Colorectal cancer is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. Despite an increase in overall survival throughout the years, the prognosis of metastatic colorectal cancer remains poor. Until recently, its treatment was based on the use of standard chemotherapy combined with, anti-epidermal growth factor receptor (for RAS wild-type tumors) or anti-vascular endothelial growth factor, or immunotherapy for tumors with mismatch repair deficiency. Over the last years, precision medicine has become a challenge in oncology and there has been an increasing development of biomarker-driven therapies for metastatic colorectal cancer leading to better outcomes for specific molecular subgroups of patients. Human epidermal growth factor receptor 2 (HER2) amplification/overexpression has been identified in about 6 % of patients with RAS wild-type metastatic CRC and established as an important and drugable biomarker. Its prognostic and predictive implications are still debated but HER2 becoming a therapeutic target with promising results of anti-HER2 therapies for HER2-positive metastatic CRC. Multiple HER2-targeted regimens are now part of National Comprehensive Cancer Network and European Society for Medical Oncology guidelines with two recent Food and Drug Administration approvals for previously treated HER2-positive metastatic colorectal cancer for tucatinib (in combination with trastuzumab) and for trastuzumab-deruxtecan in patients with previously treated HER2-positive metastatic colorectal cancer. This review explores the prognostic and predictive value of HER2 as a biomarker in CRC, describing its molecular structure, the clinical characteristics of patients with HER2 alterations, diagnostic approaches and the most relevant clinical trials assessing its current and future role as a therapeutic target in metastatic colorectal cancer.

Targeted therapy has significantly transformed the treatment landscape of colorectal cancer (CRC), enabling personalized treatment approaches and improving patient prognosis. This study employs bibliometric analysis to explore the research hotspots and development trends in the field of CRC-targeted therapy from 2000 to 2023.

Based on the Web of Science Core Collection, this study collected literature related to CRC-targeted therapy published between 2000 and 2023. CiteSpace and VOSviewer were used for data analysis, with a focus on publication trends, key contributors, and keyword co-occurrence patterns.

A total of 2252 relevant articles were included, demonstrating a steady growth trend in research output. China ranked first in terms of the number of publications, while the University of Texas MD Anderson Cancer Center was identified as the institution with the highest research output. Josep Tabernero was the most prolific author in this field. Among journals, Cancers had the highest impact, while Clinical Cancer Research held a significant advantage in citation frequency. Keyword co-occurrence and clustering analysis indicated that research primarily focused on treatment strategies and precision medicine, with emerging technologies such as cell therapy and liquid biopsy garnering increasing attention.

This study reveals the research trends, core hotspots, and emerging directions in the field of CRC-targeted therapy, providing valuable insights for future research.

Immunoscore (IS) and circulating tumor DNA (ctDNA) are two emerging technologies in improving prognostication and tailoring adjuvant treatments in patients resected from a stage III colon cancer (CC). Here, we analyzed the prognostic value of the two biomarkers in patients who participated in the randomized phase III IDEA-France and HORG trials.

Plasma samples were collected after surgery and before adjuvant chemotherapy. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed 16-plex protein chain reaction assay. Multivariable analyses for time to recurrence (TTR; patients without recurrence or death due to CC) and overall survival (OS) were performed using ctDNA and IS results, along with other parameters including treatment duration and disease risk group.

Of the 554 patients with available ctDNA results, 445 were ctDNA-negative (80.3%) and 109 were ctDNA-positive (19.7%); baseline characteristics showed more T4/N2 and venous embolism/lymphatic invasion/perineural invasion+ in ctDNA-positive patients. With a median follow-up of 6.7 years, the 2-year TTR rate was 43.5% (95% CI, 34.1 to 52.6) for ctDNA-positive patients and 88.1% (95% CI, 84.7 to 90.8) for ctDNA-negative patients (P < .0001). ctDNA was confirmed as an independent prognostic marker for both TTR (adjusted hazard ratio [adjHR], 5.21 [95% CI, 3.59 to 7.58]; P < .001) and OS (adjHR, 4.84 [95% CI, 3.40 to 6.89]; P < .001). ctDNA remained the most significant prognostic factor irrespective of disease stage, treatment duration, and IS results. IS was not prognostic in ctDNA-positive patients but remained a significant prognostic tool for ctDNA-negative patients.

