A response-adapted and genomically informed strategy to optimize neoadjuvant chemotherapy versus endocrine therapy plus CDK4/6 inhibition in high-risk HR+/HER2− breast cancer.

591 Background: Premenopausal patients with locally advanced hormone receptor–positive, HER2-negative (HR+/HER2−) breast cancer are routinely recommended neoadjuvant chemotherapy (NAC) despite heterogeneous and often limited response. In advanced disease, endocrine therapy (ET) plus CDK4/6 inhibition has replaced chemotherapy as first-line treatment. Whether patients with poor early response to NAC may benefit from chemotherapy-sparing strategies remains unclear. We conducted a prospective response-adapted study integrating early chemosensitivity assessment with exploratory genomic profiling to guide neoadjuvant treatment selection. Methods: A total of 116 premenopausal patients with stage II-III HR+/HER2− breast cancer received two initial cycles of TAC chemotherapy (docetaxel, doxorubicin, and cyclophosphamide). Radiologic response was assessed after two cycles. Patients achieving partial response (PR) continued TAC. Patients with stable disease (SD) were randomized to either continue TAC (NAC) or switch to 16 weeks of ET consisting of dalpiciclib (CDK4/6 inhibitor), exemestane, and goserelin (NET). Whole-exome sequencing was performed in an exploratory subset. The primary endpoint was objective response rate (ORR). Results: After two cycles of TAC, 30 patients achieved PR, while 86 exhibited SD and were subsequently randomized. Among evaluable patients, the ORR was 68.3% in the NET group (41 evaluable patients) compared with 48.7% in the continued NAC group (39 evaluable patients), indicating a higher response rate with NET in tumors demonstrating poor early chemosensitivity. Exploratory genomic analyses further showed that NET-sensitive tumors were predominantly TP53 wild-type and lacked PIK3CA or AKT alterations, consistent with a highly endocrine-dependent biology. In contrast, nonresponders to NET frequently harbored TP53 mutations, often in combination with PIK3CA/AKT pathway alterations, whereas patients who responded to continued chemotherapy commonly exhibited TP53 or TTN mutations, suggesting a chemotherapy-responsive but endocrine-refractory phenotype. Conclusions: Taken together, our findings indicate that in premenopausal patients with stage II-III HR+/HER2− breast cancer who demonstrate suboptimal early response to intensive neoadjuvant chemotherapy, continued cytotoxic treatment may not be optimal for all patients. A response-adapted strategy integrating early functional assessment with genomic features, particularly TP53 and PI3K/AKT pathway status, distinguishes endocrine-sensitive from chemotherapy-sensitive disease. These results provide a biologically informed framework for neoadjuvant treatment selection and support biomarker-enriched randomized trials evaluating chemotherapy-sparing strategies in selected patients. Clinical trial information: NCT06009627 .