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PubMed2025

Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration.

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

Humans↗

PubMed2026

Clinically actionable genomic alterations in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. RESULTS: WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. CONCLUSIONS: ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

ESCAT↗

PubMed2026

In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.

PURPOSE: The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. MATERIALS AND METHODS: We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. RESULTS: SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG (P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6-48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. CONCLUSION: Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

Actionable genomic alterations↗

PubMed2026

PIK3CA in Cancer: Structure, Biology, Alterations, and Actionability.

PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.

PI3K signaling↗

PubMed2026

The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.

INTRODUCTION: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS: We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS: In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.

Humans↗

PubMed2026

Network-Integrated Platform for Clinical Trial Navigation from the New South Wales Early Phase Clinical Trials Alliance.

PURPOSE: Access to early-phase clinical trials (EPCT) is increasingly constrained by delays in genomic testing and lack of coordinated system-level navigation. The New South Wales Early Phase Clinical Trials Alliance (NECTA) was established to improve EPCT access. Practical Assessment of NECTA Network Assistance in Cancer Outpatient Trials Access (PANNA-COTA) prospectively evaluated whether integrating circulating tumor DNA (ctDNA) profiling with a real-time, cross-site molecular tumor board (MTB) facilitates EPCT enrollment. PATIENTS AND METHODS: In this multicenter prospective study across nine NECTA sites, patients referred for EPCT consideration underwent ctDNA testing using the Guardant360 74-gene assay. The results were reviewed at a fortnightly MTB incorporating cross-site trial mapping and dynamic eligibility review. The primary endpoint was proportion enrolled into EPCTs. Secondary endpoints included ctDNA findings and trial outcomes. RESULTS: Of 104 consented participants, 101 were eligible. Participants had advanced, heavily pretreated solid tumors; 48% lacked prior tumor next-generation sequencing. ctDNA alterations were detected in 85%, with actionable alterations in 44%. Therapeutic options were identified in 88%, and EPCTs were recommended in 76%. Despite this, only 7% of participants received genomically matched therapy. In contrast, 37% enrolled in EPCTs within 3 months and 47% overall [95% confidence interval (CI), 0.37-0.56]. Among evaluable participants on trial, the disease control rate was 81% and objective response rate was 33%. CONCLUSIONS: PANNA-COTA demonstrates that integrating liquid biopsy with real-time, network-level trial navigation enables high rates of EPCT enrollment despite low rates of genomically matched therapy. These findings indicate that clinical trial access is influenced by navigation, eligibility, and system-level coordination rather than genomic actionability alone.

Humans↗

PubMed2026

Real-World Actionability Analysis of Comprehensive Genomic Profiling Versus Single/Small-Gene Panels.

INTRODUCTION: Comprehensive genomic profiling (CGP) enables identification of patients eligible for targeted treatments, making it essential in the management of advanced cancer. This retrospective real-world study compared actionable mutations in CGP-tested patients with advanced/metastatic solid tumors to those who received single-gene/small-panel (SP) tests. METHODS: Patients aged > 18 years with advanced/metastatic solid tumors (including non-small cell lung cancer (NSCLC), colorectal cancer, prostate cancer, breast cancer, or melanoma) with a CGP or SP test reported between 1 January 2018, and 31 December 2022, were included. OncoKB-derived actionability was compared between the two cohorts. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline characteristics. A weighted generalized linear model with log link was used to report actionability ratio (AR) and 95% confidence intervals (CI). RESULTS: Among 406 patients (CGP-tested cohort: 202, SP-tested cohort: 204), approximately half were diagnosed with NSCLC. After adjusting for baseline characteristics, CGP testing detected more actionable alterations than SP: OncoKB level 1 (50.0% versus 31.4%; AR 1.76 [95% CI: 1.24, 2.51]; p = 0.002), OncoKB level 2 (22.8% versus 10.3%; AR 2.53 [95% CI: 1.17, 5.48]; p = 0.018), and OncoKB level 1 or level 2 or level R1 (55.9% versus 41.2%; AR 1.5 [95% CI: 1.11, 2.01]; p = 0.008). CONCLUSIONS: CGP testing identified more actionable genetic alterations compared with SP testing methods for patients with advanced/metastatic NSCLC, colorectal cancer, prostate cancer, breast cancer, or melanoma. Expanding reimbursement and coverage for CGP testing as well as expanding CGP use can facilitate equitable treatment access for patients with advanced/metastatic cancer.

