Overview of Molecular Diagnostics in Irish Clinical Oncology

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Hynes" }, { "@type": "Person", "name": "Maeve Lowery" }, { "@type": "Person", "name": "Patrick Gillespie" }, { "@type": "Person", "name": "Walter Kolch" }, { "@type": "Person", "name": "Cathal Seoighe" } ], "publisher": { "@type": "Organization", "name": "HRB Open Research", "logo": { "@type": "ImageObject", "url": "https://hrbopenresearch.org/img/AMP/HRB_image.png", "height": 566, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://hrbopenresearch.org/img/AMP/HRB_image.png", "height": 1200, "width": 127 }, "description": " Background Molecular diagnostics are critical for informing cancer patient care. In Ireland, the National Cancer Control Programme (NCCP) develops cancer therapy regimens, which include relevant information on molecular indications. Here, we present a collated overview of the current molecular indications of all NCCP systemic anti-cancer therapy regimens and the funding statuses of their associated drugs. Furthermore, we also provide estimates for the scale of required molecular testing in cancer therapy and for the clinical genetic sequencing capacity of Ireland, and provide a summary of current cancer clinical trials in Ireland which have molecular components. Methods Through a combination of web scraping, keyword search, and manual review, we performed a full review of all 757 indications included in the 476 therapy regimens published to date by the NCCP to identify therapy indications with explicit molecular criteria. For all cancer types identified in these indications, we obtained incidence rates in Ireland from National Cancer Registry Ireland to predict the number of patients yearly who stand to benefit from a molecular test. We then applied molecular subtype rates from published literature to estimate the number of patients who would then qualify for a relevant molecularly guided therapy. Results We identified 210 indications for 148 NCCP therapy regimens that include molecular criteria. These 210 molecular indications encompassed 85 genetic criteria, 137 cellular biomarker criteria, 57 molecularly informed drugs, and over 20 cancer types. We estimated that up to approximately 50% of cancer patients in Ireland could qualify for a molecular test and that the majority of tested patients would qualify for a treatment informed by a molecular test. Conclusions As personalised cancer medicine continues to develop in Ireland, this study will provide a baseline understanding of current practices. We anticipate that work such as this will help to inform planning in the healthcare system. 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HRB Open Res 2024, 7 :16 ( https://doi.org/10.12688/hrbopenres.13822.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] Tyler Medina https://orcid.org/0000-0003-4199-9255 1,2 , Seán O. Hynes 3,4 , Maeve Lowery 5 , Patrick Gillespie 6,7 , Walter Kolch https://orcid.org/0000-0001-5777-5016 8,9 , Cathal Seoighe 1 Tyler Medina https://orcid.org/0000-0003-4199-9255 1,2 , Seán O. Hynes 3,4 , [...] Maeve Lowery 5 , Patrick Gillespie 6,7 , Walter Kolch https://orcid.org/0000-0001-5777-5016 8,9 , Cathal Seoighe 1 PUBLISHED 26 Mar 2024 Author details Author details 1 School of Mathematical & Statistical Sciences, University of Galway, Galway, County Galway, Ireland 2 SFI Centre for Research Training in Genomics Data Science, Science Foundation Ireland, Dublin, Ireland 3 Discipline of Pathology, School of Medicine, University of Galway, Galway, County Galway, Ireland 4 Division of Anatomical Pathology, University Hospital Galway, Galway, Ireland 5 Trinity St James’s Cancer Institute, St James's Hospital and Trinity College Dublin, Dublin, Ireland 6 CURAM, SFI Research Centre for Medical Devices, University of Galway, Galway, County Galway, Ireland 7 Health Economics and Policy Analysis Centre, Institute for Lifecourse and Society, University of Galway, Galway, County Galway, Ireland 8 Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland 9 Systems Biology Ireland, University College Dublin, Dublin, Ireland Tyler Medina Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Seán O. Hynes Roles: Supervision, Writing – Review & Editing Maeve Lowery Roles: Supervision, Writing – Review & Editing Patrick Gillespie Roles: Supervision, Writing – Review & Editing Walter Kolch Roles: Supervision, Writing – Review & Editing Cathal Seoighe Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Molecular diagnostics are critical for informing cancer patient care. In Ireland, the National Cancer Control Programme (NCCP) develops cancer therapy regimens, which include relevant information on molecular indications. Here, we present a collated overview of the current molecular indications of all NCCP systemic anti-cancer therapy regimens and the funding statuses of their associated drugs. Furthermore, we also provide estimates for the scale of required molecular testing in cancer therapy and for the clinical genetic sequencing capacity of Ireland, and provide a summary of current cancer clinical trials in Ireland which have molecular components. Methods Through a combination of web scraping, keyword search, and manual review, we performed a full review of all 757 indications included in the 476 therapy regimens published to date by the NCCP to identify therapy indications with explicit molecular criteria. For all cancer types identified in these indications, we obtained incidence rates in Ireland from National Cancer Registry Ireland to predict the number of patients yearly who stand to benefit from a molecular test. We then applied molecular subtype rates from published literature to estimate the number of patients who would then qualify for a relevant molecularly guided therapy. Results We identified 210 indications for 148 NCCP therapy regimens that include molecular criteria. These 210 molecular indications encompassed 85 genetic criteria, 137 cellular biomarker criteria, 57 molecularly informed drugs, and over 20 cancer types. We estimated that up to approximately 50% of cancer patients in Ireland could qualify for a molecular test and that the majority of tested patients would qualify for