Chemotherapy Before Radiotherapy in Adjuvant Breast Cancer: The Origins of a Convention and the Case for Revisiting Sequence in the Era of Hypofractionation

Guidelines in early breast cancer place adjuvant chemotherapy before radiotherapy, permit radiotherapy concurrently with endocrine and anti-HER2 agents, but discourage it before or during cytotoxic chemotherapy. This narrative review asks whether that convention remains defensible. Its historical basis, a single randomised trial whose distant-metastasis signal did not survive long-term follow-up, is weaker than is commonly assumed. Its contemporary basis is stronger and is stated here explicitly: an asymmetry of absolute benefit, in which a two-point gain in locoregional control yields roughly half a percentage point of mortality benefit once the EBCTCG four-to-one relationship is applied, whereas degradation of systemic therapy reaches mortality undiscounted. We specify three conditions under which a sequencing change could be justified and note that the absolute loss from a short chemotherapy delay cannot presently be quantified from randomised data. Meanwhile, chemotherapy has lengthened while radiotherapy has contracted to a one- to three-week whole-breast schedule, potentially extended when a sequential tumour-bed boost is required. The retrospective evidence is limited: one cohort offers a hypothesis-generating locoregional signal qualified by an unexpectedly high control-arm event rate and an unplanned subgroup analysis, while another supports only short-term feasibility and tolerability; neither demonstrates benefit in distant control or survival. We further argue that the population in which the question remains clinically live is narrow and probably contracting, since genomic de-escalation withdraws from chemotherapy the phenotypes with the most favourable arithmetic. Adjuvant sequencing is best regarded as an open, testable question within a defined population rather than a general case for change.