In this combined analysis of two adjuvant trials dedicated to patients with stage III CC after surgery, ctDNA was detectable in 19.7% of the patients and was confirmed as a major independent prognostic biomarker. IS seems to bring additional prognostic information in the 80.3% of patients who are ctDNA-negative.

Precision medicine has brought revolutionary changes to the diagnosis and treatment of cancer patients, and is currently a hot and challenging research topic. Currently, the treatment regimens for most colorectal cancer (CRC) patients are mainly determined by several biomakers, including Microsatellite Instability (MSI), RAS, and BRAF. However, the roles of promising biomarkers such as HER-2, consensus molecular subtypes (CMS), and circulating tumor DNA (ctDNA) in CRC are not yet fully clear. Therefore, it is urgent to explore the potential of these emerging biomarkers in the diagnosis and treatment of CRC patients. In this paper, we discuss recent advances in CRC biomarkers, especially clinical data, and focus on the roles of biomarkers in prognosis, prediction, treatment strategies, and the intrinsic connections with clinical pathological features, hoping to promote better precision medicine for colorectal cancer.

ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC.

Patients with RAS/BRAF-WT mCRC after central confirmation of HER2 positivity (immunohistochemistry 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]) were assigned (1:1) to either trastuzumab plus pertuzumab (TP; trastuzumab 6 mg/kg and pertuzumab 420 mg once every 3 weeks) or cetuximab plus irinotecan (CETIRI; cetuximab 500 mg/m2 and irinotecan 180 mg/m2 once every 2 weeks) until progression or unacceptable toxicity. Crossover to TP was allowed after progression on CETIRI. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, safety, and HER2 gene copy number (GCN ≥20/<20) as a predictive factor.

Between October 2017 and March 2022, 54 participants were assigned to TP (n = 26) and CETIRI (n = 28). Median PFS did not vary significantly by treatment: 4.7 (95% CI, 1.9 to 7.6) and 3.7 (95% CI, 1.6 to 6.7) months in the TP and CETIRI groups, respectively. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN ≥20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; P interaction = .003). On TP, ORR was 34.6% (57.1% with GCN ≥20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively (P = .004). Grade ≥3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively.

TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with RAS/BRAF-WT, HER2-positive mCRC. Higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP vis-à-vis CETIRI.

This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2-amplified biliary tract cancer (BTC).

This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort.

Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2-amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2-amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001).

HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2-amplified BTC derive significant benefit from HER2-targeted therapy.

The utility of capturing heterogeneity by circulating tumor DNA (ctDNA) genotyping combined with tissue analysis or applying it in a sequential manner remains uncertain.

We assessed the clinical value of ctDNA genotyping using data from 2,187 patients with advanced solid tumors enrolled in SCRUM-Japan MONSTAR-SCREEN-1, a nationwide cancer genome screening project, which examined ctDNA from longitudinally collected blood samples and tumor tissue samples (UMIN 000036749).

Among 667 patients with both baseline ctDNA and tissue genotyping results, 51 (7.6%) had actionable biomarkers identified exclusively through ctDNA genotyping. The most frequent targets of genotype-matched therapy guided by solely ctDNA were immune checkpoint, estrogen receptor, and poly(ADP-ribose) polymerase (PARP). Comparison of objective response rates (ORRs) and progression-free survival (PFS) between patients treated based on tissue versus ctDNA alone showed no significant difference, with ORRs of 34.0% versus 23.1% (P = .54) and a median PFS of 11.5 versus 13.8 months (hazard ratio [HR], 1.4 [95% CI, 0.72 to 2.80]), respectively. Among 924 patients undergoing sequential ctDNA genotyping, the detection of actionable biomarkers increased from 63.2% to 72.5% following subsequent ctDNA. Targets for genotype-matched therapy guided by subsequent ctDNA alone commonly included PARP, immune checkpoint, and BRAF. The ORR was 23.2% and 26.7% (P = .75), and the median PFS was 5.2 and. 3.7 months (HR, 1.5 [95% CI, 0.79 to 2.80]) for genotype-matched therapy based on initial versus subsequent ctDNA alone, respectively.

Combining ctDNA with tissue analysis, followed by sequential ctDNA assessments, effectively enhances the identification of actionable biomarkers. This strategy facilitates clinically beneficial, genetically informed therapies, underscoring its significant value in precision oncology.