a treatment informed by a molecular test. Conclusions As personalised cancer medicine continues to develop in Ireland, this study will provide a baseline understanding of current practices. We anticipate that work such as this will help to inform planning in the healthcare system. READ ALL READ LESS Keywords personalised medicine, molecular diagnostics, genomics, cancer, clinical oncology, Ireland Corresponding Author(s) Tyler Medina ( [email protected] ) Cathal Seoighe ( [email protected] ) Close Corresponding authors: Tyler Medina, Cathal Seoighe Competing interests: Maeve Lowery has a consulting or advisory role in Roche/Genentech, AstraZeneca, and Servier, and receives research funding through her institution from MSD, Exelixis, Basilea, Astellas Pharma, Zymeworks, Legend Biotech, and Genuity Science. Sean Hynes has received honoraria for speaking and meeting support from Roche. All other authors have no conflicts of interest to disclose, including financial interest. Grant information: Health Research Board [CES-2023-025], Science Foundation Ireland [18/CRT/6214], Science Foundation Ireland [16/IA/4612], H2020 Marie Skłodowska-Curie Actions, [H2020-MSCA-COFUND-2019-945385]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Medina T et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Medina T, Hynes SO, Lowery M et al. Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.12688/hrbopenres.13822.1 ) First published: 26 Mar 2024, 7 :16 ( https://doi.org/10.12688/hrbopenres.13822.1 ) Latest published: 09 Jun 2025, 7 :16 ( https://doi.org/10.12688/hrbopenres.13822.2 )  There is a newer version of this article available. Suppress this message for one day. Introduction Modern genetics and genomics have played a vital role in human health for decades. However, since the advent of high-throughput next-generation sequencing (NGS), the role of genomics and molecular diagnostics in healthcare has increased dramatically 1 . As the science, engineering, and data analysis surrounding genomics continue to develop through research and innovation, genomics technologies progressively move from research and development into practical clinical usage in applications ranging from neonatal screening 2 and hereditary disease risk 3 to chemotherapy management and prognostics 4 . To facilitate the integration of genomics and healthcare, many nations are in the process of developing or implementing strategies, legislation, policy, and infrastructure for clinical genomics 5 – 9 . Ireland is among these nations, having recently published a national plan for genomics medicine under the National Genomics and Genetics Strategy, which will oversee and guide implementation of the strategy as part of the national healthcare system in coming years 10 . While science and innovation drive novel technologies and techniques in genomics, familiarity with current clinical practices is vital to matching research effort and expertise to clinical need and application. Here we aim to highlight actionable and informative molecular diagnostics in use in clinical oncology in Ireland by examining the cancer therapies and clinical trials currently informed by molecular diagnostics in Ireland. In addition, amidst increasing cancer incidence each year, we predict the number of patients in Ireland requiring a molecular diagnostic yearly and the number that would potentially benefit from molecular diagnostics and compare this to the availability of NGS infrastructure in major hospitals around the country. Molecular Diagnostics in Cancer Treatment Regimens in Ireland Under the Health Service Executive (HSE), the National Cancer Control Programme (NCCP) is the leading national body addressing the diagnosis and treatment of cancer in Ireland. With the principal aim of implementing the Irish National Cancer Strategy, the NCCP's activities include reviewing new cancer therapies and developing national regimens for their use as part of the National Cancer Information System 11 . New cancer drugs approved by the European Medicines Agency are assessed by the National Centre for Pharmacoeconomics, Ireland (NCPE) to produce a health technology assessment (HTA), which addresses the benefit vs. financial cost of the drug in question and recommends whether the drug should or should not be reimbursed by the HSE 12 . These reports, as well as information from experts and research, are assessed by the NCCP Technology Review Committee to recommend cancer drugs for funding under HSE drug schemes such as the Oncology Drugs Management Scheme (ODMS) or the Primary Care Reimbursement Services (PCRS) community drugs schemes 13 , 14 . Independent of the funding status of a drug, the NCCP also develops, manages, and reviews national drug regimens addressing when and how these drugs should be used. In addition to information about drug combinations and dosing, these regimens also include, when relevant, the molecular indications required for the use of certain drugs in particular cancer types 15 . Note that while these regimens set guidelines for therapy, they are not exhaustive and clinical practice may differ when appropriate. Genetic Indications Cancer is, by nature, a disease of genetic origins 16 . Though there are many different genome sequence mutations associated with many cancer types, only a small subset of these are currently known to be clinically informative or actionable, typically by informing diagnosis, prognosis, and/or treatment options 17 . For example, the EGFR gene encodes a tyrosine kinase which, when activated, signals for increased DNA replication and general cell proliferation; as such, over-activation of EGFR is associated with a variety of cancer types, including non-small cell lung cancer (NSCLC), in which approximately 14% of European patients harbour an EGFR-activating mutation 18 . For these patients, tyrosine-kinase inhibitor (TKI) therapies specifically targeting EGFR (e.g., osimertinib, gefitinib) are more effective and are associated with more favourable outcomes compared to chemotherapy 19 , 20 . In colorectal cancer patients, however, the presence of KRAS-activating mutations greatly reduces the efficacy of anti-EGFR TKI chemotherapies, as KRAS is a downstream activation