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Neoadjuvant Chemotherapy Increases Genomic Radioresistance in Hormone Receptor–positive, Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer: Implications for Radiation Sensitivity Index/Genomic-Adjusted Radiation Dose–Guided Radiation Therapy Personalization

Year: 2026

Type: article

Abstract: Purpose: Adjuvant radiation therapy (RT) improves locoregional control after breast cancer surgery, but dose prescription remains based mainly on clinicopathologic risk rather than individual tumor radiosensitivity. The radiation sensitivity index (RSI) and genomic-adjusted radiation dose (GARD) provide a framework for biologically guided radiation therapy personalization. In the neoadjuvant setting, however, radiosensitivity measured on the diagnostic biopsy may not reflect the residual disease ultimately targeted by adjuvant radiation therapy. Methods and Materials: We analyzed matched pretreatment and posttreatment RNA sequencing data from 2 public cohorts of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer treated with neoadjuvant chemotherapy. The discovery cohort included 16 matched pairs from GSE191127, and the validation cohort included 14 matched HR+/HER2- pairs from GSE309004. The RSI was computed using a 10-gene rank-based model. The ΔRSI was defined as RSI_post - RSI_pre. Immune fractions were inferred using quanTIseq, and the GARD was calculated for START B, RTOG 1005, and FAST-Forward adjuvant radiation therapy schedules. Results: 005). Higher pretreatment M2 macrophage fraction correlated with a larger ΔRSI. The RSI changes translated into heterogeneous GARD dose modifications across fractionation schedules. Conclusions: Neoadjuvant chemotherapy is associated with a reproducible increase in RSI in HR+/HER2- breast cancer, suggesting that residual tumors may become more radioresistant at the genomic level after systemic therapy. A postneoadjuvant chemotherapy RSI warrants prospective evaluation for individualized adjuvant radiation therapy strategies.

Source: Advances in Radiation Oncology

DOI: 10.1016/j.adro.2026.102174

Authors: Pierre Loap, Gilles Crehange, Youlia Kirova

Institutions: Imagerie, Radiothérapie Innovante et médecine des Systèmes, Institut Curie

Language: English

Topic: Breast Cancer Treatment Studies

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,500