Contrary to expectations, TROP2 expression is not a reliable predictive biomarker for response to TROP2-targeting antibody-drug conjugates (ADCs). These drugs have shown activity across various expression levels, challenging the standard biomarker-driven approach to patient selection.
The difficulty in finding a single predictive biomarker for antibody-drug conjugate (ADC) efficacy suggests that complex, multi-marker classifiers, like those in the ISPY 2.2 trial, represent the future for guiding ADC therapy selection over simple IHC cutoffs.
Testing antibody-drug conjugate (ADC) and immunotherapy combinations in the neoadjuvant setting is strategically superior because an intact tumor's antigen load enhances T-cell priming and immunotherapy efficacy, an advantage lost in the post-surgery adjuvant setting.
In clinical practice, the choice between competing post-neoadjuvant antibody-drug conjugate (ADC) trials is often driven by the practical reality of which study is open and geographically accessible, rather than a clear biological signal suggesting one ADC is superior.
For frail, elderly, or low-tumor-burden patients with early-stage TNBC, single-agent ADCs in the neoadjuvant setting are being explored to de-escalate treatment, potentially sparing them the harsh toxicities of standard multi-agent chemotherapy regimens like KEYNOTE-522.
For TNBC patients with a germline BRCA mutation, a completely chemotherapy-free neoadjuvant regimen using an oral PARP inhibitor is showing impressive pathologic complete response rates, potentially transforming the treatment paradigm for this genetically-defined subgroup.