Actionable mutations↗

PubMed2026

Comprehensive Clinicopathologic, Immunohistochemical, and Genomic Profiling of Sporadic Ampullary Somatostatin-producing D-cell Neuroendocrine Tumors Identifies Recurrent HRAS Hotspot Mutations.

Ampullary somatostatin-producing D-cell neuroendocrine tumors are rare neoplasms that may be associated with type 1 neurofibromatosis. The molecular features of sporadic ampullary somatostatin-producing D-cell neuroendocrine tumors (SAMSOM-NETs) remain poorly characterized. We performed an integrated morphological, immunohistochemical, and genomic analysis of a multicenter series of SAMSOM-NETs. Eleven cases were included (73% male; median age: 63 years). All six patients who underwent lymphadenectomy were staged as pN1, and liver metastases were found in three cases; however, no tumor-related deaths occurred (median follow-up: 104 months). Common histologic features that can pose diagnostic challenges in the differential diagnosis with adenocarcinoma included a tubulo-glandular architecture (100%), periodic Acid-Schiff (PAS)-positive intraluminal mucin (73%), MUC1 expression (100%), and carcinoembryonic antigen (45%) expression. All tumors exhibited dot-like cytoplasmic reactivity for cytokeratins (CK) CAM5.2 or CK AE1/AE3, and 82% were CK7-positive. ISL1 and PDX1 were diffusely expressed in all cases, while CDX2 was positive in 54% and ARX showed only focal expression in four tumors. Genomic profiling revealed microsatellite stability and low tumor mutational burden. Alterations in the RAS pathway, including HRAS mutations (4 cases, 36%), a KRAS mutation (1 case), and NF1 alterations (one case), were identified in 54% of cases and in all tumors with liver metastases. Additional molecular findings included a CDK12 splice-site alteration and an NTRK3::PRDM4 fusion. Potentially actionable alterations affecting kinase-related pathways were detected in 64% of tumors. Our findings support SAMSOM-NET as a peculiar neuroendocrine tumor subtype showing distinctive histologic and molecular characteristics with potential diagnostic and therapeutic implications.

Humans↗

PubMed2026

Case Report: Pancreatic amphicrine-like carcinoma with acinar differentiation harboring a KANK4-RAF1 gene fusion.

Pancreatic amphicrine-like carcinoma (ALC) is an exceptionally rare neoplasm characterized by simultaneous exocrine and endocrine differentiation within the same tumour cells. These tumours represent a diagnostic challenge because they must be distinguished from mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), which consist of morphologically distinct tumour components. We report a case of pancreatic ALC with acinar differentiation harboring a KANK4::RAF1 fusion identified by comprehensive genomic profiling. Histologically, the tumour demonstrated acinar differentiation with expression of trypsin and BCL10 together with neuroendocrine differentiation characterized by synaptophysin and INSM1 expression within the same neoplastic population. Molecular analysis revealed a RAF1 rearrangement, a potentially actionable alteration previously described in a subset of pancreatic acinar carcinomas. The patient showed rapid disease progression despite systemic chemotherapy. Treatment with the MEK inhibitor trametinib was initiated based on the presence of a RAF1 fusion but was discontinued after 1 month because of toxicity, preventing assessment of therapeutic efficacy. This case expands the molecular spectrum of pancreatic ALC with acinar differentiation and highlights the importance of comprehensive molecular profiling in rare pancreatic neoplasms to identify potentially actionable genomic alterations.