target of the EGFR signalling pathway; once permanently activated through mutation, KRAS promotes tumour growth regardless of EGFR inhibition, and is associated with poorer outcomes 21 . As in these examples, identifying genetic mutations can be critical in directing cancer treatment. Among all cancer treatment regimens developed by the NCCP, there are currently 13 genetic factors (including 2 broader genetic phenotypes) informing 85 therapy indications across 63 chemotherapy regimens. These regimens involve combinations of 42 different genomics-informed drugs, 37 of which are approved for funding through either the PCRS or the ODMS for approved indications ( Table 1 ) 15 , 22 – 25 . Table 1. Aggregate summary of genetic indications in NCCP cancer therapies. Genetic indications per cancer type are listed with their associated drugs and drug reimbursement status in Ireland. (NSCLC: non-small cell lung cancer; mCRC: metastatic colorectal cancer; mCRPC: metastatic castration-resistant prostate cancer; ALL: acute lymphoblastic leukaemia; CLL: chronic lymphocytic leukaemia; AML: acute myeloid leukaemia; CML: chronic myelogenous leukaemia; GIST: gastrointestinal stromal tumour; PCRS: Primary Care Reimbursement Service; ODMS: Oncology Drugs Management System; MSI-H: microsatellite instability-high; dMMR: deficient mismatch repair; HRD: homologous recombination deficiency). Cancer Type Subtype Indication Drugs Reimbursement Breast metastatic breast cancer BRCA1/2 germline mutation talazoparib PCRS Lung NSCLC ALK mutation alectinib PCRS brigatinib PCRS ceritinib PCRS crizotinib PCRS lorlatinib PCRS EGFR-activating mutation afatinib PCRS dacomitinib PCRS erlotinib PCRS erlotinib and bevacizumab erlotinib: PCRS; bevacizumab: Hospital gefitinib PCRS osimertinib PCRS EGFR T790M mutation osimertinib PCRS normal EGFR and ALK atezolizumab ODMS ipilimumab and nivolumab ODMS pembrolizumab ODMS ROS1 mutation crizotinib Reimbursement for indication not approved entrectinib PCRS Gastro-intestinal mCRC normal RAS cetuximab Hospital panitumumab Hospital MSI-H or dMMR pembrolizumab ODMS ipilimumab and nivolumab ODMS Skin metastatic melanoma BRAF V600 mutation dabrafenib PCRS dabrafenib and trametinib PCRS encorafenib and binimetinib PCRS vemurafenib PCRS vemurafenib and cobimetinib PCRS Gynae-cological epithelial ovarian, fallopian tube, and peritoneal cancers HRD+, BRCA1/2 somatic mutation, or genomic instability olaparib and bevacizumab olaparib: ODMS; bevacizumab: Hospital BRCA1/2 germline or somatic mutation olaparib PCRS Genito-urinary mCRPC BRCA1/2 germline or somatic mutation olaparib PCRS niraparib and abiraterone acetate (akeega®) PCRS Leukaemia ALL BRC-ABL1 fusion inotuzumab ozogamicin ODMS BRC-ABL1 fusion with T315I mutation ponatinib PCRS BRC-ABL1 fusion negative blinatumomab ODMS CLL TP53 mutation or deletion acalabrutinib PCRS idelalisib and rituximab idelalisib: PCRS; rituximab: Hospital ibrutinib PCRS venetoclax PCRS zanubrutinib PCRS AML FLT3 mutation midostaurin PCRS CML BRC-ABL1 fusion bosutinib PCRS asciminib PCRS BRC-ABL1 fusion with T315I mutation ponatinib PCRS Sarcoma GIST CD117 mutation imatinib PCRS Tumour-agnostic NTRK fusion larotrectinib PCRS Techniques and Technologies Depending on clinical purpose and cost, testing for relevant genetic mutations in cancer occurs at several levels of scale. Small-scale single-gene tests can be used to identify known point mutations, such as EGFR T790M or KRAS G12C chemotherapy resistance mutations 26 , 27 , or to identify known fusion genes, such as the BCR-ABL1 gene fusion found in chronic myelogenous leukaemia (CML) 28 . These single-gene tests are generally performed using techniques such as quantitative polymerase chain reaction (qPCR) or fluorescent in-situ hybridization (FISH), and can also be performed on both Sanger sequencing and next-generation sequencing (NGS) platforms, though using high-throughput NGS with very small targets is generally not cost efficient without very large numbers of samples. Multiple genes can be tested for mutations simultaneously by sequencing on an NGS instrument. These NGS assays range from small disease-focused gene panels, targeting tens to hundreds of genes; to whole exome sequencing (WES or WXS), targeting tens of thousands of genes; to whole genome sequencing (WGS), which generates data from both genic and non-genic regions. In all NGS applications, results can then be subset virtually to focus on disease-specific genes or regions of interest. While methods like qPCR or genotyping microarrays can be used to detect known mutations, genome sequencing does not require a priori knowledge of mutations of interest, thus allowing for discovery of novel relevant genomic variation in cancer 29 . While novel mutations are not likely to be clinically actionable upon discovery, they may have potential for use in research, trials, and treatment in the future. More comprehensive genomic sequencing additionally allows for more complex genomic profiling strategies which can further inform disease aetiology, progression, and prognosis. In Ireland, qPCR and FISH single-gene tests, gene panels including ThermoFisher's Oncomine Focus panels and other ThermoFisher Ion AmpliSeq small gene panels, and clinical exome gene panels are all routinely used. While whole genome sequencing can be clinically useful, this is generally not performed in Ireland as routine care outside of clinical trials or research applications. In addition to the genetic sequencing performed by Irish medical laboratories, patient samples are also sent to external sequencing facilities in cases requiring, for example, rapid turnaround time, Sanger sequencing variant confirmation, or specialty assay sequencing. Notably, homologous recombination deficiency (HRD) has recently been added as an NCCP indication for olaparib treatment of ovarian cancer. While largely determined by the presence of deleterious BRCA1/2 mutations, HRD is a wider genetic phenotype influenced by larger genomic factors such as loss-of-heterozygosity and rearrangement events. Similarly, high microsatellite instability (MSI-H), which was recently added as an NCCP indication for immune checkpoint inhibitors in colorectal cancer, requires profiling