In the practice of colorectal cancer (CRC), traditional tumor tissue analysis is limited by intratumoral and intertumoral heterogeneity and its invasive nature. Circulating tumor DNA (ctDNA) analysis, a promising liquid biopsy approach, has been increasingly explored in clinical studies. Biologically, ctDNA is characterized by tumor-specific diversity and rapid clearance from circulation, enabling real-time, dynamic, and repeatable assessments. Technologically, PCR- and NGS-based downstream analysis methods have been developed and validated. However, variables in pre-analytical and analytical procedures underscores the need for standardized protocols. Compared with clinicopathology-based risk stratification, ctDNA-based molecular residual disease detection has demonstrated significant potential in guiding treatment decisions. Qualitative and quantitative changes in ctDNA have also shown predictive and prognostic value during neoadjuvant or adjuvant treatment, as well as in later-line treatment for metastatic CRC. Specific molecular aberrations in ctDNA can not only assist in identifying candidates for targeted therapies but also reveal resistance mechanisms. Additionally, emerging research is exploring the potential of ctDNA in early cancer detection. Overall, as a novel biomarker, ctDNA holds substantial promise in advancing clinical practice. This review focuses on the biological characteristics, pre-analytical variables, and downstream analysis methods of ctDNA and summarizes its role across various clinical scenarios in CRC.

This editorial comments on the review by Da Silva et al, published in the World Journal of Clinical Oncology which focuses on the molecular perspectives of lung cancer. With the rapid development of molecular technology, new diagnostic methods are constantly emerging, including liquid biopsy, the identification of gene mutations, and the monitoring biomarkers, thus providing precise information with which to identify the occurrence and development of lung cancer. Biomarkers, such as circulating tumor cells, circulating tumor DNA, and circulating RNA can provide helpful information for clinical application. Common types of genetic mutations and immune checkpoints include epidermal growth factor receptor, anaplastic lymphoma kinase, c-ROS proto-oncogene 1, programmed death-1 and cytotoxic T-lymphocyte-associated protein. According to specific biomarkers, targeted therapy and immunotherapy can improve survival outcomes based on the types of gene mutation and immune checkpoints. The application of molecular approaches can facilitate our ability to control the progression of disease and select appropriate therapeutic strategies for patients with lung cancer.

Circulating tumor DNA (ctDNA) has emerged as a dynamic biomarker in cancer, as evidenced by its increasing integration into clinical practice. Carrying tumor specific characteristics, ctDNA can be used to inform treatment selection, monitor response, and identify drug resistance. In this review, we provide a comprehensive, up-to-date summary of ctDNA in monitoring treatment response with a focus on lung, colorectal, and breast cancers, and discuss current challenges and future directions.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. In cases of metastatic CRC (mCRC) that are resistant to conventional chemotherapy-based treatments, the efficacy of available therapeutic options is typically low. CRC exhibiting overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) gene has shown responsiveness to HER2-targeted therapies.

We present the case of a 69-year-old woman diagnosed with mCRC with an NRAS p.G12V mutation and microsatellite stability, identified through tumor sequencing, along with HER2 overexpression detected by immunohistochemistry. She exhibited an excellent response to disitamab vedotin-containing therapy. To our knowledge, this is the first reported case of mCRC with HER2 overexpression and an NRAS p.G12V mutation achieving a remarkable clinical response to anti-HER2 therapy.

Disitamab vedotin demonstrates promising anti-tumor effects in HER2-overexpressing mCRC, offering patients an additional treatment option.

Standard adjuvant treatment of stage III colon cancer (CC) is fluoropyrimidine with oxaliplatin. Recently, stage III was subdivided into low-risk (T1-3, N1) and high-risk (T4 and/or N2), with the benefit of adding oxaliplatin varying across these substages. In this study, we aimed to assess the impact of oxaliplatin on survival outcomes in subdividing stage III CC patients based on T and N staging.

A total of 4942 stage III CC patients were pooled from the three randomized pivotal trials of oxaliplatin. Kaplan-Meier curves, Cox models stratified by study, and interaction tests were used to assess the oxaliplatin effect across subgroups based on T and N stages. The primary endpoint was overall survival (OS).

The prevalence of tumor stages was T1-2 12.4%, T3 74.4%, and T4 13.1%; nodal stages were N1 64.7% and N2 35.3%. A significant OS benefit from oxaliplatin was seen only in T3 (5-year OS = 77.2% versus 73.0%, P < 0.001): T3N1 (hazard ratio 0.72, 95% confidence interval 0.62-0.85, P < 0.001) and T3N2 (hazard ratio 0.81, 95% confidence interval 0.69-0.95, P = 0.010). No benefit was observed for T1-2 (5-year OS = 87.8% versus 88.7%, P = 0.644) or T4 patients (5-year OS = 62.6% versus 60.2%, P = 0.648). Subgroup analysis revealed a significant interaction between T stage and the effect of oxaliplatin treatment on OS, whereas no such interaction was observed for N stage.

