efficacy, showing substantial reductions in the risk of breast cancer recurrence and improvements in overall patient survival rates.
However, this treatment too has its own challenges, as it frequently induces adverse effects that closely mimic the symptoms of natural menopause in a significant number of women. Common complaints include debilitating hot flashes, persistent joint and muscle pain, reduced bone mineral density that increases osteoporosis risk, and elevations in cholesterol levels that could lead to cardiovascular issues over time.
To mitigate some of these side effects, especially the hot flashes, doctors may prescribe megestrol acetate, which is a synthetic form of progesterone. Multiple studies have shown that even relatively low doses of megestrol acetate can significantly decrease the frequency and severity of hot flashes among people undergoing letrozole therapy.
In the PIONEER trial, researchers enrolled 244 women diagnosed with early-stage ER-positive breast cancer across 10 hospitals in the United Kingdom. Participants were randomly assigned to one of three groups prior to their scheduled breast cancer surgery.
- Group A included 62 participants who received letrozole alone.
- Group B included 91 participants who received letrozole along with 40 mg of megestrol.
- Group C included 91 participants who received letrozole along with 160 mg of megestrol.
Among those who began the treatment, 198 individuals successfully completed the two-week course, providing tumour samples that were adequate for evaluating proliferation markers, which measure cell growth and replication rates.
The researchers, in their analysis, observed that adding megestrol acetate substantially amplified the anti-proliferative effects of letrozole on tumour cells. This benefit was seen with both the higher (160 mg) and lower (40 mg) doses of megestrol, revealing no meaningful difference in efficacy between the two megestrol groups.
While megestrol proves valuable in reducing hot flashes for many letrozole users, it has its own set of potential side effects, such as unwanted weight gain, increased blood pressure, paradoxical hot flashes, shortness of breath, facial swelling or puffiness, and a heightened risk of blood clots.
The trial's key insight that the lower 40 mg dose matched the high dose in slowing tumor proliferation suggests patients could get megestrol's anti-cancer benefits along with a reduced likelihood of severe side effects. Given that these therapies often continue for 5 to 10 years, reducing side effects is important as it can help them continue the medication.
Dr. Richard Baird, corresponding author, Department of Oncology at the University of Cambridge and Honorary Consultant Medical Oncologist at Cambridge University Hospitals NHS Foundation Trust, said, "The results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect."
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