Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in theASCO Guidelines Methodology Manual. ASCO Living Guidelines follow theASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only). Updates are published regularly and can be found athttps://ascopubs.org/nsclc-da-living-guideline.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in theASCO Guidelines Methodology Manual. ASCO Living Guidelines follow theASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only). Updates are published regularly and can be found athttps://ascopubs.org/nsclc-non-da-living-guideline.

The authors present the guidelines of the REFCOR (French Rare Head-and-Neck Cancer Expert Network) for sinonasal mucosal melanoma.

With the approval of PARP inhibitors (PARPi), both as monotherapy and in combination with androgen receptor signalling inhibitors (ARSi), for metastatic castration-resistant prostate cancer (mCRPC) and their rapid development in earlier disease settings, there is an urgent need to integrate homologous recombination repair (HRR) testing into daily clinical practice to identify patients who may benefit from these therapies and to improve patient management. Alterations in HRR genes are found in approximately 15-30% of patients with mCRPC and are associated with poor prognosis. In addition, some alterations are hereditary; therefore, testing also has implications for the identification of hereditary cancer risk. The successful implementation of HRR gene testing depends not only on access to sequencing technologies but also on the establishment of a comprehensive pre- and post-analytical framework. The aim of this document is to establish a multidisciplinary expert opinion consensus on the optimisation of molecular assessment of BRCA1/2 and other HRR gene alterations in metastatic prostate cancer to support implementation in clinical practice.

Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase-activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor-based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumors that appear as metastases for which a standard diagnostic work-up fails to identify the tissue of origin. There is now high-level evidence showing that actionable genomic alterations should be routinely determined in patients with CUP to enable molecularly guided therapy as appropriate. In this guideline (updated in 2025), we summarize diagnostic processes and therapeutic options for CUP, as well as new developments in molecular medicine that will help to improve the poor outcomes associated with this unique disease entity.

Management of chronic lymphocytic leukemia/ small lymphocytic lymphoma. (CLL/SLL) has undergone a significant paradigm shift, with chemo immunotherapy being virtually abandoned in favor of targeted agents. A panel of CLL/SLL experts from Tuscany proposes an updated real-life diagnostic and therapeutic approach that integrates genomic and somatic prognostic factors into routine risk stratification and treatment decisions. While the safety and efficacy of new agents are well-established in both clinical trials and real-world series, the rapid introduction of second-generation BTK inhibitors and BCL-2 antagonists necessitates a uniform and shared approach for daily clinical practice. This updated consensus reinforces the essential role of FISH for 17p deletion and TP53 mutational status before every treatment line, while IGHV mutation status should be performed for initial risk assessment. Reflecting current evidence, the proposal emphasizes a comprehensive pretreatment workup, with a particular focus on cardio-oncological screening and monitoring according to recent ESC guidelines to mitigate risks associated with BTKIs. The consensus reaffirms abdominal and superficial lymph node ultrasound as the gold standard radiological investigation for both diagnosis and response evaluation in CLL, offering a practical and radiation-free tool for longitudinal monitoring. Treatment selection is tailored based on age, genetic risk, and comorbidities, prioritizing zanubrutinib, acalabrutinib, and venetoclax-based regimens to prevent unnecessary toxicities. Furthermore, the consensus addresses the management of high-risk scenarios, including Richter transformation and the emerging role of pirtobrutinib and BTK degraders. By combining the latest clinical evidence with extensive daily experience, this updated Tuscany consensus provides a practical framework for optimized, personalized management of CLL/SLL patients in the modern therapeutic era.

Genomic technologies including next-generation sequencing (NGS) and arrays for cytogenetic anomalies are now standard of care in England for the diagnostic evaluation of patients with suspected haematological malignancies. Challenges remain in the management of potential germline findings as a result of NGS panels and copy number variant analyses in haemato-oncology pathways. The first national consensus meeting in April 2022 organised by the UK Cancer Genetics Group (UKCGGG), in collaboration with the CanGene-CanVar research programme and the NHS England haemato-oncology working group led to published best practice recommendations on laboratory and clinical pathways where there was potential to identify germline predisposition to haematological malignancies. On 3 and 4 April 2025, a second national meeting was held to address further challenges in these pathways and review updates in the national landscape subsequent to the 2022 recommendations. The meeting specifically focussed on TP53, DDX41, myeloproliferative neoplasm driver genes, non-single nucleotide variation and identification of gene carriers for addition to the National Inherited Cancer Predisposition Register (NICPR) through the National Disease Registration Service (NDRS). Using the format of a pre-workshop survey followed by structured discussion and in-meeting polling, high-level consensus was achieved for UK best practice across these areas.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

