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

@article{loap2026neoadjuvant,
  title = {{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}},
  author = {Pierre Loap and Gilles Crehange and Youlia Kirova},
  journal = {Advances in Radiation Oncology},
  year = {2026},
  month = aug,
  doi = {10.1016/j.adro.2026.102174},
  url = {https://doi.org/10.1016/j.adro.2026.102174},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - 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
AU  - Pierre Loap
AU  - Gilles Crehange
AU  - Youlia Kirova
PY  - 2026
DA  - 2026/08/19
JO  - Advances in Radiation Oncology
DO  - 10.1016/j.adro.2026.102174
UR  - https://doi.org/10.1016/j.adro.2026.102174
AB  - 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: In the discovery cohort, the mean RSI increased from 0.602 to 0.677 after neoadjuvant chemotherapy, with 12 of 16 patients (75%) showing a posttreatment increase. In the validation cohort, the mean RSI increased from 0.489 to 0.593 (Wilcoxon P = .014), with 11 of 14 patients (78.6%) showing an increase. In the pooled cohort, the mean ΔRSI was +0.089, and 23 of 30 patients (76.7%) showed an increased RSI after chemotherapy (Wilcoxon P = .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.
SN  - 2452-1094
ER  -