Response-adaptive breast cancer care in the grey zones: integrating ER and HER2 targeted PET, FDG PET/CT under immunotherapy, and ctDNA kinetics.

Breast cancer management increasingly hinges on decisions made in "grey zones" where tissue sampling is scarce, and tumour biology evolves under therapeutic pressure. This narrative review synthesises evidence on how whole-body imaging biomarkers and circulating tumour DNA (ctDNA) can support response-adaptive pathways at the interface of surgical and systemic care. Four clinically actionable domains are discussed. (a) 16α-[18F]fluoro-17β-estradiol ([18F]FES) positron emission tomography/computed tomography (PET/CT) enables non-invasive, whole-body mapping of functional oestrogen receptor (ER) expression to address receptor discordance, heterogeneous metastases, and selection of endocrine-based strategies. (b) Human epidermal growth factor receptor 2 (HER2)-targeted PET (notably ⁸⁹Zr-trastuzumab, with emerging alternatives) provides whole-body receptor assessment to uncover actionable HER2-positive disease despite HER2-negative primaries, informing anti-HER2 treatment selection when repeat biopsy is infeasible. (c) In triple-negative breast cancer treated with immune checkpoint inhibitors, 18F-fluorodeoxyglucose (18F-FDG) PET/CT offers quantitative response and whole-body burden assessment but requires immunotherapy-aware interpretation (e.g., confirmation strategies for apparent early progression) to mitigate pseudoprogression and dissociated responses, while simultaneously visualising immune-related adverse events. (d) Pairing early metabolic change on FDG PET/CT with ctDNA kinetics is presented as a biologically complementary approach for response monitoring and risk stratification, with potential to inform trial-embedded response-adaptive hypotheses, with ctDNA offering a rapid systemic trajectory and PET providing lesion-level localisation in heterogeneous or oligoprogressive disease. Overall, these tools add value only when linked to prespecified clinical questions and consensus actions; prospective studies are needed to validate standardised, outcome-improving response-adaptive algorithms that integrate imaging and liquid biopsy. Key implementation challenges include tracer availability, harmonised acquisition/reconstruction, threshold definition, and avoiding overtesting. Near-term impact may be greatest in problem-solving and in trial-embedded decision rules that operationalise biomarker-guided care.