Humans↗

PubMed2026

Marked response to dabrafenib plus trametinib in a patient with BRAF V600E-mutant pancreatic hepatoid carcinoma: a case report and systematic analysis of 57 cases.

BACKGROUND: Pancreatic hepatoid carcinoma (PHC) is an extremely rare pancreatic malignancy characterized pathologically by hepatocellular-like differentiation. Some patients may present with elevated serum alpha-fetoprotein (AFP). Owing to the limited number of reported cases, the clinical features, molecular characteristics, and systemic treatment strategies for PHC remain poorly defined. BRAF V600E is an actionable alteration with established therapeutic value in several solid tumors; however, its clinical significance in PHC remains unclear. CASE PRESENTATION: We report the case of a 64-year-old man with advanced PHC who presented with painless jaundice, dark urine, and recent weight loss. Laboratory tests showed marked cholestatic liver injury and significantly elevated AFP. Imaging revealed a pancreatic head-neck mass with portal vein tumor thrombus and regional lymph node metastases, corresponding to cT4N1M1, stage IV disease. Percutaneous transhepatic biliary drainage was first performed to relieve obstructive jaundice. Biopsy of the pancreatic lesion showed poorly differentiated carcinoma. Based on hepatoid morphology, immunophenotype, elevated serum AFP, imaging findings, and exclusion of primary hepatocellular carcinoma, the patient was diagnosed with PHC. Comprehensive genomic profiling identified a BRAF V600E mutation with a variant allele frequency of 31.89%, together with MDM2 and MYC amplification. The molecular profile was characterized by microsatellite stability, low tumor mutational burden, MGMT promoter methylation, and low PD-L1 expression. After two cycles of pembrolizumab-based first-line therapy combined with paclitaxel, S-1, and lenvatinib, AFP continued to increase and imaging showed rapid tumor enlargement, consistent with immune checkpoint inhibitor-related hyperprogressive disease. The treatment was then switched to dabrafenib plus trametinib. AFP declined rapidly and returned to the normal range within approximately two months. Imaging showed marked regression of the pancreatic primary lesion, disappearance of the portal vein tumor thrombus and metastatic lymph nodes, and conversion of peripheral blood minimal residual disease to negative. The best response was partial response. After approximately six months of targeted therapy, occult disease progression emerged. Subsequent addition of cetuximab, replacement of the MEK inhibitor, and dose escalation of targeted therapy did not restore sustained systemic disease control, although local disease remained manageable with subsequent treatment adjustments. Proton radiotherapy was then delivered to the residual pancreatic lesion, followed by CyberKnife radiotherapy for a newly detected 2.3-cm metastasis in the caudate lobe of the liver. As of April 2026, the patient's AFP level remained close to normal at 14 ng/mL, local lesions were well controlled, peripheral blood minimal residual disease had turned positive, and the patient remained in a stable tumor-bearing state. SYSTEMATIC ANALYSIS: We further summarized 57 previously reported cases of PHC. The median age was 54 years, and 66.7% of patients were male. Tumors occurred at different pancreatic sites, including the pancreatic head in 21 cases, body in 8 cases, tail in 13 cases, and multifocal lesions in 15 cases. More than half of the patients had metastatic disease at initial diagnosis. The immunophenotype of PHC was highly heterogeneous. Regarding treatment, 47 patients underwent surgery, 20 received chemotherapy, and 6 received targeted therapy. The 1-year and 3-year overall survival rates were 70.7% and 43.1%, respectively, indicating an overall poor prognosis. CONCLUSION: This case suggests that BRAF V600E may represent a clinically actionable driver alteration in PHC. Dabrafenib plus trametinib induced a rapid and deep response in this patient with advanced BRAF V600E-mutant PHC. Microsatellite stability, low tumor mutational burden, low PD-L1 expression, and MDM2 amplification may be associated with limited benefit from immunotherapy and a risk of hyperprogression. After resistance to targeted therapy, local radiotherapy may serve as an important strategy for controlling oligoresidual and oligometastatic lesions. Together with the literature review, this case supports early comprehensive molecular profiling and individualized multidisciplinary management for advanced PHC.