of multiple locations throughout the genome. Both HRD and MSI-H testing thus require larger or specialty NGS gene panels, such as the Myriad MyChoice HRD test, FoundationOne panel, and Illumina TSO500 panel, all of which are currently being considered for use in Ireland. These external tests are generally funded under hospital departmental budgets rather than being reimbursed directly by the HSE, though efforts are underway by several hospitals to develop the infrastructure required to perform more genetic tests domestically in public facilities. Cellular Biomarker-Based Indications In addition to identifying mutated cancer-associated genes, confirming the presence of cellular biomarkers, which commonly include hormone receptors and antigens involved in immune cell recognition, can also be vital for accurate cancer diagnosis and treatment decisions. Lymphoma subtypes, for example, each exhibit characteristic immunophenotypes which can be essential for differential diagnosis of cancers that are otherwise morphologically similar 30 , 31 . Biomarkers expressed on the cell surface can also serve as key drug targets. Antibody-based therapies target only specific cell types exhibiting the target antigen, and thus can activate or inhibit cellular signalling pathways or elicit a patient immune response against target cells, while limiting the potential deleterious effects of cancer treatment. Antibody-drug conjugates, such as brentuximab vedotin, further exploit this specificity by directing otherwise highly toxic chemotherapy drugs only to cells exhibiting the target antigen 32 . Complementary to antibody-based therapies, small molecule drugs can also reach intracellular targets. For example, several treatment routes exist to reduce the growth-promoting effect of oestrogen on oestrogen-receptor-positive (ER+) breast tumours, including anastrozole, which binds aromatase enzymes to inhibit the production of oestrogen in the body; tamoxifen, which inhibits oestrogen binding by blocking oestrogen receptors; and fulvestrant, which binds and destabilises oestrogen receptors, inducing their breakdown by the cell 33 . Like genetic mutations, the presence or absence of cellular biomarkers can play a critical role in diagnosis, prognosis, and treatment of a patient. In Ireland, the presence or absence of 10 markers are a factor for 137 indications for 22 different therapies across 98 treatment regimens published by the NCCP, and are of particular importance for informing breast cancer and lymphoma treatments, which account for 75% of these indications. Of the 22 included therapies, 19 have funding through the ODMS and PCRS ( Table 2 ) 15 , 22 – 25 . Table 2. Aggregate summary of cellular biomarker-based indications in NCCP cancer therapies. Indications are listed per cancer type with their associated drugs and drug reimbursement status in Ireland. (NSCLC: non-small cell lung cancer; mCRC: metastatic colorectal cancer; GEJ: gastro-oesophageal junction; HNSCC: head and neck squamous cell carcinoma; B-ALL: B-cell acute lymphoblastic leukaemia; AML: acute myeloid leukaemia; NHL: non-Hodgkin lymphoma; PCRS: Primary Care Reimbursement Service; ODMS: Oncology Drugs Management System). Cancer Type Subtype Indication Drugs Reimbursement Breast ER+ fulvestrant PCRS tamoxifen PCRS HR+ anastrozole PCRS exemestane PCRS letrozole PCRS HER2+ trastuzumab Hospital trastuzumab and pertuzumab trastuzumab: Hospital; pertuzumab: ODMS trastuzumab/ pertuzumab (Phesgo ® ) ODMS trastuzumab emtansine (Kadcyla ® ) ODMS neratinib PCRS lapatinib PCRS HER2-, HR+ exemestane PCRS aromatase inhibitor or fulvestrant PCRS HER2-, HR-, PD-L1+ atezolizumab ODMS Lung NSCLC PD-L1+ atezolizumab ODMS durvalumab ODMS pembrolizumab ODMS Gastro-intestinal mCRC EGFR+ cetuximab Hospital metastatic stomach adenocarcinoma HER2+ trastuzumab Hospital metastatic gastric or GEJ cancer HER2+ trastuzumab Hospital GEJ adenocarcinoma HER2-, PD-L1+ pembrolizumab ODMS oesophageal carcinoma PD-L1+ pembrolizumab ODMS oesophageal squamous cell carcinoma PD-L1+ nivolumab ODMS Genito-urinary urothelial carcinoma PD-L1+ atezolizumab ODMS pembrolizumab ODMS Gynae-cological cervical cancer PD-L1+ pembrolizumab Reimbursement by exception Head & Neck HNSCC PD-L1+ pembrolizumab ODMS Leukaemia B-ALL CD19+ blinatumomab ODMS CD22+ inotuzumab ozogamicin ODMS AML CD33+ gemtuzumab ozogamicin ODMS Lymphoma Hodgkin lymphoma CD30+ brentuximab vedotin ODMS CD20+ rituximab Hospital non-Hodgkin B-cell lymphomas CD20+ rituximab Hospital follicular lymphoma CD20+ rituximab Hospital CD20+ obinutuzumab ODMS systemic anaplastic large cell lymphoma CD30+ brentuximab vedotin ODMS cutaneous T-cell lymphoma CD30+ brentuximab vedotin ODMS Techniques and Technologies The presence of cellular biomarkers can be determined either by direct detection, or by some indirect indication of their presence. Immunohistochemistry (IHC) techniques, which remain the gold standard for direct determination, use a combination of an antigen-specific antibody and a dye or fluorophore to indicate antigen presence in cancer tissue samples via microscopy 34 . While this technique can generally only detect one antigen per assay, the process can be parallelized in appropriate tissue samples via flow cytometry, such that multiple antibodies can be applied, allowing several antigens to be detected on cancer cells simultaneously 35 , 36 . Indirect detection, instead, can be accomplished through gene expression analysis. Rather than detecting an antigen of interest via an antibody, this approach involves the quantification of RNA transcripts encoding the biomarker. Techniques for measuring expression analysis are similar to those for detecting DNA mutations and include reverse transcription qPCR (RT-qPCR), expression microarrays, and next-generation RNA sequencing (RNA-seq). These methods also scale similarly to DNA mutation detection methods: qPCR is limited to measuring the expression of single genes, while microarrays and RNA-seq are able to simultaneously quantify thousands of transcripts. Of particular note is that RNA-seq, in addition to expression analysis, also allows for mutation detection by default. This includes more complex mutations such as fusion genes, which