Low-dose megestrol strengthens hormone therapy for ER-positive breast cancer

Low-dose megestrol strengthens hormone therapy for ER-positive breast cancer

A preoperative study shows that progesterone receptor activation with low-dose megestrol can deepen estrogen blockade and curb tumor proliferation without additional toxicity, suggesting an easier route to strengthening hormonal therapy in ER-positive breast cancer.

Study: Evaluation of the progesterone receptor agonist megestrol plus letrozole in women with estrogen receptor-positive early breast cancer: the phase 2b randomized time-window PIONEER trial. Photo credit: Gorodenkoff/Shutterstock.com

According to the World Health Organization (WHO), breast cancer causes 670,000 deaths each year. Approximately three quarters of these cancers express estrogen receptors (ER), and these are mainly treated with antiestrogens in the adjuvant and metastatic setting. A recent article inNatural cancerreported the PIONEER study, which examined the effect of adding the progesterone receptor (PR) agonist megestrol acetate, a synthetic progestin, to this therapy in a short preoperative window-of-opportunity study.

Reevaluation of progestins after decades of clinical controversy

Antiestrogens such as the aromatase inhibitor letrozole are the first choice for ER-positive breast cancer. Treatment failures and side effects occur that are so serious that treatment must be discontinued. These include unbearable hot flashes and other perimenopausal symptoms.

Some of these could be alleviated by progestins, which act on PR. Megestrol acetate is a progestogen approved for metastatic ER-positive breast cancer at a dosage of 160 mg per day. Potentially dangerous side effects of this high dose include high blood pressure, weight gain, and venous thromboembolism (VTE). Lower doses of megestrol (20 to 40 mg per day) reduce hot flashes in women taking antiestrogens, as shown in previous randomized trials, but are not yet approved for this use.

Some studies suggest that progestins increase the risk of breast cancer. Notably, early data from the Women's Health Initiative on menopausal hormone therapy suggests the progestin medroxyprogesterone acetate. However, 18-year follow-up data showed no difference in all-cause mortality attributable to the addition of a progestin, and the association with breast cancer incidence remains controversial.

Recent studies on combination hormone therapy with gestagens such as dydrogesterone and progesterone contradict this connection. Premenopausal women with higher endogenous progesterone levels have a lower risk of breast cancer.

In vitro breast cancer studies also indicate dramatic shifts in ER-mediated target gene transcription following progesterone exposure. As a result, a combination of antiestrogens with progesterone results in a stronger antiproliferative effect than with either agent alone. This effect could reflect both PR activation mediated by ER reprogramming and PR-ER interactions that reduce ER binding to canonical target genes.

The current PIONEER study, a preoperative study of letrozole plus PR agonist megestrol acetate compared to letrozole alone in postmenopausal women with ER-positive breast cancer, aims to evaluate tumor activity in postmenopausal operable ER-positive human epidermal growth factor receptor 2 (HER2, also known as ERBB2)-negative breast cancer with combined letrozole-megestrol therapy compared Letrozole alone should be investigated. Two doses of megestrol were used, namely the higher 160 mg dose, which is approved as an anticancer drug for metastatic ER-positive breast cancer, and the lower 40 mg dose, which is safer and better tolerated but is not approved as an antiproliferative agent in this disease.

Comparison of low- and high-dose megestrol with letrozole

The PIONEER study randomized 244 participants, 198 of whom were evaluable for the primary endpoint, in a three-arm randomized controlled trial (RCT). The aim was to compare early-stage ER-positive breast cancer treated with letrozole with and without megestrol at a dosage of 40 mg or 160 mg per day. Based on Ki67 expression, tumor proliferation was observed with each alteration, with Ki67 being a protein marker of cell proliferation that serves as an early pharmacodynamic biomarker rather than a clinical outcome.

Study results

Megestrol inhibits proliferation

The combination of megestrol with letrozole was associated with a greater decrease in tumor cell proliferation compared to letrozole alone. This finding persisted even after adjustment for tumor grade. Megestrol dosage did not alter the final antiproliferative effect.

These effects were confirmed using Aurora Kinase A (AURKA) assays, which were highly correlated with Ki67 results. This confirms the alternative use of AURKA as a measure of proliferative activity.

At the end of treatment, mean Ki67 levels were 30% lower with combined letrozole and megestrol treatment than with letrozole alone, regardless of dosage. An excellent treatment response, as indicated by a Ki67 value of 10% or less, was achieved in approximately 65% ​​of participants on letrozole alone, and approximately 80% in the other two combined treatment arms. Similarly, complete cell cycle arrest was observed in approximately 27% of monotherapy recipients, compared to approximately 40% of combination therapy recipients.

Megestrol suppresses PR

Megestrol resulted in PR suppression with comparable efficacy at both doses. Of 196 participants with complete PR data, 174 were PR positive and 25% of these, 44 participants, had less than 1% PR positive cells after completion of treatment. Interestingly, 91% of them received megestrol.

Again, 61% of PR-positive tumors had 10% or more PR-positive cells at the end of treatment, with 66% of these tumors occurring in combination therapy arms. The highest ER-positive and PR-positive expression levels predict exceptional response to aromatase inhibitors based on exploratory subgroup analyzes that outline a subgroup that may not require additional megestrol.

These results highlight the importance of using diagnostic histology from core biopsy rather than surgical histology to guide adjuvant management of preoperative antiestrogen therapy.

Megestrol impairs ER genome binding

Tumor biopsies showed megestrol-induced reduced ER binding at key regulatory ER binding sites adjacent to canonical ER target genes. This resulted in ER repression. This confirms the results of previous preclinical studies and suggests that megestrol activates PR, leading to functional ER suppression and reprogramming; However, independent of the megestrol dosage, additional nuclear receptor-mediated effects cannot be excluded.

Side effects were similar in all three arms; However, the duration of the experiment was too short to allow proper safety assessments. The most common symptoms were joint pain, fatigue, headache and nausea, although taking megestrol caused dry mouth, shortness of breath and vaginal bleeding in 10% or less of recipients. Treatment-emergent hypertension was observed in the 160 mg arm but not in the 40 mg or letrozole monoarm. The postoperative venous thromboembolism rates were not above expected values, but an association with megestrol could not be determined.

Low-dose megestrol reduces hot flashes in women on antiestrogen therapy, as shown in previous studies, promoting adherence and thus improving outcomes. Furthermore, it directly inhibits tumor cell proliferation, most likely through PR activation with downstream repression of ER activity, rather than through PR repression itself, as reflected in short-term biomarker changes.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as abemaciclib are currently routinely used for the adjuvant treatment of high-risk tumors. In cases of poor tolerability or inaccessibility, they could potentially be supplemented or selectively replaced with megestrol in carefully selected patients until long-term clinical benefit is confirmed in future studies, which is also more cost-effective.

Low-dose PR activation enhances endocrine therapy signals

The study suggests that the combination of low-dose megestrol with letrozole increases therapeutic efficacy at the level of tumor proliferation biomarkers. In addition to relieving hot flashes, as previously reported in other studies, thereby improving adherence and improving patient outcomes, it is shown here to have a direct antiproliferative effect mediated by PR activation and ER reprogramming, a hypothesis that needs to be validated in longer-term, outcome-oriented studies.

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