An analysis of matched genomic data before and after treatment concludes that neoadjuvant chemotherapy is associated with a reproducible increase in radioresistance in hormone receptor-positive, HER2-negative breast cancer. The residual tumour that is later irradiated may therefore be biologically less sensitive to radiation than the one biopsied at diagnosis.
What was known
Adjuvant radiotherapy improves locoregional control after surgery, but dose prescription relies mainly on clinicopathological risk rather than on the individual radiosensitivity of the tumour. Genomic tools can refine that decision: the radiation sensitivity index (RSI), a rank-based model built on ten genes, and the genomic-adjusted radiation dose (GARD), which translates it into a biologically equivalent dose for a given fractionation schedule. The open question was whether radiosensitivity measured on the diagnostic biopsy reflects the residual disease that ultimately receives radiotherapy.
What this work adds
The authors analysed matched pre- and post-treatment RNA sequencing data from two public cohorts of HR+/HER2- tumours: 16 pairs in the discovery cohort (GSE191127) and 14 in the validation cohort (GSE309004), 30 pairs in total. They computed the RSI with the ten-gene model, defined the change (ΔRSI) as the post-treatment minus the pre-treatment value, inferred immune fractions with quanTIseq and calculated GARD for three adjuvant schedules: START B, RTOG 1005 and FAST-Forward.
Main results
In the discovery cohort mean RSI rose from 0.602 to 0.677, and 12 of 16 patients (75%) showed an increase. In the validation cohort it rose from 0.489 to 0.593 (p = 0.014), with 11 of 14 patients (78.6%) moving in the same direction. Across the 30 pairs, mean ΔRSI was +0.089 and 23 patients (76.7%) had a higher RSI after treatment (p = 0.005). A higher pre-treatment M2 macrophage fraction correlated with a larger RSI increase. Dose modifications derived from GARD were heterogeneous across fractionation schedules.
What it means
The study suggests that residual tumours may become more radioresistant at the genomic level after systemic therapy, so planning radiotherapy on diagnostic information could overestimate true sensitivity. The authors note that an RSI measured after chemotherapy warrants prospective evaluation before it is used to individualise adjuvant radiotherapy. As an analysis of small public cohorts, the result is a solid biological hypothesis rather than an immediate change in clinical practice.
Reading from the breast unit
If confirmed, the organisational implication is clear: adjuvant radiotherapy dose and technique should draw on the residual surgical specimen and not only on the initial biopsy, which requires pathology, surgery and radiation oncology to share post-treatment molecular information at the breast multidisciplinary meeting.
Reference: Loap P, Crehange G, Kirova Y. Neoadjuvant Chemotherapy Increases Genomic Radioresistance in HR-positive, HER2-negative Breast Cancer: Implications for RSI/GARD-Guided Radiation Therapy Personalization. Advances in Radiation Oncology, 2026. https://doi.org/10.1016/j.adro.2026.102174