are frequently highly associated with cancer and can serve as drug targets for inhibitors such as ponatinib, which inhibits BCR-ABL1 fusion proteins found in CML 37 , and larotrectinib, a novel tumour-agnostic Trk inhibitor that can be used for any cancer in which NTRK -family fusions are detected 38 . While RNA expression assays are less commonly used in clinical practice, recent studies have shown comparable test results between RNA-seq and IHC 39 . In Irish hospitals, cellular biomarker detection methods generally include single gene tests like IHC and RT-qPCR. In addition, the external testing service Oncotype DX ® is available in Ireland for breast cancer patients and uses RT-qPCR to measure the expression of 16 genes, including HER2 and both oestrogen and progesterone receptor genes 40 – 42 . While RNA-seq remains uncommon, reimbursement for larotrectinib in Ireland notably requires submission of RNA-seq results 43 . Requirement for Cancer Molecular Diagnostics Data on the incidence of cancer in Ireland has been centrally recorded by National Cancer Registry Ireland (NCRI) since 1994. While the total incidence of cancer in Ireland has doubled since 1994 ( Figure 1a, 1c ), the rate of cancer incidence has increased by approximately 50% ( Figure 1b ) and age-adjusted incidence has increased by approximately 15% ( Figure 1d ), reflecting at least in part the advancing age profile of the larger population and increases in life expectancy 44 , 45 . Latest available figures (from 2020) show a current 1 in 2 lifetime risk of invasive cancer 46 . Fortunately, overall cancer survival in Ireland has also increased ( Figure 2 ), with a gain of approximately 15 percentage point survivorship over the same time period 47 . Figure 1. Incidence of all invasive cancers (except NMSC) in Ireland from 1994–2019. Top: For males (blue), females (red), and total population (green), a ) case counts of cancers per year and b ) case counts per 100,000 individuals in each category per year. Bottom: For 0–49 (purple), 50–64 (green), 65–74 (red), and 75+ (blue) years old, c ) cancer case counts per year and d ) cancer case counts per 100,000 individuals in each category per year. Cancer incidence data taken from National Cancer Registry Ireland 44 . National population estimates per year taken from the Central Statistics Office Ireland 45 . (NMSC: non-melanoma skin cancer). Figure 2. Net survival of all invasive cancers (except NMSC) in Ireland over time, from 1994–2014. Survival curve estimates showing percent net survival at selected time points for diagnoses made during the given time period. Data provided by and plot adapted from National Cancer Registry Ireland 44 . (NMSC: non-melanoma skin cancer). Advances in personalised medicine continue to contribute to this survival improvement, with cancer molecular diagnostics enabling a wide range of modern therapy options. However, it is not clear how many patients in Ireland currently receive or stand to benefit from molecular cancer diagnostics. Data on the rate of molecular diagnostics usage in Ireland is not publicly available and is not currently centrally recorded. This information is relevant to quantification of the potential benefits of genomic tests on the population level and for resource planning, not least as part of the National Genomics and Genetics Strategy. Furthermore, while NCRI collects and provides information on cancer incidence, specific cancer rates are categorised by International Classification of Diseases 10th revision (ICD-10) definitions largely classed by tissue type, leaving molecular subtype rates in Ireland unknown. Based on current disease-informing molecular diagnostics listed in NCCP treatment regimens, cancer incidence rates published by NCRI, published studies on molecular cancer subtypes, and the single most common molecular subtype per cancer, we estimate that over 12,000 patients should be receiving some form of molecular diagnostic test yearly to identify the subpopulation of at least 7,000 cancer patients that stand to benefit from current molecular-diagnostic-guided therapeutics used in Ireland. These include over 1,500 patients who would qualify for a genetic-guided therapy, and 6,500 patients who would qualify for a cellular biomarker-guided therapy ( Table 3 and Table 4 ). This testing burden represents approximately 50% of the 24,000 invasive cancer cases in Ireland yearly (excluding non-melanoma skin cancer), with about 30% directly benefiting from a test result 46 . It should be noted that these numbers only include tests that directly inform therapy, and do not include the large body of molecular tests performed primarily for diagnostic or prognostic purposes. In addition, NTRK -fusion testing is not included in these estimates, as treatment is tumour-agnostic and NTRK -fusion incidence is quite variable across various tumour types 48 . Table 3. Predicted incidence of cancers with genetic indications for therapy in Ireland. Yearly incidence of cancer types with a genetic indication in Ireland, with predicted numbers of positive molecular diagnoses based on rates from literature. Incidence in Ireland published by National Cancer Registry Ireland 46 , unless otherwise noted by citation. Molecular subtype rate estimates (MD+ Rate) for each cancer obtained from indicated references. (ICD-10: International Classification of Diseases 10th Revision; MD: Molecular diagnostic; NSCLC: non-small cell lung carcinoma; mCRC: metastatic colorectal cancer; B-ALL: B-cell acute lymphoblastic leukaemia; CLL: chronic lymphocytic leukaemia; AML: acute myeloid leukaemia; CML: chronic myelogenous leukaemia; mCRPC: metastatic castration-resistant prostate cancer; GIST: gastrointestinal stromal tumour; MSI-H: microsatellite instability-high; dMMR: deficient mismatch repair) *Only female cases included. **Chemotherapy resistance mutation incidence is variable, with incidence typically increasing in response to therapy. Cancer Type ICD-10 Label Subtype Incidence in Ireland Molecular Diagnostic (MD) MD+ Rate MD+ Incidence in Ireland References Breast C50: Malignant neoplasm of breast 3363 * BRCA1/2 germline mutation 0.024 81 51 – 54 Lung C34: Malignant neoplasm of bronchus and lung NSCLC 55 – 