Cancer predisposition syndromes (CPSs), including genetic tumour risk syndromes (genturis), are a heterogeneous group of genetic disorders characterised by an increased risk of developing tumours compared to the general population. CPSs raise reproductive issues for affected individuals because of the risk of passing the disease-causing genetic alterations on to offspring. The demand for reproductive counselling is often unmet due to the lack of sufficient healthcare professionals with the specialised knowledge, experience and skill. Based on a comprehensive literature review of 851 publications and expert consensus (multidisciplinary medical experts and patient representatives), the European Reference Network on genetic tumour risk syndromes (ERN GENTURIS) developed a guideline providing 16 recommendations for reproductive counselling in CPSs. The central recommendation is to offer reproductive counselling proactively to all individuals with a CPS and their relevant family members, together with psychological support and in multidisciplinary collaborations. This guideline aims to standardize the offer of reproductive counselling for individuals with a CPS across Europe, empowers healthcare professionals for their specific tasks, and helps patients dealing with their own challenges.

Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key end point in clinical trials. The 2025 update of the MRD guideline provides a comprehensive and refined framework for MRD assessment, aligned with the European LeukemiaNet (ELN) 2022 genetic risk classification. Developed by members of the ELN AML MRD Working Party, the guidelines incorporate expert consensus determined through a 2-stage Delphi round. They address the clinical implementation of MRD methodologies, technical considerations, integration into clinical trials, and future directions. Importantly, MRD recommendations are tailored to individual prognostic and genetic subgroups. A new qualitative MRD response category, designated as optimal, warning, or high risk of treatment failure, has been introduced to facilitate contextual interpretation of the MRD burden and its clinical relevance. Notably, ultrahigh-sensitivity next-generation sequencing-based MRD assessment is now recommended for FLT3 internal tandem duplication-mutated AML after intensive chemotherapy and before allogeneic hematopoietic cell transplantation. A total of 56 recommendations were formulated, with 53 achieving a high level of consensus (≥90%). These updated guidelines represent a major step forward toward harmonizing MRD assessments in AML and enhancing its clinical utility across diverse treatment settings.

Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma that predominantly affects older adults. In recent years, significant progress has been made in understanding its pathogenesis, identifying relevant biomarkers, and developing novel therapeutic approaches to complement traditional chemoimmunotherapy-collectively reshaping the management landscape of WM. In this article, we provide comprehensive, evidence-based recommendations for the diagnosis, molecular evaluation, and treatment of WM, including strategies for both frontline and relapsed disease. These guidelines are informed by the latest clinical research, expert consensus, and current practice standards, with the goal of equipping clinicians with a practical and effective framework for delivering optimal care to patients with WM.

It has been five years since the last version of the clinical practice guidelines for the management of adult diffuse gliomas was published by the Asian Glioma Genome Atlas (AGGA). Significant progress and revisions have occurred in the diagnosis and treatment of adult diffuse gliomas in recent years. In response to these updates, the joint guideline committee of the Chinese Glioma Cooperative Group (CGCG), the Society for Neuro-Oncology of China (SNO-China), and the Chinese Brain Cancer Association (CBCA) has revised the clinical practice guidelines. This updated guideline emphasizes molecular and pathological diagnostics, as well as the primary treatment modalities of surgery, radiotherapy, chemotherapy, and targeted therapy. Additionally, we have incorporated findings from recent clinical trials of new therapies to align with cutting-edge treatment strategies. This guideline is designed to serve as a practical resource for all professionals involved in managing adult diffuse glioma patients, while also providing valuable information for insurance companies and other institutions responsible for regulating cancer care costs in China and beyond.

Approximately 5% of all colorectal cancers have a strong genetic component and are classified as hereditary colorectal cancer (HCRC). Some of the unique features commonly seen in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics require different management approaches, including diagnosis, treatment or surveillance, from those used in the management of sporadic colorectal cancer. Accurate diagnosis of HCRC is essential because it enables targeted surveillance and risk reduction strategies that improve patient outcomes. Recent genetic advances revealed several causative genes for polyposis and non-polyposis syndromes. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) first published guidelines for the management of HCRC in 2012, with subsequent revisions every 4 years. The 2024 update to the JSCCR guidelines for HCRC was developed by meticulously reviewing evidence from systematic reviews and the consensus of the JSCCR HCRC Guidelines Committee, which includes representatives from patient advocacy groups for FAP and Lynch syndrome. These guidelines provide an up-to-date summary of HCRC, along with clinical recommendations for managing FAP and Lynch syndrome.