Our analysis revealed that oxaliplatin-based chemotherapy offers a significant survival benefit in stage III CC patients with T3 tumors. In contrast, no survival benefit was observed for T1-2 or T4 patients. These results suggested that T stage plays a more crucial role than N stage in predicting treatment benefit, highlighting the need for tailored treatment strategies based on tumor characteristics.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to treatment failure, poor progression-free survival, and cancer recurrence. Mechanisms of resistance in CRC are multifaceted, involving genetic mutations, epigenetic alterations, tumor heterogeneity, and the tumor microenvironment. Understanding these mechanisms at the molecular level is crucial for identifying novel therapeutic targets and developing strategies to overcome resistance. This review provides an overview of the diverse mechanisms driving drug resistance in sporadic CRC and discusses strategies currently under investigation to counteract this resistance. Several promising strategies are being explored, including targeting drug transport, key signaling pathways, DNA damage response, cell death pathways, epigenetic modifications, cancer stem cells, and the tumor microenvironment. The integration of emerging therapeutic approaches that target resistance mechanisms aims to enhance the efficacy of current CRC treatments and improve patient outcomes.

Single-cell spatial omics analysis requires consideration of biological functions and mechanisms in a microenvironment. However, microenvironment analysis using bioinformatic methods is limited by the need to detect histological morphology and extend it to the surrounding area. In this study, we developed SpatialKNifeY (SKNY), an image-processing-based toolkit that detects spatial domains that potentially reflect histology and extends these domains to the microenvironment. Using spatial transcriptomic data from breast cancer, we applied the SKNY algorithm to identify tumor spatial domains, followed by clustering of the domains, trajectory estimation, and spatial extension to the tumor microenvironment (TME). The results of the trajectory estimation were consistent with the known mechanisms of cancer progression. We observed tumor vascularization and immunodeficiency at mid- and late-stage progression in TME. Furthermore, we applied the SKNY to integrate and cluster the spatial domains of 14 patients with metastatic colorectal cancer, and the clusters were divided based on the TME characteristics. In conclusion, the SKNY facilitates the determination of the functions and mechanisms in the microenvironment and cataloguing of the features.

Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2-3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3-4% in mCRC and increases up to 8% in patients with KRAS/NRAS/BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS WT mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients randomized 1:1 to either treatment arm. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests.Clinical trial registration: NCT05253651 (ClinicalTrials.gov).

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have shown promise in treating HER2-amplified metastatic colorectal cancer (mCRC). Identifying optimal biomarkers for treatment decisions remains challenging. This study explores the potential of artificial intelligence (AI) in predicting treatment responses to trastuzumab plus pertuzumab (TP) in patients with HER2-amplified mCRC from the phase II TRIUMPH trial.

AI-powered HER2 quantification continuous score (QCS) and tumor microenvironment (TME) analysis were applied to the prescreening cohort (n = 143) and the TRIUMPH cohort (n = 30). AI analyzers determined the proportions of tumor cells (TCs) with HER2 staining intensity and the densities of various cells in TME, examining their associations with clinical outcomes of TP.

The AI-powered HER2 QCS for HER2 immunohistochemistry (IHC) achieved an accuracy of 86.7% against pathologist evaluations, with a 100% accuracy for HER2 IHC 3+ patients. Patients with ≥50% of TCs showing HER2 3+ staining intensity (AI-H3-high) exhibited significantly prolonged progression-free survival (PFS; median PFS, 4.4 v 1.4 months; hazard ratio [HR], 0.12 [95% CI, 0.04 to 0.38]) and overall survival (OS; median OS, 16.5 v 4.1 months; HR, 0.13 [95% CI, 0.05 to 0.38]) compared with the AI-H3-low (<50% group). Stratification among patients with AI-H3-high included TME-high (all lymphocyte, fibroblast, and macrophage densities in the cancer stroma above the median) and TME-low (anything below the median), showing a median PFS of 1.3 and 5.6 months for TME-high and TME-low respectively, with an HR of 0.04 (95% CI, 0.01 to 0.19) for AI-H3-high with TME-low compared with AI-H3-low.