57 2268 ALK mutation 0.05 113 58 – 60 ROS1 mutation 0.02 45 61 EGFR-activating mutation 0.14 320 18 , 58 EGFR T790M mutation Builds ** 62 , 63 Gastro-intestinal C18-21: Malignant neoplasm of: - colon - rectosigmoid junction - rectum - anus and anal canal mCRC 64 1058 normal RAS 0.39 416 64 MSI-H or dMMR 0.04 42 65 – 68 Skin C43: Malignant melanoma of skin Melanoma 1170 BRAF V600 mutation 0.5 585 69 – 71 Leukaemia C91.0: Acute lymphoblastic leukaemia [ALL] B-ALL 72 49 BCR-ABL1 fusion 0.04 paediatric, 0.25 adult 5 73 BCR-ABL1 fusion with T315I mutation Builds ** 74 C91.1: Chronic lymphocytic leukaemia of B-cell type CLL 202 TP53 mutation or deletion 0.1 20 75 C92.0: Acute myeloblastic leukaemia [AML] AML 138 FLT3 mutation 0.3 41 76 C92.1: Chronic myeloid leukaemia [CML], BCR/ABL-positive CML 63 BCR-ABL1 fusion 0.94 59 77 BCR-ABL1 fusion with T315I mutation Builds ** 77 Gynae-cological C56: Malignant neoplasm of ovary Epithelial ovarian cancer 78 – 80 360.9 BRCA1/2 germline or somatic mutation 0.25 90 81 – 83 C57.0: Malignant neoplasm: Fallopian tube Fallopian tube cancer 25 0.35 9 81 – 83 C48: Malignant neoplasm of retroperitoneum and peritoneum Peritoneal carcinoma 24 * 0.16 4 81 – 83 Genito-urinary C61: Malignant neoplasm of prostate mCRPC 84 , 85 534 BRCA1/2 germline or somatic mutation 0.14 75 86 Sarcoma C49: Malignant neoplasm of other connective and soft tissue GIST 87 20 CD117 mutation 0.8 16 88 , 89 Total, max per cancer type 9274 1721 Table 4. Predicted incidence of cancers with cellular biomarker indications for therapy in Ireland. Yearly incidence of cancer types with a cellular biomarker-based diagnostic in Ireland, with predicted numbers of positive molecular diagnoses based on rates from literature. Incidence in Ireland published by National Cancer Registry Ireland 46 , unless otherwise noted by citation. Molecular subtype rate estimates (MD+ Rate) for each cancer obtained from indicated references. (ICD-10: International Classification of Diseases 10th Revision; MD: Molecular diagnostic; NSCLC: non-small cell lung carcinoma; mCRC: metastatic colorectal cancer; GEJ: gastro-oesophageal junction; ALCL: anaplastic large cell lymphoma; CTCL: cutaneous T-cell lymphoma; HNSCC: head and neck squamous cell carcinoma; B-ALL: B-cell acute lymphoblastic lymphoma; AML: acute myeloid leukaemia) *Only female cases included. Cancer Type ICD-10 Label Subtype Incidence in Ireland Molecular Diagnostic (MD) MD+ Rate MD+ Incidence in Ireland References Breast C50: Malignant neoplasm of breast 3363 * ER+ 0.806 2711 90 HR+ 0.818 2751 90 HER2+ 0.154 517 90 PD-L1+ 0.197 663 91 Lung C34: Malignant neoplasm of bronchus and lung NSCLC 55 – 57 2268 PD-L1+ 0.336 739 92 , 93 Gastro-intestinal C18-21: Malignant neoplasm of: - colon - rectosigmoid junction - rectum - anus and anal canal mCRC 64 1058 EGFR+ 0.6 635 94 , 95 C16: Malignant neoplasm of stomach stomach or GEJ cancer 557 HER2+ 0.221 123 96 C15: Malignant neoplasm of oesophagus oesophageal or GEJ cancer 515 PD-L1+ 0.45 232 97 – 100 Lymphoma C81: Hodgkin lymphoma Hodgkin lymphoma 101 127 CD30+ 1.00 127 30 , 101 C82: Follicular lymphoma C83: Non-follicular lymphoma C85: Other and unspecified types of non-Hodgkin lymphoma C88: Malignant immunoproliferative diseases non-Hodgkin B-cell lymphomas 712 CD20+ 0.98 698 102 C84: Mature T/NK-cell lymphomas ALCL and CTCL 83 CD30+ 1.00 83 103 Head & Neck C00-14: Malignant neoplasms of lip, oral cavity and pharynx C30-C32: Malignant neoplasm of: - nasal cavity and middle ear - accessory sinuses - larynx HNSCC 786 PD-L1+ 0.85 668 104 Genito- urinary C65-68: Malignant neoplasm of: - renal pelvis - ureter - bladder - other and unspecified urinary organs urothelial carcinoma 105 – 107 536 PD-L1+ 0.303 162 108 , 109 Gynae-cological C53: Malignant neoplasm of cervix uteri cervical cancer 253 PD-L1+ 0.85 215 110 , 111 Leukaemia C91.0: Acute lymphoblastic leukaemia [ALL] B-ALL 72 49 CD19+ 1.00 49 112 CD22+ 0.98 48 113 C92.0: Acute myeloblastic leukaemia [AML] AML 138 CD33+ 0.85 117 114 Total, max per cancer type 8682 6599 To accommodate the clinical needs of these individuals, clinical laboratories in the Republic of Ireland operate several makes of instruments, each with their own capacity and throughput. In total, there are four Illumina NextSeq, one Illumina MiniSeq, and four ThermoFisher Ion Torrent NGS instruments currently operating in clinical practice across 5 Irish hospitals. In addition, there are a number of qPCR machines available for single-gene tests, as well as one Sanger sequencing platform for confirmation testing. Based on published technical specifications 49 , 50 , the combination of high-throughput NextSeq and Ion Torrent instruments in Ireland represent a maximum nominal capacity of approximately 44 – 68 deep whole exomes sequenced in a 30 hour period, depending on targeted depth, exome size, and amplification, though in reality this number is also greatly dependent upon sample batching, laboratory operation and sample preparation time, specific instrument configuration, and operating costs, among numerous other factors. Molecular Indications for Clinical Trial Inclusion In addition to routine care pathways, clinical trials offer some patients access to cancer therapies that would not otherwise be available, typically because the therapy is novel or is not yet offered in Ireland. Clinical trials for cancer therapies dictate strict enrolment criteria, and these are often based on molecular diagnosis of cancer subtypes. Cancer Trials Ireland, for example, currently lists 86 clinical trials for cancer available in the country. Of these, at least 43 list a molecular diagnostic as either eligibility criteria or as a factor in the trial ( Table 5 ) 115 . For example, the KRYSTAL-10 and LOXO 101 trials are both currently active in Ireland: KRYSTAL-10 is currently recruiting at several Irish hospitals, and is investigating the use of a novel KRAS-inhibiting drug, known currently as MRTX849, to treat colorectal cancer patients who have the KRAS-activating G12C mutation 116 , while LOXO 101 is investigating the use of larotrectinib to treat any cancer harbouring an NTRK gene fusion that has been confirmed via molecular assay 117 . Besides drug trials, other