Pretreatment DCE-MRI Resolves Response Quality Within Pathologic Endpoints in Neoadjuvant Breast Cancer

Pathologic complete response (pCR) is a strong neoadjuvant endpoint, yet 5-15% of complete responders recur and clinical/genomic variables do not reliably identify them. We tested whether pretreatment dynamic contrast-enhanced MRI entropy - intratumoral enhancement heterogeneity - resolves response quality hidden within pCR and residual cancer burden (RCB). Across four cohorts (1,200 patients), a prespecified entropy threshold defined favorable and adverse structural states. Crossing structure with pathology yielded a four-tier framework spanning 4.1-fold recurrence in I-SPY1 and 7.7-fold at response extremes. In I-SPY2, 55 of 219 complete responders (25.1%) were structurally adverse, pretreatment. In an external HER2-positive responder synthesis (I-SPY1 pathology-confirmed pCR plus UCSF best-response proxy; n = 33, 10 events), adverse structure was associated with higher recurrence risk (HR = 2.87, 95% CI 1.38-5.96) capturing 7 of 10 recurrences, enriching rather than determining risk. In a HER2-positive RCB-0 subset, recurrence was 12.5% with favorable and 80.0% with adverse structure; Firth Cox regression preserved the association (HR = 8.13, 95% CI 1.71-49.21; n = 21, 6 events). In Duke (n = 908; 76 events), favorable structure remained independently associated with lower distant-recurrence risk (adjusted HR = 0.61, 95% CI 0.41-0.91). RNA linked favorable structure to a directionally reproduced immune-architecture program among non-overlapping patients within ISPY2; EMT-pathway enrichment was favorable-side, while the adverse tier contained a broadly immune-depleted substate. Yet full-cohort RNA models weakly discriminated structural state and did not recover continuous entropy. Pretreatment MRI therefore does not replace pCR or RCB; it reveals response-quality differences that these endpoints compress and identifies a recurrence-enriched group for prospective validation.