Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.

Complex RNA-seq signatures involving the transcription factors ASCL1, NEUROD1, and POU2F3 classify Small Cell Lung Cancer (SCLC) into four subtypes: SCLC-A, SCLC-N, SCLC-P, and SCLC-I (triple negative or inflamed). Preliminary studies suggest that identifying these subtypes can guide targeted therapies and potentially improve outcomes. This study aims to evaluate whether the expression levels of these three key transcription factors can effectively classify SCLC subtypes, comparable to the use of individual antibodies in immunohistochemical (IHC) analysis of formalin-fixed, paraffin-embedded (FFPE) tumor samples. We analyzed preclinical models of increasing complexity, including eleven human and five mouse SCLC cell lines, six patient-derived xenografts (PDXs), and two circulating tumor cell (CTC)-derived xenografts (CDXs) generated in our laboratory. RT-qPCR conditions were established to detect the expression levels of ASCL1, NEUROD1, and POU2F3. Additionally, protein-level analysis was performed using Western blot for cell lines and IHC for FFPE samples of PDX and CDX tumors, following our experience with patient tumor samples from the CANTABRICO trial (NCT04712903). We found that the analyzed SCLC cell line models predominantly expressed ASCL1, NEUROD1, and POU2F3, or showed no expression, as identified by RT-qPCR, consistently matching the previously assigned subtypes for each cell line. The classification of PDX and CDX models demonstrated consistency between RT-qPCR and IHC analyses of the transcription factors. Our results show that single-gene analysis by RT-qPCR from FFPE-extracted RNA simplifies SCLC subtype classification. This approach provides a cost-effective alternative to IHC staining or expensive multi-gene RNA sequencing panels, making SCLC subtyping more accessible for both preclinical research and clinical applications.

Real-world evidence on the direct healthcare costs of patients with KRASG12C-mutant non-small-cell lung cancer (NSCLC) is limited. Multicenter, observational, retrospective study in patients newly diagnosed with advanced-stage NSCLC harboring the KRASG12C mutation within real-world clinical practice in Spain. Patient characteristics, treatment patterns, outcomes, and direct healthcare costs were collected from medical records and administrative databases between January 1, 2016, and March 9, 2022. 127 patients were included in the study, with global and disease-related economic data available for 125 and 104 patients, respectively. Most patients (97.6%) were current or former smokers. The most prevalent co-mutations or genetic alterations at baseline involved TP53 (38.2%), ATM (20.0%), and STK11 (15.4%) genes. 94 patients (74.0%) received systemic therapy. Chemotherapy was the most common first-line (63.8%) and immunotherapy the most common second-line therapy (64.6%). Median progression-free survival (95% CI) for the first, second and third treatment lines was 4.6 (2.8-7.8), 3.8 (1.5-8.2), and 2.2 (0.1-9.9) months, respectively. Median overall survival (95% CI) was 7.7 (4.9-11.0), 9.0 (3.0-14.3), and 8.9 (0.1-19.7) months, respectively. Total global cost over the study period amounted to €5,706,820 (€46,023 per patient), with pharmacological costs totaling €2,353,299 (€18,978 per patient). Disease-related costs were €4,219,410 (€40,965 per patient), with disease-related pharmacological costs of €2,157,627 (€20,948 per patient). These real-world data highlight the limited outcomes for most NSCLC patients with KRASG12C mutations, underscoring the significant clinical and economic burden associated with their care. The evaluation of the impact of novel and effective targeted therapies is therefore warranted.