efforts in the field of genomics are also underway in clinical trials in Ireland, including fundamental research into the genetic profiling of cancers and DNA biobanking 118 . Table 5. Current cancer clinical trials in Ireland with a molecular component. Summary of cancer clinical trials listed by Cancer Trials Ireland whose study designs include a molecular component. Clinical trial IDs are given as clinicaltrials.gov IDs where available (except trial ITCC-059, which is listed by EudraCT ID). (miRNA: microRNA; GEJ: gastro-oesophageal junction; MIBC: muscle invasive bladder cancer; ctDNA: circulating tumour DNA; dMMR: deficient mismatch-repair; HNSCC: head and neck squamous cell carcinoma; AML: acute myeloid leukaemia; MDS-EB2: myelodisplastic syndromes with excess blasts-2; NSCLC: non-small cell lung carcinoma; NGS: next-generation sequencing; DLBCL: diffuse large B-cell lymphoma; CML: chronic myelogenous leukaemia; B-ALL: B-cell acute lymphoblastic leukaemia; CNS: central nervous system; ALL: acute lymphoblastic leukaemia; MDS: myelodysplastic syndrome; JNML: juvenile myelomonocytic leukaemia; HRRm: homologous recombination repair mutation; HRD: homologous recombination deficiency). Cancer Type Subtype Trial Name Clinical Trial ID Molecular Component Breast SHAMROCK study NCT05710666 Requires HER2+ DESTINY-Breast05 NCT04622319 Requires HER2+ SASCIA NCT04595565 Requires HER2- KEYNOTE-B49 NCT04895358 Requires HER2-, HR+ EPIK-B5 NCT05038735 Requires HER2-, HR+, PIK3CA mutation Proteomics/ Molecular Breast NCT01840293 Gene-protein interaction study CNS glioma Serum Protein Markers for Glioma NCT03698201 Identification of blood miRNA biomarkers Gastro-intestinal gastric cancer FORTITUDE-101 NCT05052801 Requires FGFR2b overexpression; excludes HER2+ colorectal cancer KRYSTAL-10 NCT04793958 Requires KRAS G12C mutation stomach and oesophageal cancers HERIZON-GEA-01 (ZWI-ZW25-301) Zymeworks NCT05152147 Requires HER2+ gastric or GEJ adenocarcinoma DESTINY DS8201-A-U306 NCT04704934 Requires HER2+ pancreatic adenocarcinoma Astellas 8951-CL-5201 NCT03816163 Requires CLDN18.2+ Genito-urinary urothelial carcinoma / MIBC MK3475-905 (KEYNOTE-905) NCT03924895 Requires tissue for PD-L1 testing MIBC IMvigor011 B042843 NCT04660344 Requires ctDNA positive; will perform PD-L1 expression testing Gynae-cological endometrial carcinoma ENGOT-en15/ KEYNOTE-C93-00/ GOG-3064 NCT05173987 Requires dMMR Head & Neck HNSCC MK-3475-630/ KEYNOTE-630 NCT03833167 Requires tissue for PD-L1 testing HNSCC MK-3475-689 NCT03765918 Stratified by PD-L1 expression Leukaemia AML or MDS-EB2 HOVON 156 NCT04027309 Requires FLT3 mutation HOVON 150 NCT03839771 Requires IDH1/2 mutation Lung NSCLC 22-09 ADEPPT NCT05673187 Requires KRAS G12C mutation KRYSTAL-12 NCT04685135 Requires KRAS G12C mutation KRYSTAL-7 NCT04613596 Requires KRAS G12C mutation; phase depends on PD-L1 expression AcceleRET-Lung NCT04222972 Requires RET fusion; excludes other known driver mutations such as EGFR , ALK , ROS-1 , MET , and BRAF mutations AbbVie M14-239 NCT03539536 Requires c-Met overexpression; excludes EGFR mutation CA224-104 (RELATIVITY) NCT04623775 Excludes EGFR , ALK , ROS-1 , and BRAF V600E mutations 23-12 LATIFY NCT05450692 Excludes EGFR and ALK mutations 22-15 PLAN NCT05542485 ctDNA genotyping via NGS 22-23 NeoCOAST-2 NCT05061550 Will confirm PD-L1, ALK , and EGFR status Lymphoma DLBCL MOR208C310 NCT04824092 Requires CD20+ Paediatric CML ITCC-054 NCT04258943 Requires BCR-ABL1 fusion; excludes BCR-ABL1 T315I or V299L mutations B-ALL ITCC-059 2016-000227-71 (EudraCT) Requires CD22+ CNS tumour LOXO TRK 15003 NCT02637687 Requires NTRK fusion ALL or biphenotypic leukaemia Interfant 06 NCT00550992 Requires MLL rearrangement; excludes BCR-ABL1 fusions and t(8;14) ependymoma SIOP EPENDYMOMA II NCT02265770 Will evaluate several molecular markers, including 1q copy numbers, Tenascin C, RELA fusions, YAP fusion, H3.3K27me3, and methylation hepatoblastoma and hepatocellular carcinoma PHITT NCT03017326 Develop genomic analysis to predict chemotherapy toxicity severe aplastic anaemia EWOG-SAA-2010 Genetic characterisation study MDS or JNML EWOG-MDS-2006 Genetic characterisation study any OLCHC Tumour Bank DNA biobanking Multiple Types multiple MK7339-002 / LYNK-002 NCT03742895 Requires HRRm or HRD solid tumours LOXO 101 NCT02576431 Requires NTRK fusion any WAYFIND-R Requires NGS tumour genomic profiling solid tumours PUMA-NER 5201/SUMMIT NCT01953926 Requires HER2 mutation or EGFR exon 18 mutation cancer of unknown primary site CUPISCO NCT03498521 Will perform genomic profiling; excludes specific immunophenotypes Conclusions Molecular diagnostics, in the form of both genetic and cellular biomarker testing, are a vital component of cancer diagnostics and treatment. In Ireland, the NCCP lists 148 treatment regimens with a molecular diagnostic component, through which 30% of the Irish cancer patient population stands to directly benefit. Cancer cases are predicted to double in Ireland by 2045 119 , underscoring the need to ensure that the increasing requirement for testing is met by Irish infrastructure. As research highlights further drug repurposing and new off-label drug uses, as novel precision medicine therapies are produced against innovative drug targets in more cancer types, and as clinical trials become more widely available in Ireland, the need for molecular testing is likely to increase steadily until the total number of required molecular tests converges with, and exceeds, the total number of cancer cases. It should also be noted that these numbers do not include testing for inherited cancer risk or any non-cancer disease, each of which will add to the requirement for molecular diagnostics. While this presents a challenge to any national healthcare system, it promises great improvements in personalised cancer care and outcomes for patients in the near future if the challenge can be met. Ireland's recent National Genomics and Genetics Strategy will represent the first major strides in addressing this challenge. While the strategy encompasses many aspects, a key consideration that should be highlighted is the need for a collaborative approach from all stakeholders. Fundamental to this approach must be the facilitation