Discussion
tumor, ER+/HER2− primary breast cancer, breast tumors, cancer, giredestrant reduced tumor, ER+ breast cancer
TUMOR, BREAST TUMORS, INVASIVE BREAST CANCER, BREAST CANCER, CANCER, MINOR, DISEASE
The findings of AMEERA-4 indicate that both amcenestrant and letrozole have antiproliferative activity in participants with previously untreated ER+/HER2− breast tumors and high baseline Ki67 scores. Most participants had at least a 50% reduction in Ki67 after 14 days’ treatment. The reduction in Ki67 was numerically greater with letrozole compared with that in either of the amcenestrant treatment groups. As predicted by its mechanism of action, amcenestrant produced marked reductions in ER H-scores, whereas letrozole was associated with only minor reductions. PgR H-scores were also reduced, which was expected from the relationship between ER signaling and PgR expression, and consistent with previous findings [There are several oral SERDs currently in clinical development for ER+/HER2− breast cancer, of which elacestrant (RAD1901), camizestrant (AZD9833), giredestrant (GDC-9545), and imlunestrant (LY3484356) are now in Phase 3 trials. Interim results from the first 46 patients in a WOO study of giredestrant (10 mg, 30 mg [the dose being studied in Phase 3 clinical trials], or 100 mg once daily for 14 days) administered to postmenopausal women with newly diagnosed ER+/HER2− breast cancer showed that, overall, giredestrant reduced tumor Ki67 expression by 79% [Differences in study design and population may explain why giredestrant had a greater antiproliferative effect than anastrozole in coopERA, whereas the effects of amcenestrant and letrozole appeared comparable in AMEERA-4. The choice of comparator (anastrozole in coopERA; letrozole in AMEERA-4) may be relevant, but a previous WOO study in patients with ER+ invasive breast cancer found that anastrozole 1 mg and letrozole 2.5 mg (both once daily) were similarly effective in suppressing Ki67 after 14 days [An alternative explanation is that baseline median Ki67 scores were higher in coopERA than in AMEERA-4 despite a lower inclusion threshold (≥ 5% in coopERA, vs. ≥ 15% in AMEERA-4). Baseline median Ki67 in coopERA was 32.6% among giredestrant recipients and 39.6% among anastrozole recipients [WOO studies of camizestrant and elacestrant are ongoing, with no results released to date. SERENA-3 (NCT04588298) is investigating the effects of 5–7 days’ treatment with 3 different doses of camizestrant on ER H-scores and Ki67 in 132 women with ER+/HER2− primary breast cancer [Although WOO studies do not have therapeutic intent, the potential clinical utility of Ki67 response to neoadjuvant endocrine therapy (fulvestrant, anastrozole, or both in combination) in patients with ER+ breast cancer is being investigated in the ALTERNATE (Alliance A011106; NCT01953588) trial [Our study has several limitations, not least of which is the early termination of the trial and the resulting absence of formal inferential statistical analyses. WOO studies are primarily intended to provide information about the pharmacologic effects of new treatments, and as such no definitive conclusions can be drawn about the clinical efficacy or safety of amcenestrant. Additionally, we studied amcenestrant in postmenopausal women with luminal B-type cancer; thus, the results should not be generalized to premenopausal women or those with other disease subtypes. Lastly, the clinical development of amcenestrant has been discontinued, limiting the applicability of the results. However, the study design also has strengths. Although it was an open-label trial, potential bias was reduced by using centralized randomization and masking the histopathologists who assessed the primary endpoint (Ki67) to treatment allocation. The prospective, controlled trial design provides reassurance that the effects on tumor biology were real rather than chance occurrences. Moreover, the multinational, multicenter design of the study reduced potential bias associated with center-specific factors.