Association of neoadjuvant subcutaneous trastuzumab with higher pathological complete response in HER2-positive breast cancer: a real-world doubly robust study

Randomized trials have demonstrated the non-inferiority of subcutaneous (SC) versus intravenous (IV) trastuzumab. Its association with pathological complete response (pCR) in routine neoadjuvant practice warrants further study. The ability of serial ultrasound measurements to discriminate pCR between administration routes is also uncertain. This single-center retrospective cohort study included 450 patients with HER2-positive breast cancer receiving neoadjuvant trastuzumab (IV, n = 367; SC, n = 83). Inverse probability weighting regression adjustment (IPWRA) was used to reduce confounding by measured baseline variables. An additional baseline body-weight stratified and interaction analysis assessed whether body weight modified the association between administration route and total pCR (tpCR). Serial ultrasound monitoring was evaluated as a secondary radiological endpoint. In the IPWRA model, SC trastuzumab was associated with higher odds of tpCR (odds ratio [OR] 1.79, 95% confidence interval [CI] 1.02–3.14, P = 0.044); the unadjusted tpCR rate was 68.7% in the SC group and 56.1% in the IV group ( P = 0.036). Baseline body weight was comparable between groups, and no significant treatment-route-by-continuous-weight interaction was observed (adjusted interaction P = 0.961). Serial ultrasound showed broadly similar tumor and lymph-node size trajectories between groups at the assessed treatment time points and did not discriminate the difference in final pathological response. In this single-center East Asian real-world cohort, SC trastuzumab was associated with a higher tpCR rate than IV trastuzumab after adjustment for measured baseline variables. The direction of this association was consistent across complementary analyses and, together with randomized non-inferiority evidence, supports SC trastuzumab as a clinically reasonable administration option within dual HER2 blockade. Prospective multicenter validation and longer oncological follow-up are warranted.