AI-powered HER2 QCS and TME analysis demonstrated potential in enhancing treatment response predictions in patients with HER2-amplified mCRC undergoing TP therapy.

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

Liquid biopsy using circulating tumor DNA (ctDNA) has been reported to be less invasive and effective for comprehensive genetic analysis of heterogeneous solid tumors, including decision-making for therapeutic strategies, predicting recurrence, and detecting genetic factors related to treatment resistance in various types of cancers. Breast cancer, colorectal cancer, and lung cancer are among the most prevalent malignancies worldwide, and clinical studies of liquid biopsy for these cancers are ongoing. Liquid biopsy has been used as a companion diagnostic tool in clinical settings, and research findings have accumulated, especially in cases of colorectal cancer after curative resection and non-small cell lung cancer (NSCLC) after curative chemoradiotherapy, in which ctDNA detection helps predict eligibility for adjuvant chemotherapy. Liquid biopsy using ctDNA shows promise across a wide range of cancer types, including breast cancer, and its clinical applications are expected to expand further through ongoing research. In this article, studies on liquid biopsy in breast cancer, colorectal cancer, and NSCLC are compared focusing on ctDNA.

To explore the potential of circulating tumor DNA (ctDNA) as a prognostic biomarker to predict treatment response and survival outcomes in patients with metastatic colorectal cancer (mCRC).

A retrospective analysis was conducted on 134 patients with mCRC who were treated between January 2020 and December 2021. The patients were classified into ctDNA-negative and ctDNA-positive groups based on plasma ctDNA detection. Demographic, clinical, and laboratory parameters, treatment response, survival outcomes, and adverse events were recorded and analyzed.

No significant differences were observed in baseline characteristics between the two groups. Compared to the ctDNA-positive patients, ctDNA-negative patients exhibited superior outcomes, including a higher objective response rate (65.22% vs. 46.15%), disease control rate (81.16% vs. 63.08%), progression-free survival (8.24 ± 1.02 vs. 7.86 ± 0.91 months), overall survival (24.58 ± 3.58 vs. 23.27 ± 3.46 months), and 1-year survival rate (73.91% vs. 55.38%). The ctDNA-positive group had a significantly higher incidence of adverse events. Correlation analyses revealed significant associations between ctDNA status, tumor markers, treatment response, and survival outcomes.

ctDNA is a promising noninvasive biomarker for predicting treatment response, survival, and adverse events in mCRC, potentially guiding personalized therapeutic strategies.

Liquid biopsy using circulating tumor DNA (ctDNA) has emerged as a minimally invasive, timely approach to provide molecular diagnosis and monitor tumor evolution in patients with cancer. Since the molecular landscape of metastatic colorectal cancer (mCRC) is substantially heterogeneous and dynamic over space and time, ctDNA holds significant advantages as a biomarker for this disease. Numerous studies have demonstrated that ctDNA broadly recapitulates the molecular profile of the primary tumor and metastases, and have mainly focused on the genotyping of RAS and BRAF, that is propaedeutic for anti-EGFR treatment selection. However, ctDNA soon broadened its scope towards the assessment of early tumor response, as well as the identification of drug resistance biomarkers to drive potential molecular actionability. In this review article, we provide an overview of the current state-of-the-art of this methodology and its applications, focusing on ongoing clinical trials that employ ctDNA to prospectively guide treatment in patients with mCRC.

The low probability of identifying druggable mutations through comprehensive genomic profiling (CGP) and its financial and time costs hinder its widespread adoption. To enhance the effectiveness and efficiency of cancer precision medicine, it is critical to identify patient characteristics that are most likely to benefit from CGP.

This nationwide retrospective study employed machine learning models to predict the identification of genome-matched therapies by CGP, utilizing a national database covering 99.7% of the patients who underwent CGP in Japan from June 2019 to November 2023. Prediction models were constructed for the overall cancer population, specific cancer types, and adolescent and young adult (AYA) group. The SHapley Additive exPlanations (SHAP) algorithm was applied to elucidate clinical features contributing to model predictions.

