Abstract 1023: Ki67-kinetics and tumor biology shifts during neoadjuvant letrozole and ribociclib in ER-pos./HER2-neg. breast cancer: Insights from the NEOLETRIB-trial

Abstract Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have recently transformed the treatment algorithms for hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. This has led to approval in combination with antihormonal therapies for first- and second-line therapy in the metastatic setting as well as in the adjuvant setting. The NEOLETRIB trial investigated the combination of the CDK4/6 inhibitor ribociclib with the aromatase inhibitor letrozole as neoadjuvant therapy in patients will locally advanced HR+/HER2- breast cancer characterized by cT3-cT4 tumors and/or cN2-3 lymph node involvement. This analysis focused on a comprehensive exploration of Ki67 kinetics and biology shifts to improve patient selection. Patients and Methods: NEOLETRIB was a single-arm, multicenter, open-label, phase II neoadjuvant trial enrolling 85 patients who received six cycles of ribociclib (starting dose: 600 mg once daily, 21 days on / 7 days off) combined with continuous letrozole prior to surgery. Ki67 was evaluated on tumor-biopsies obtained at baseline, day 21 of cycles 1 and 6, and at surgery. Thirty one patients from the Akershus cohort were randomly selected for additional Prosigna® testing in order to assess molecular subtype shifts between baseline and surgery. Results: Of 85 patients enrolled in this trial, 4 withdrew consent or were excluded due to screening failure. Complete tumor biopsy sets at all four time points were available from 71 patients. Patients were grouped in mutually exclusive groups based on Ki-67 profiles: Group 1 (Ki67 20% at any timepoint) included 43 patients; Group 2 (Ki67 ≥20% at baseline and 20% later) included 21 patients. Four patients maintained Ki67 ≥20% at both baseline and surgery (Group 3) and 3 patients experienced Ki67 ≥30% at both baseline and surgery (Group 4). A total of 8 patients had Ki67 ≥50% at any given timepoint (Group 5). Among 31 patients analyzed by Prosigna, 9 were classified as Luminal B at baseline, out of whom 8 converted to Luminal A after treatment. Three patients were classified as HER2-enriched at both time points despite having HER2 negative disease by immunohistochemistry routine staining. All three belonged to the high-proliferation (Ki67 50%) subgroup 5. Conclusions: Neoadjuvant treatment with ribociclib in combination with letrozole appears to induce antiproliferative effects and a shift of molecular subtype from Luminal B to Luminal A in the majority of HR-positive, HER2-negative breast cancer patients in this trial. Improved understanding of the Ki67 dynamics and Prosigna-signatures may help identify subgroups of patients who may benefit from neoadjuvant letrozole/ribociclib combination and may potentially inform postneoadjuvant treatment decisions in the long run. Citation Format: Julius Johannes Grindahl Hettich, Kamilla Fjermeros, Stephanie Beate Geisler, Manouchehr Seyedzadeh, Xavier Tekpli, Vessela N. Kristensen, Elin Edda Seland Agustsdottir, Unn-Cathrin Edvardsen Buvarp, Marie Fongaard, Tatiana Bosnjak-Olsen, Oeyvind Sundby, Alina Carmen Porojnicu, Helle Kristine Skjerven, Tone Hovda, Kristine Kleivi Sahlberg, Andliena Tahiri, Torben Lüders, Lilly Anne Torland, Silje Mathiassen, Sofie Flovik Ranestad, John Christopher Noone, Elma Bahonjic Hönigsperger, Clara Hammarstrøm, Jürgen Geisler. Ki67-kinetics and tumor biology shifts during neoadjuvant letrozole and ribociclib in ER-pos./HER2-neg. breast cancer: Insights from the NEOLETRIB-trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1023.