RAD51C, RAD51D, and BRIP1 germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing RAD51C, RAD51D, and BRIP1 heterozygotes in clinical practice are limited.

The Italian Society of Pathology's Molecular Pathology and Precision Medicine Study Group (PMMP/SIAPeC) has released a three-part set of best practice guidelines to stan-dardize and enhance molecular testing in solid tumors. Part I focuses on the pre-analytical phase, emphasizing proper tissue handling and quality control to preserve nucleic acid integrity. Part II addresses the analytical phase, outlining workflows for next-generation sequencing (NGS), from extraction to variant interpretation, with recommendations on choice of platform, gene panels, and bioinformatics. Part III covers the post-analytical phase, offering guidance on structured, clinically meaningful reporting to support thera-peutic decisions, including standards for both tissue and liquid biopsies. Together, these documents aim to harmonize molecular diagnostics, ensuring reliable, high-quality results that support precision oncology.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

UK Guidelines for the management of uveal melanoma (UM) were first published in 2015 using an evidence-based systematic approach. The primary aim of this guideline was to optimise patient care by providing recommendations based on the best available scientific evidence. The resulting guideline reflected the strengths and weaknesses of the available evidence, made recommendations that were clinically impactful around prognostication, surveillance, and treatment for patients with primary lesions and metastatic disease. The guideline development process and content met the standards required by NICE and were ultimately NICE accredited. Here, we present an update to these guidelines, highlighting where practice or treatment has changed to such an extent that the original recommendations are now out of date. Presented here are updated guidelines on molecular and genetic testing, management of metastatic disease and clinical surveillance.

Microsatellite instability (MSI) is the accumulation of insertion and deletion variants (instability) in short tandem repeat DNA sequences (microsatellites). High levels of MSI occur following loss of function of the DNA mismatch repair system (MMR). MMR deficiency is an increasingly important cancer biomarker that is associated with chemotherapy resistance and response to immune checkpoint blockade, as well as one of the commonest hereditary cancer syndromes, Lynch syndrome. Since its discovery over two decades ago, our biological understanding, the testing methods, and the clinical implications of MSI analysis have expanded rapidly and up-to-date best practice guidelines are needed. An expert working group reviewed the literature and devised 15 best practice recommendations that were finalised following consultation with clinical and laboratory scientists partnered with EMQN. These include seven recommendations on key technical aspects of MSI testing and eight recommendations on the clinical interpretation and reporting of results. The latter focuses on Lynch syndrome screening and immune checkpoint blockade therapy. Example report wording is provided to assist implementation and standardisation. Common terminology and MSI analysis methods are also discussed. These guidelines are aimed primarily at genomic scientists working in diagnostic testing laboratories, but will provide a useful review of MSI for clinicians, academics, and other related professionals.

The classification and diagnosis of penile intraepithelial neoplasia (PeIN) remains inconsistent among pathologists, despite its recognized role and understanding as a precursor to penile squamous cell carcinoma (PSCC). The International Society of Urological Pathology (ISUP) convened a consensus group of multidisciplinary thought leaders to assess current global practices regarding the usage of terminology, grading, and molecular testing in penile cancer precursor lesions. A preconference survey was distributed to ISUP members in 2024, collecting responses from 112 pathologists, predominantly genitourinary specialists, to evaluate the use of penile cancer precursor lesion classification systems, grading approaches, and diagnostic biomarkers. The results were presented at the ISUP Multidisciplinary Consensus Conference on Cancer Precursor Lesions in September 2024, where further consensus was achieved through electronic voting. The survey revealed that 89.4% of respondents classify PeIN based on HPV association, with 76% supporting further subtyping into basaloid, warty, and differentiated subtypes. Grading of PeIN remains controversial; 51.3% initially favored grading, but 82% finally voted that PeIN should not be graded. p16 immunohistochemistry (IHC) was widely utilized (91.5%) to distinguish HPV-associated from HPV-independent PeIN, whereas p53 IHC and HPV genotyping lacked consensus for routine use. Reporting practices for PeIN margins and their association with lichen sclerosis were widely endorsed, while the value and concordance of subtyping HPV-independent PeIN remains an area for further investigation. This ISUP consensus paper guides PeIN classification, confirming the importance of HPV-related stratification and p16 IHC staining and reporting as standard practice. However, significant variability persists in PeIN grading and molecular testing strategies. These findings highlight the need for further research and standardization to optimize diagnostic accuracy and clinical relevance in PeIN.