BRAF V600E↗

PubMed2026

Comparative Analysis of Potential Clinical Actionability of Genomic Alterations in Early-Onset Versus Later-Onset GI Cancers.

PURPOSE: As biomarker-directed therapy increasingly shapes GI oncology, it remains unclear whether early-onset (EO) and later-onset (LO) GI cancers harbor comparable opportunities for clinically actionable targeting. We compared the landscape of potentially actionable genomic alterations in EO versus LO GI cancers using American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange v19.0. METHODS: GI tumor samples were assigned to 10 prespecified tumor groups using OncoTree codes. Samples were annotated with OncoKB therapeutic levels and classified as potentially actionable if they harbored at least one level 1-3B alteration. EO and LO disease were defined as age at sequencing <50 years and ≥50 years, respectively. Group-wise comparisons used Wilcoxon rank-sum, chi-square, or Fisher exact testing as appropriate and with false discovery rate correction. Multivariable logistic regression evaluated age group associations overall and within tumor groups. RESULTS: Among 53,945 GI tumor samples, 10,573 (19.6%) were EO and 43,372 (80.4%) were LO. EO tumors had lower prevalence of potentially actionable alterations in colorectal (71% v 78.1%, q < 0.001), esophagogastric (53.3% v 57.9%, q = 0.0097), GI stromal tumor (GIST) (75.1% v 90.9%, q < 0.001), liver (25.4% v 35.4%, q = 0.0021), and pancreatic tumors (82.9% v 90.7%, q < 0.001). In the overall model, LO status was associated with higher odds of potential actionability (odds ratio, 1.39 [95% CI, 1.33 to 1.47]; P < .001). Tumor group-specific associations persisted in colorectal, GIST, liver, and pancreatic tumors after multivariable adjustment. CONCLUSION: Potential clinical actionability differs between EO and LO GI cancers in a tumor lineage-specific manner. Several major EO GI tumor groups appear relatively depleted of potentially actionable alterations, suggesting that the expanding therapeutic reach of precision oncology may not be distributed evenly across age-defined GI cancer populations and underscoring the need for EO-focused biomarker discovery and therapeutic development.

Humans↗

PubMed2026

Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC): An Aggressive Disease Course and Limitations for Personalized Oncology.

Neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. We report a male patient diagnosed with a gastroenteropancreatic (GEP)-NEC with synchronous liver metastasis at the time of surgery who underwent a radical resection attempt. Despite radical-intent surgery followed by adjuvant carboplatin/etoposide, early recurrence developed with progression through multiple subsequent chemotherapy lines. During the treatment process, genetic profiling was performed twice to identify actionable genomic targets, with inclusion in the national IMPRESS study as a last resort. Comprehensive genomic profiling revealed TP53 mutation and RB1 loss but no actionable alterations. A patient-derived organoid (PDO) was successfully established from resected tumor tissue and retained key neuroendocrine and proliferative features, with partial genomic concordance to the primary tumor. Differences between the primary and subsequent PDO in variant allele frequencies suggest clonal selection during culture. Exploratory metabolomic profiling of tryptophan pathway metabolites in patient serum and PDO-culture media indicated tumor-associated metabolic alterations. We present clinical and translational efforts in difficult-to-treat NEC, illustrating both the translational challenges and the potential role of PDOs in advancing personalized treatment strategies for a cancer with very limited treatment options.

Gastroenteropancreatic neuroendocrine carcinoma↗

PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗

PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗

PubMed2026

The future of blood-based biomarkers in liver cancer.