This study included 60 655 patients [mean age (standard deviation), 60.8 years (14.5 years); 50.1% males]. CGP identified at least one genome-matched therapy in 11 227 cases (18.5%). The best prediction model was eXtreme Gradient Boosting (XGBoost) with an area under the receiver operating characteristic curve of 0.819. Cancer type was the most important predictor (negative for pancreas and positive for breast and lung), followed by the age, presence of liver metastasis, and number of metastatic sites. Analysis of cancer type-specific models identified several organ-specific features, including the sex, interval between the cancer diagnosis and CGP, sampling site, and CGP panel. Among 3455 AYA patients, genome-matched therapies were identified in 459 patients (13.3%). The AYA-specific model achieved an area under the receiver operating characteristic curve of 0.768, with bone tumor identified as a negative predictor in addition to those identified in the overall cancer population model.

Several factors predicting the identification of genome-matched therapies through CGP were identified for the overall cancer population and cancer type-specific subpopulations. Expedited CGP is recommended for patients who match the identified profile to facilitate early targeted therapy.

Colorectal cancer (CRC) represents a global health threat, standing as the second leading cause of cancer-related death worldwide. Targeted therapies brought new hope for the metastatic stage, which historically bore a very poor prognosis. Human epidermal growth receptor 2 (HER2) overexpression concerns about 5 % of the metastatic CRC (mCRC) patients, including both gene amplifications and point mutations. Albeit its controversial prognostic role, preclinical and clinical data indicate HER2 as a negative predictive biomarker of response to anti-EGFR therapies. Tissue and plasma-based NGS testing, could permit a precise identification of this resistance mechanism both at baseline and during treatment, thus guiding decision-making. Furthermore, promising results come from completed and ongoing randomized trials, testing HER2 as an actionable target. In this review, we discuss the available evidence on HER2 targeting in advanced CRC, analyzing its possible future role in the treatment algorithm.

HERALD/EPOC1806 was conducted as a multicenter phase II trial assessing trastuzumab deruxtecan (T-DXd) therapy for patients with human epidermal growth factor receptor 2 (HER2)-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing.

Patients exhibited advanced solid tumors with HER2 amplification that was identified via next-generation sequencing of cfDNA testing, without the requirement for immunohistochemical HER2 testing. The studied group was administered T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity.

Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated HER2 amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma HER2 copy number (CN) of 8.55 (range, 2.4-73.9). Confirmed overall response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3 to 69.0), thus showing a value beyond the 5% threshold. Responses were evaluated for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma HER2 CN above versus below the baseline median value did not differ for impact response; however, clearance of HER2 amplification in cfDNA on cycle 2 day 1 had higher response values compared with persistence. Median progression-free survival and response duration were 7.0 (95% CI, 4.9 to 9.7) and 8.8 (95% CI, 5.8 to 11.2) months, respectively, with the majority of complications being mild to moderate. Interstitial lung diseases were identified in 16 (26%) patients, including 14 patients with grade 1 disease, one patient with grade 2 disease, and one patient with grade 3 disease.

T-DXd treatment demonstrated high ORR with durable response in patients with advanced HER2-amplified solid tumors determined with cfDNA testing.

Trastuzumab (TRA) is a key drug in human epidermal growth factor receptor type 2 (HER2)-positive breast cancer treatment. Infusion reactions (IR) with TRA are frequently observed in practice. Although the efficacy of premedication has been previously reported, it remains uncommon. The probability of severe IR due to TRA is low; however, when it does occur, it is associated with patient discomfort and expenditure of medical resources. This study aimed to analyze the factors associated with the occurrence of IR in patients with breast cancer who received TRA.

We retrospectively studied 204 patients who underwent TRA for breast cancer treatment between September 2008 and June 2023, identifying factors influencing the occurrence of IR at the time of TRA administration.

A total of 182 patients were included in this study, and the incidence of IR was 25.8% (47/182 patients). Multiple logistic regression analysis showed that pertuzumab (PER) use, high alkaline phosphatase (ALP), and low high-density lipoprotein (HDL) cholesterol levels were associated with IR.

IR should be considered when PER is combined with TRA. ALP and HDL cholesterol levels may be predictive markers of TRA-induced IR in patients with breast cancer.

Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE.

The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included.

The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments.

Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multiomics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% have participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% CI, 13.4-16.3) for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83). Significance: Our nationwide molecular profiling initiative played pivotal roles in facilitating the enrollment of patients with advanced solid tumors into matched clinical trials and highlighted the substantial survival benefits of patients treated with matched therapy. We aim to facilitate an industry-academia data-sharing infrastructure ecosystem, fostering new drug discovery paradigms and precision medicine.