Abstract Background: Chemotherapy-based neoadjuvant treatment in HR-positive (HR+), HER2-negative (HER2-) breast cancer (BC) patients is associated with the lowest pathologic complete response (pCR) rates among all subtypes. However, despite the exquisite hormone sensitivity of these tumors and a more favorable toxicity profile compared to chemotherapy, pCR rates after neoadjuvant endocrine therapy are even lower. Elacestrant, an oral selective estrogen receptor degrader (SERD), has recently demonstrated its efficacy in the metastatic setting. The use of preoperative radiation therapy (RT) has been questioned due to a potential immunosuppressive effect that may be detrimental for tumor control. This potential negative aspect may be circumvented by the introduction of Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR), a novel concept in with each fraction is administrated at least 10-20 days apart, resulting in excellent tolerability and a potential enhancement of anti-tumor immunity. ELIPSE was a window of opportunity trial evaluating the effect of 4 weeks of Elacestrant in postmenopausal women with HR+ HER2- BC amenable to surgery. It significantly reduced Ki67 expression and was associated with a shift towards a more endocrine sensitive and less proliferative phenotype, higher levels of tumor infiltrating lymphocytes (TILs) and increased expression of immune-response genes. The combination with an adaptive, repeated RT strategy such as PULSAR may further enhance the immune response. In this proof-of-concept trial, the primary objective will be to investigate the safety of this combinatory approach, along with a preliminary evaluation of clinical efficacy. Trial design: This is a proof-of-concept phase II trial to assess the safety (as primary endpoint) and clinical efficacy of neoadjuvant therapy with Elacestrant and PULSAR (Fig.1). The study will enroll postmenopausal patients with early HR+ HER2- node positive BC, clinically staged II-III. Considering an overall incidence of acute skin toxicity of 66.5% with whole breast irradiation (WBI), a number of 21 patients is required to obtain an overall rate of 30% with PULSAR combined with Elacestrant. Patients will receive Elacestrant 4 mg orally once daily for 20 weeks and PULSAR on the MRI-based breast gross tumor volume (GTVt), consisting of 10 Gy “pulses” every 4 weeks for a maximum of 5 or less in case of radiologic complete response. Tumor response will be assessed, as compared to baseline, by monthly breast MRI. Surgery will be planned within 6 weeks from the last Elacestrant administration. Patients will then receive adjuvant endocrine therapy with or without CDK4/6 inhibitors as per standard of care and postoperative RT to the locoregional lymph nodes in case of nodal residual disease, if clinically indicated. Clinical trial identification: EU Clinical Trial Number 2025-520762-22-00; NCT Number NCT07005882 Citation Format: L. Visani, C. Becherini, M. Valzano, V. Salvestrini, M. Loi, G. Simontacchi, D. Greto, M. Carracino, M. Pacinico, A. Duatti, C. Mattioli, L. Caprara, C. Bellini, J. Nori, D. Cassetti, L. Orzalesi, S. Bianchi, A. Morandi, L. Livi, I. Meattini. Hormone receptor (HR)-positive HER2 negative breast cancer patients treated with preoperative Elacestrant and PULSAR adaptive radiotherapy: a phase II study (HELP Trial) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-01.
Visani et al. (Tue,) studied this question.