Liquid biomarkers hold substantial promise in liver cancer, with potential applications in risk stratification, surveillance and early detection, therapeutic decision-making, and treatment-response monitoring. In parallel with oncologic advances, liquid biopsy has gained increasing attention. However, despite expanded research efforts, prospective clinical validation remains limited. While cell-free DNA-based detection of actionable alterations has entered clinical practice in select contexts, most candidate liquid biomarkers still require rigorous evaluation through translational research embedded in clinical trials and prospective cohort studies. In this review, we summarise the current landscape of blood-based biomarkers across the cancer care continuum for individuals at risk, or diagnosed with hepatocellular carcinoma and biliary tract cancers, and discuss the key challenges and opportunities that lie ahead.

Humans↗

PubMed2026

Detection of a Rare Intra-ALK Inversion and ALK Rearrangement in a Lung Adenocarcinoma Patient by FoundationOne Liquid CDx and Successful Treatment with Alectinib: Case Report.

A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

ALK-EML4 rearrangement↗

PubMed2025

Next-generation sequencing in breast cancer: current clinical applications and future directions.

INTRODUCTION: Breast cancer is a heterogeneous disease that claims 670,000 lives by 2022. Omic technologies, particularly next generation sequencing (NGS) offers promising avenues for precision medicine. American Society of Clinical Oncology (ASCO) outlines genomic testing's utility, emphasizing prognostic and diagnostic potential. OBJECTIVES: This review succinctly explores NGS's evolution and clinical applications of NGS in breast cancer, thereby guiding future research to enhance patient care. METHODS: Comprehensive literature searches were conducted using databases such as PubMed, Google Scholar, and ResearchGate, focusing on keywords including breast cancer, HER-2 low breast cancer, circulating tumour DNA, single-cell RNA sequencing, and next-generation sequencing. Peer-reviewed, high-quality articles published in English were selected for inclusion. RESULTS: Previous studies have explored the evolution of NGS technology and its clinical applications in breast cancer, including genomic and transcriptomic characterization, treatment guidance, and resistance prediction. Molecular profiling of challenging entities such as early-onset breast cancer and HER-2 low tumours was summarized, with key findings highlighted. This review also discusses emerging technologies, including circulating DNA and single-cell sequencing, as promising avenues for discovery. CONCLUSION: NGS has revealed the genomic and transcriptomic diversity of breast cancer, identifying actionable alterations associated with chemotherapy response and resistance to therapies such as trastuzumab, TKIs, and CDK4/6 inhibitors. Circulating tumour DNA (ctDNA) shows potential for diagnosis, prediction, prognosis, and monitoring, despite tumour heterogeneity. Single-cell analysis enables exploration of individual cell transcriptomes, though high costs and low throughput remain barriers to widespread adoption. HER2-low tumours continue to pose significant research challenges.

Humans↗

PubMed2026

Liquid biopsy for biliary tract cancer: available evidence and future research directions.

INTRODUCTION: Biliary tract cancers (BTCs) are molecularly heterogeneous, and early genomic profiling is becoming increasingly important for treatment decisions. Because tissue sampling is often limited or inadequate, there is a clear need for minimally invasive biomarkers that can support treatment selection and longitudinal disease assessment. AREAS COVERED: This narrative review summarizes current and emerging liquid-biopsy (LB) applications in BTC, with a primary focus on plasma circulating tumor DNA (ctDNA). The evidence base was assembled through targeted searches of PubMed/MEDLINE and Embase up to 1 February 2026, supported by selective ClinicalTrials.gov searches for ongoing biomarker-driven studies. We discuss ctDNA-based molecular profiling for actionable alterations, its prognostic role including minimal residual disease assessment, and its use in serial monitoring of treatment response and acquired resistance. We also consider how LB may support clinical-trial enrichment and biomarker-guided endpoints, and briefly review complementary approaches using bile and other analytes, while highlighting current evidence gaps. EXPERT OPINION: In BTC, ctDNA is best viewed as a complement to tissue-based profiling, especially when tissue is inadequate or when rapid genotyping is needed. Its broader clinical impact will depend on assay standardization, clearer interpretation frameworks for low-shedding disease, and prospective studies showing that ctDNA-guided decisions improve patient outcomes.

Humans↗