Micronised Progesterone Adds No Ki67 Benefit to Letrozole in ER+ Breast Cancer

Adding micronized progesterone to letrozole (Femara) for 14 days before surgery did not improve tumor cell proliferation suppression compared with letrozole alone in postmenopausal women with early-stage, estrogen receptor–positive (ER+), progesterone receptor–positive (PR+), HER2-negative breast cancer, according to results of the phase 2 WinPro trial (ACTRN12618000928213) published in npj Breast Cancer.¹

Median Ki67 suppression—the trial's primary end point—was 88.2% with letrozole alone vs 89.2% with letrozole plus micronized progesterone (P =.39). The proportion of tumors achieving complete cell cycle arrest was similarly comparable between the 2 arms (77.6% vs 82.8%, respectively; P =.46). An exploratory arm combining tamoxifen with micronized progesterone showed numerically lower Ki67 suppression (61.5%), but the trial included no tamoxifen monotherapy comparator, limiting interpretation of that finding.

The randomized, multicenter, open-label trial enrolled 244 postmenopausal women across 7 Australian sites between February 2018 and June 2024. Patients were randomized 1:1:1 to letrozole 2.5 mg daily, letrozole plus micronized progesterone 300 mg daily, or tamoxifen 20 mg plus micronized progesterone 300 mg daily for 14 days (±3 days) preoperatively. Of 239 randomized patients, 189 completed treatment per protocol and were evaluable for the primary end point.

On safety, hot flushes occurred less frequently with letrozole plus micronized progesterone (13.3%) than with letrozole alone (22.4%) or tamoxifen plus micronised progesterone (20.5%). However, dizziness was more common in both micronised progesterone–containing arms, and treatment discontinuations due to adverse events were more frequent with the combination regimens: 6 withdrawals occurred in the letrozole-plus-progesterone arm and 2 in the tamoxifen-plus-progesterone arm, compared with none in the letrozole-alone arm. Serious adverse events considered possibly, probably, or definitely related to treatment included 2 transient ischemic attacks in the letrozole-plus-progesterone arm and 1 case of Takotsubo cardiomyopathy in the tamoxifen-plus-progesterone arm; both transient ischemic attacks occurred in patients older than 75 years.

The investigators, led by Lucy Haggstrom, MBBS, of St Vincent's Hospital Sydney, noted several possible explanations for the null primary result. Median Ki67 suppression with letrozole alone (88.2%) exceeded rates reported in prior window-of-opportunity studies, likely reflecting the trial's enrollment criteria, which favored tumors with high baseline ER and PR expression and low baseline Ki67—biology associated with a strong endocrine response and, potentially, a floor effect that reduced the ability to detect additional benefit from micronized progesterone. The authors also noted that the micronized progesterone dose used was based on dosing approved for menopausal hormone therapy rather than one optimized for antiproliferative effect.

The findings contrast with those of the PIONEER trial (NCT03306472), a similarly designed window-of-opportunity study that found adding the synthetic progestin megestrol acetate to letrozole significantly improved Ki67 suppression compared with letrozole alone (80% vs 71%; P =.013).² The WinPro authors suggested that megestrol acetate's additional activity at androgen and glucocorticoid receptors, beyond progesterone receptor agonism alone, may account for the greater antiproliferative effect observed with that agent, compared with micronized progesterone, which is a more selective progesterone receptor ligand.

Limitations of WinPro include the absence of a tamoxifen-only control arm, the short-term, preoperative design (which precludes conclusions about long-term efficacy or safety), and a study population with predominantly high baseline ER expression that may limit generalizability. Analysis of spatial transcriptomic data from trial tissue samples is ongoing and is expected to clarify whether micronized progesterone adequately engaged the progesterone receptor at the dose used.

The authors concluded that although micronized progesterone did not enhance letrozole's antiproliferative activity, the short-term data do not suggest a pro-tumorigenic effect, and the observed reduction in hot flushes may warrant further study of micronised progesterone as an adjunct for managing aromatase inhibitor–related vasomotor symptoms, pending confirmation in trials with longer follow-up.

REFERENCES

1. Haggstrom L, Middleton K, Parker A, et al. The WinPro trial: window-of-opportunity study of endocrine therapy with micronised progesterone in ER-positive breast cancer. npj Breast Cancer. Published online July 21, 2026. doi:10.1038/s41523-026-01008-w

2. Burrell RA, Kumar S, Provenzano E, et al. Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial. Nat Cancer. Published online January 5, 2026. doi:10.1038/s43018-025-01087-x