Hot flash drug slows tumor growth even at low doses

• Breast cancer is the most common cancer in women in almost all countries around the world.
• Around three-quarters of breast cancers are ER-positive, meaning that the tumors have many estrogen receptors.
• Treatment for these cancers includes anti-estrogen medication, the side effects of which, such as hot flashes, can be combated using artificial progesterones.
• Now, research has found that these artificial progesterones, even at a low dose, also slow the growth of breast tumors.

According to the World Health Organization, more than 99% of breast cancers are diagnosed in women, and less than 1% in men. And it is the most common cancer in women in 157 out of 185 countries, diagnosed in around 2.3 million women around the world each year.

Around 75% of breast cancers are estrogen-receptor positive, with tumor cells stimulated to grow by estrogen, so effective treatment includes anti-estrogen medication. However, this medication can cause uncomfortable side effects similar to those experienced during menopause, such as hot flashes, joint and muscle pain, and potential bone loss.

Now, the PIONEER trial, led by researchers in Cambridge, United Kingdom, has found that artificial progesterones, such as megestrol acetate, which help combat these uncomfortable side effects, have an added benefit — they can slow the growth of ER-positive breast tumors.

The research, published in Nature Cancer, found that when megestrol was given in addition to the estrogen-inhibitor letrozole, cell proliferation in the tumors was slowed, even at low doses of megestrol.

“These findings could have significant clinical impact by improving treatment adherence while positively impacting tumor control. However, further studies will be required to substantiate these claims.”

— Esha Sachdev, MD, breast medical oncologist, of the MemorialCare Todd Cancer Institute at Long Beach Medical Center in Long Beach, CA, not involved in the study.

Anti-estrogen therapy, such as letrozole (sold as Femara in the U.S.) is a common adjuvant (secondary) treatment for ER-positive breast cancer. Prescribed mainly to post-menopausal women after initial breast cancer treatment, it works by reducing the amount of estrogen produced in the body. In studies, it has proven effective in preventing breast cancer recurrence and improving survival.

However, it can cause adverse effects, similar to menopause symptoms, in many women. These include hot flashes, joint and muscle pain, reduction in bone density, and increased cholesterol.

To help combat these effects, women may be prescribed megestrol acetate, a synthetic progesterone marketed in the U.S. as Megace. Studies have shown that even low doses of megestrol can decrease the incidence of hot flashes in people taking letrozole.

In the PIONEER trial, researchers recruited 244 women with early-stage ER-positive breast cancer from 10 UK hospitals. They were randomly divided into 3 groups for drug treatment before surgery for their breast cancer.

• Group A (62 people) received Letrozole alone
• Group B (91) received Letrozole plus 40mg megestrol
• Group C (91) received Letrozole plus 160mg megestrol.

Of those starting the treatment, 198 completed the two-week course and had tumor samples that were suitable for assessment for proliferation (cell growth and replication).

Overall, researchers found that megestrol enhanced the anti-proliferative effect of letrozole. This effect was seen at both the higher and lower dose, with no significant difference between the megestrol groups.

Although it is effective in combating the hot flashes experienced by many people taking letrozole, megestrol can also cause side effects, including weight gain, high blood pressure, hot flashes, shortness of breath, swelling or puffiness around the face, and blood clots. Sachdev explained that these adverse effects are dose-dependent.

Because, in this trial, the lower dose was as effective at slowing tumor growth as the high dose, patients could potentially benefit from megestrol’s anti-proliferative effect while having a lower risk of distressing side effects. As people may have to take these treatments for between 5 and 10 years, reducing side effects is key to helping them continue the medication.

“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.”

— 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.

Although these are promising findings, the study sample was less than 200 people and the treatment was given for only 2 weeks. The researchers emphasize that their results would need to be validated in larger trials before the treatment can be recommended.

“A larger randomised trial would be needed. We don’t currently have funding for this. Hopefully, the wider research community will help take this forward,” Baird told MNT.

Sachdev echoed these comments:

“Several additional studies are needed to strengthen and validate the results from this trial,” she told MNT.

“First, a randomized phase 3 efficacy trial comparing letrozole plus megestrol versus letrozole alone with the primary endpoint of invasive disease-free survival is essential to establishing a new clinical guideline. In the current study, ki67 was used as a primary endpoint, and this is typically not clinically relevant in predicting long-term benefit.”

“Second, a dose-finding study would be valuable since this trial only evaluated megestrol dosing for two weeks. A longer duration is necessary to assess safety and tolerability in conjunction with efficacy,” she added.