Cancers

Receptor tyrosine kinase (RTK) signaling is a major driver of oncogenesis and an important target in precision oncology. However, the presence of an oncogenic RTK alteration does not necessarily confer sustained functional dependency on the affected receptor or predict a durable therapeutic response. RTK-targeted therapy can trigger early adaptive signaling responses and, under continued therapeutic selection pressure, promote acquired resistance through compensatory pathway activation, secondary genetic alterations, phenotypic plasticity, and metabolic reprogramming. These processes are further shaped by receptor trafficking, intratumor heterogeneity, and the tumor microenvironment. Although individual resistance mechanisms are increasingly understood, their integration into a unified model of RTK dependency and tumor evolution remains incomplete. Here, we propose a multiscale framework integrating oncogenic alterations, functional signaling dependencies, and their evolution under therapeutic selection pressure. We examine how structural biology, functional genomics, multi-omics, and longitudinal biomarker profiling can characterize RTK activity, functional dependency and emerging vulnerabilities across molecular, cellular, and spatial contexts. We further discuss their potential to inform adaptive therapeutic strategies. This framework positions RTK dependency as a dynamic, context-dependent state rather than an invariant consequence of tumor genotype, highlighting the need to distinguish oncogenic driver status from functional dependency. Integrating genomic, functional, and longitudinal assessments may provide a basis for improved characterization of therapeutic response, evolving resistance, and emerging vulnerabilities in RTK-directed precision oncology.

Background/Objectives: We evaluated the association between early alpha-fetoprotein (AFP) decline and documented disease control during first-line immune checkpoint inhibitor (ICI)-based therapy for unresectable hepatocellular carcinoma (HCC). Methods: This retrospective health-system cohort included treatment initiation during 2020–2026. Eligibility required an exact positive baseline AFP, classifiable AFP measurements during days 14–56, and documented response. The primary exposure was any ≥20% AFP decline; ≥50% was a sensitivity threshold. Response was abstracted from routine imaging reports and oncologist documentation without independent RECIST reassessment. The primary Firth logistic model adjusted for age, performance status, macrovascular invasion, extrahepatic disease, and log baseline AFP. Secondary response, subgroup, and day-56 landmark survival analyses were exploratory. Results: Of 527 distinct patients, 392 met treatment/period/setting criteria and 167 (42.6%) entered analysis. Disease control occurred in 88/167 (52.7%); 68/167 (40.7%) had ≥20% decline. The primary adjusted association was an OR of 3.00 (95% CI 1.40–6.75; p = 0.004; n = 156), compared with an unadjusted OR of 2.29 (95% CI 1.21–4.33; p = 0.011; n = 167). At ≥50%, the adjusted disease-control association was an OR of 3.65 (95% CI 1.46–9.81; p = 0.005; n = 155). The first-draw sensitivity supported the association, whereas the day-21–35 analysis was inconclusive (p = 0.082). The response-after-day-56 analysis included 87 patients. Adjusted objective-response associations differed by threshold (p = 0.002 at ≥20%; p = 0.183 at ≥50%). Conclusions: Early AFP decline was associated with documented disease control among selected patients with reassessment data. Selection, temporal overlap, and potential response misclassification preclude claims of prospective predictive utility. Exploratory survival findings do not establish surrogacy.

Background: FoxP3 and programmed cell death protein 1 (PD-1) are immunoregulatory markers involved in the tumor microenvironment (TME) of Hodgkin lymphoma. Their prognostic significance in classical Hodgkin lymphoma (cHL) remains controversial. Objective: This study aimed to evaluate the prognostic significance of FoxP3- and PD-1-positive immune cells in cHL patients in an Ethiopian cohort. Methods: Clinical records of 68 consecutive patients diagnosed with cHL between 2015 and 2019 were retrospectively reviewed, with follow-up for up to 8 years. Tissue microarray sections were stained for FoxP3 and PD-1 by immunohistochemistry, and positive immune cells were quantified using HALO 2.3 digital image analysis. Overall survival (OS) and event-free survival (EFS) were assessed using Kaplan–Meier analysis and Cox proportional hazards regression. Results: The 5-year overall survival (OS) and event-free survival (EFS) rates were 82.8% and 79.9%, respectively, while the corresponding 8-year rates were 78.6% and 63.1%. Patients in the high-risk modified International Prognostic Score (IPS) group had lower 8-year OS and EFS rates of 63.5% and 45.4%, respectively (p = 0.04). In univariate Cox regression, low lymphocyte count (≤0.6 × 10⁹/L) was associated with inferior OS (HR = 5.1, 95% CI: 1.2–23; p = 0.02) and EFS (HR = 4; 95% CI: 1.3–11.9.0; p = 0.014). High expression of FoxP3 (≥9%) and PD-1 (≥24.6%), defined as categorical variables, were associated with poorer OS, with HRs of 4.3 (95% CI: 1.2–15.7; p = 0.015) and 3.4 (95% CI: (1.1–10.6); p = 0.02), respectively. High-risk IPS (≥3) was associated with inferior OS and EFS (p = 0.04). In multivariable analysis, low lymphocyte count, high FoxP3, and high PD-1 remained significantly associated with poorer OS. Conclusions: High FoxP3 and PD-1 expression, and low lymphocyte count were associated with unfavorable overall survival. However, neither marker (PD1 nor FoxP3) when defined as a continuous variable was significantly associated with OS. These findings require validation in larger independent cohorts.