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589 Background: Endocrine therapy (ET) is the therapeutic mainstay for ER+ BC. Giredestrant is a highly potent, nonsteroidal, oral, selective ER antagonist and degrader (SERD) which has demonstrated robust ER occupancy, is well tolerated, and has previously shown encouraging antitumor activity as monotherapy and in combination with P in metastatic BC. coopERA BC (NCT04436744) evaluated giredestrant in eBC and met its primary endpoint, highlighting superior Ki67 suppression with single-agent giredestrant vs A at Week 2. Giredestrant was well tolerated. Here, we report the final analysis. Methods: Eligible patients (pts) with measurable ER+/HER2– untreated eBC and baseline Ki67 score ≥5% (202 planned) were randomized 1:1 to receive, on Days 1–14 of a neoadjuvant window-of-opportunity phase, 30 mg oral daily (PO QD) giredestrant or 1 mg PO QD A followed by a 16-week neoadjuvant phase of QD giredestrant or A for four 28-day cycles with 125 mg PO P on Days 1–21. Randomization was stratified by tumor size, baseline Ki67 score, and progesterone receptor status. Endpoints assessed here included Ki67 suppression from baseline to surgery, complete cell cycle arrest (CCCA; Ki67 ≤2.7%) at surgery, objective response rate (ORR), and safety. Results: At final analysis (cutoff: Nov 24, 2021), 112 and 109 pts were randomized to the giredestrant and A arms, respectively (median age: 62 years each; stage I/IIa disease: 60% vs 54%). Consistent with the primary analysis, greater suppression of Ki67 was observed at surgery with giredestrant + P (–81% [95% confidence interval (CI): –86%, –75%]) vs A + P (–74% [95% CI: –80%, –67%]). Similarly, greater CCCA was achieved at surgery with giredestrant + P (20%) vs A + P (14%). ORR was similar between the two arms (giredestrant + P: 50% [95% CI: 40%, 60%]; A + P: 49% [95% CI: 39%, 59%]). ET-related adverse events (AEs) were non-serious and occurred at similar rates between the two arms. Related Grade ≥3 AE rates were also similar at 6% each. Interruption/withdrawal of ET due to AEs was low and similar for both arms. Conclusions: In this final analysis of coopERA BC, the greater suppression of Ki67 with giredestrant vs A observed at Week 2 in the primary analysis was maintained at surgery, and safety data remained consistent with the known safety profile of giredestrant. coopERA BC is the first randomized study to show superior antiproliferative activity of an oral SERD (giredestrant) over an aromatase inhibitor (A) in ER+/HER2– eBC; studies are ongoing to further assess giredestrant’s clinical benefit. Clinical trial information: NCT04436744.

In triple-negative breast cancer (TNBC), the pleiotropic NDRG1 (N-Myc downstream regulated gene 1) promotes progression and worse survival, yet contradictory results were documented, and the mechanisms remain unknown. Phosphorylation and localization could drive NDRG1 pleiotropy, nonetheless, their role in TNBC progression and clinical outcome was not investigated. We found enhanced p-NDRG1 (Thr346) by TGFβ1 and explored whether it drives NDRG1 pleiotropy and TNBC progression. In tissue microarrays of 81 TNBC patients, we identified that staining and localization of NDRG1 and p-NDRG1 (Thr346) are biomarkers and risk factors associated with shorter overall survival. We found that TGFβ1 leads NDRG1, downstream of GSK3β, and upstream of NF-κB, to differentially regulate migration, invasion, epithelial-mesenchymal transition, tumor initiation, and maintenance of different populations of cancer stem cells (CSCs), depending on the progression stage of tumor cells, and the combination of TGFβ and GSK3β inhibitors impaired CSCs. The present study revealed the striking importance to assess both total NDRG1 and p-NDRG1 (Thr346) positiveness and subcellular localization to evaluate patient prognosis and their stratification. NDRG1 pleiotropy is driven by TGFβ to differentially promote metastasis and/or maintenance of CSCs at different stages of tumor progression, which could be abrogated by the inhibition of TGFβ and GSK3β.

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