Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights.

Metastatic uveal melanoma (mUM) is a rare disease associated with poor prognosis and limited therapeutic options. Recent studies showed that detecting ctDNA is feasible and can aid treatment decisions for patients with mUM. We systematically searched PubMed, EMBASE, and Cochrane databases for eligible studies published up to May 2025 that included patients with mUM and reported data on the association between ctDNA and survival outcomes (OS and PFS). Statistical analyses were performed using Review Manager 5.4 software. Of the initial 450 records, seven studies met eligibility, including 518 patients with mUM. At baseline, ctDNA positivity was associated with significantly worse PFS (HR 2.34; 95% CI 1.56–3.51; p < 0.01; I² = 0%) and OS (HR 3.32; 95% CI 2.09–5.29; p < 0.01; I² = 48%). In patients treated with tebentafusp, ctDNA clearance was associated with superior OS (HR 0.19; 95% CI 0.07–0.49; p < 0.01; I² = 46%) and any decrease in ctDNA was associated with better OS (HR 0.42; 95% CI 0.22–0.80; p < 0.01; I² = 0%). This meta‐analysis underscores ctDNA as a potential predictor of worse survival in patients with mUM, highlighting its potential to refine risk stratification and guide treatment strategies.Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO): CRD42025638076

Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy, with a high rate of recurrence due to minimal residual disease (MRD). Traditional surveillance methods have limited sensitivity for detecting MRD. ctDNA has emerged as a promising biomarker for real-time tumor monitoring and early detection of MRD. We performed a systematic search of Medline, Embase, and CENTRAL through July 2025. Eligible studies included cohort studies involving adults with EOC that reported ctDNA data, collected post-surgery or after adjuvant chemotherapy. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), were extracted and stratified by ctDNA status (detectable vs. undetectable). All statistical analyses were performed at Review Manager version 5.4. This study is prospectively registered in PROSPERO (CRD420251124631). A total of 1291 records were identified, of which 11 studies met eligibility criteria, encompassing 627 patients with EOC. The pooled analysis showed that ctDNA positivity after surgery was significantly associated with worse PFS (HR 3.83; 95% CI 2.55-5.77; I²= 5% p < 0.01) and OS (HR 2.84; 95% CI 1.22-6.57; I²=0; p < 0.01) compared with ctDNA-negative patients. Similarly, post-adjuvant chemotherapy detection of ctDNA yields worse PFS (HR 4.95) and OS (HR 5.95). Our findings suggest that ctDNA is a novel instrument for MRD detection, and its presence serves as a potent prognostic indicator for recurrence and mortality in ovarian cancer. These results support integrating ctDNA into clinical trial designs and highlight its potential for risk-adapted surveillance and treatment strategies.

Direct Oral Anticoagulants (DOACs) are generally not recommended during breastfeeding due to limited data on milk transfer and potential effects on the infant. The main advantages of DOACs over the other anticoagulants are absence of a need for regular laboratory monitoring, rapid onset of action, fewer drug and food interactions, fixed dosing and short half-life. We conducted a systematic review of published evidence aiming to understand the effects of DOACs in breast milk and the consequences for the breastfed infant. This systematic review was conducted in adherence to the PRISMA. PubMed, Cochrane, and Embase were systematically searched up to June 2025. Data was descriptively synthesized. Of the 301 citations identified, 21 full-text articles were assessed for eligibility and 5 studies met our inclusion criteria. The studies enrolled 12 lactating women and 3 breastfed infants, with infants evaluated only in one case series. For apixaban, a Relative Infant Dose (RID) of 18% and of 12.78% and a milk-to-plasma ratio of 2.61 was observed. Rivaroxaban does transfer into breast milk, but the RIDs in the women were all below 10%. Plasma rivaroxaban concentrations in the infants, measured 2 h after breastfeeding, were below the lower limit of quantification. Dabigatran did not produce a significant impact on neonatal TT, FIIa, or plasma Clauss-fibrinogen levels. Available evidence on the use of DOACs during lactation is extremely limited and of low certainty. Consequently, no definitive conclusions regarding safety or clinical use during breastfeeding can be drawn.

Background: The validity of progression-free survival (PFS) as a surrogate for overall survival (OS) in the antibody-drug conjugate era remains uncertain. We evaluated the association between treatment effects on PFS and OS in randomized trials of antibody-drug conjugates for metastatic breast cancer and explored the surrogate threshold effect. Methods: PubMed, Embase, Cochrane, and ClinicalTrials.gov were searched for published randomized controlled phase 2-4 trials evaluating antibody-drug conjugates in metastatic breast cancer and reporting hazard ratios (HRs) for PFS and OS. A meta-epidemiological approach was used. The primary metric was the ratio of hazard ratios (ratio HR = HR_PFS/HR_OS), with ratio HR less than 1 indicating a larger effect on PFS. Trial-level associations were assessed using weighted linear regression (R²) and Spearman correlation. Results: A total of 21 trials (18 phase 3) evaluating 9 antibody-drug conjugates were included. The pooled ratio HR was 0.79 (95% CI = 0.73 to 0.86), indicating a larger relative effect on PFS than OS. Numerically, the largest discrepancies were observed in triple-negative disease (ratio HR = 0.72) and trials allowing crossover (ratio HR = 0.71). Concordant statistical significance between endpoints occurred in 76% of the trials, whereas 24% showed a statistically significant PFS benefit without OS improvement. The trial-level association between PFS and OS was moderate (R² = 0.62; ρ = 0.67). Conclusion: Treatment effects on PFS consistently exceeded those on OS, although effect directions were highly concordant between endpoints. These findings provide an exploratory framework to contextualize the relationship between PFS and OS in antibody-drug conjugate trials, requiring further validation in diverse clinical settings.