Dexamethasone Timing and Infusion Reactions in HER2+ Breast Cancer

Infusion reactions (IRs) remain a persistent clinical challenge in HER2+ breast cancer, especially during initial cycles of monoclonal antibody therapies like trastuzumab and pertuzumab. A new randomized, multicenter trial presented at the 2025 San Antonio Breast Cancer Symposium offers compelling evidence that a simple, low-cost adjustment to premedication timing—administering dexamethasone before HER2-targeted agents rather than after—can substantially reduce IR incidence without adding toxicity.

Reversing the Sequence

In this prospective study, 100 women with early-stage HER2+ breast cancer were randomized to receive dexamethasone either before (experimental group) or after (control group) HER2-targeted infusions. All participants received trastuzumab, pertuzumab, and docetaxel—a combination known to be effective but often associated with IRs.

Results were striking:

• IR incidence dropped from 60% to 24% with pre-HER2 dexamethasone (P < 0.001).
• No grade ≥3 IRs occurred in either group.
• By cycle 2, IR rates fell across both arms to similar levels, suggesting immune adaptation, not differences in protocol.

Timing Matters: Insights from Onset Analysis

Detailed evaluation of the IR onset revealed that most reactions in the control group occurred before dexamethasone was administered. Conversely, in the experimental arm, earlier steroid administration shifted the curve; IRs were less frequent and temporally dispersed, suggesting effective prophylaxis during the critical immune activation window.

These findings underscore the importance of aligning steroid pharmacokinetics with the biologic agents most likely to provoke cytokine release.

Safety Profile: No Tradeoff in Toxicity

The switch in premedication timing had no meaningful effect on overall treatment-related adverse events (TRAEs). Rates were similarly high in both groups (98–100%), a reflection of standard chemotherapy side effects, not steroid timing. Specific IR-related symptoms, including chills, flushing, and vomiting, were notably reduced in the experimental arm.

Importantly, laboratory markers such as neutrophil-to-lymphocyte ratio and liver function tests had no predictive value for IRs, suggesting that individual patient risk is better mitigated through protocol-level interventions rather than baseline stratification.

Practice Implications: HER2 Disease and Beyond

Although guidelines from ESMO and others do not currently recommend corticosteroids for HER2-targeted monotherapy, this trial focused on combination therapy—where dexamethasone is already indicated for docetaxel. Adjusting the sequence rather than introducing new medications represents a pragmatic and actionable solution.

While this trial centers on early-stage breast cancer, the implications may extend to other monoclonal antibody regimens—especially those associated with early IRs, such as rituximab, cetuximab, or immune checkpoint inhibitors. In these contexts, premedication timing is often variable or empirically derived. The straightforward study design can be efficiently reproduced to determine the effectiveness of this simple timing intervention across other immunotherapies and institutions.

Reference
Matsunuma R, Nakagaki S, Nakatani E, et al. Impact of modified dexamethasone administration sequence on infusion reaction incidence on HER2-positive breast cancer: A randomized multicenter trial. Breast Cancer. 2025;32(11):1308-1317. Doi:10.1007/s12282-025-01752-0.