of a modernised, centralised exchange of expertise and data from all parties, including the NCCP and NCRI for cancer expertise and statistics, the NCPE for pharmacoeconomics, hospitals for current infrastructure and implementation, and universities for current research efforts. For this strategy to be successful, decisions must be based on accurate data gathered by these institutions. While genomics initiatives and strategies in countries with comparable population sizes (such as the Precision Medicine Centre of Excellence in Northern Ireland 120 , the regional laboratories established through the Scottish Strategic Network for Genomic Medicine 121 , the hub-and-spoke model employed in Denmark 7 , or the distributed specialisation across institutions in Norway's InPreD initiative 122 ) can inform Irish efforts, it is critical to collect and analyse healthcare data in Ireland to establish a viable and appropriate molecular medicine service capable of meeting Irish clinical demand. This data will be foundational for evaluating the utility of clinical care in Ireland moving forward, particularly in pharmacoeconomic areas such as health technology assessments, pharmaceutical pricing, and drug reimbursement approvals. Furthermore, national infrastructure to support the collection and storage of molecular patient data will enable Ireland to participate in international research initiatives, such as the European Commission's Digital Europe Call for genomics data, and the proposed EU European Health Data Space 123 . In this article, we sought to collate available data from various sources across Ireland to present a unified overview of the state of cancer molecular diagnostics in Ireland. Ultimately, to best address Ireland's future need for molecular and genomic medicine, we first need to accurately establish Ireland's current capabilities and position, and it is our hope that others will follow in contributing to this Methods Molecular Diagnostics in Cancer Treatment Regimens NCCP cancer therapy regimens were accessed via the HSE NCCP National SACT Regimens website 15 . Information on therapy indications from each tumour group subpage (as well subpages for oral anti-cancer medicines and paediatric therapies) was collected by systematic HTML parsing of tabular elements using the Python package Beautiful Soup version 4.11.2 in Python 3.11.0 124 . Raw therapy indication text was then further parsed in Python to harmonise descriptions and drug names, to combine duplicate indications by indication ID, to assign relevant disease based on website subpage and subheadings, and to group therapy indications by regimen ID. Where conflicts arose in merging duplicate indications by ID, manual harmonisation was performed by referring to the full text of the hyperlinked regimen document; where conflicts arose in the hyperlinked regimen documents, the latest revision was used as reference. After tabular export of all indications and associated information, final manual curation was performed to correct malformed entries and errors in the source material, again referring to the appropriate full-text regimen documents. For the Python parser tool created for this purpose, see Software Availability 125 and for the exported and manually curated data table, see also Software Availability 22 . Identification of indications informed by genetic diagnostics was performed through several rounds of key-word search and manual review through the short descriptions of each therapy indication. Key-words included terms associated with genetics and genomics such as gene , chromosome , and express ; known cancer gene names; and the terms and symbols positive , negative , + , and - , as well as further keywords encountered during manual review. In ambiguous cases, including cases where a molecular diagnostic was listed for one indication of a regimen, but not for other similar indications for the same regimen, both the full-text regimen document as well as published literature on the therapy in question were consulted. Note that while many regimens include CD20 antibody therapies for lymphoma, these were only included when a molecular diagnostic was explicitly referenced. Reimbursement information was obtained from NCCP indications and regimens 15 , the NCCP table of approved drugs 23 , the PCRS list of reimbursable items 24 , and the HSE list of the High Tech Drug Arrangements 25 . The regimen information in this article reflects the NCCP SACT Regimens website as of 2023-Nov-06. Predicted Rates of Actionable Cancer Molecular Diagnoses Cancer incidence rates in Ireland were obtained from the NCRI publication Cancer in Ireland 1994–2020: Annual Statistical Report of the National Cancer Registry , Appendix I: Incident Cancer Cases 46 , except where indicated. Case numbers in this publication are listed as the 3-year average incidence from 2018–2020 of each ICD-10 invasive cancer group. For each unique molecular diagnostic for each cancer subtype, incidence of the cancer subtype relative to the broader cancer type (e.g., proportion of lung cancers that are NSCLC) was obtained from literature where appropriate. Incidence rates of each molecular diagnostic within the relevant cancer subtype (e.g., proportion of NSCLC that is ALK +) were then also obtained from literature (references provided in Table 3 and Table 4 ). These rates were then applied to incident cancer rates in Ireland to estimate the positivity rate of each molecular diagnostic in Ireland. In the case of acute lymphoblastic leukaemia, B-ALL subtype incidence was estimated separately for paediatric and adult cases due to differences in B- vs T-ALL rates in adults and children and the high proportion of childhood cases 72 . Similarly, separate molecular subtype rates were applied for BCR-ABL1 fusions in adult and childhood B-ALL for the same reason 73 . Incidence of metastatic castration-resistant prostate cancer was calculated as a function of total population based on the model referenced, producing numbers in agreement with NCRI case counts 84 , 85 . Rates of urothelial carcinoma were applied separately for primary urethral urothelial carcinoma due to lower published rates of urothelial histology 105 – 107 . Clinical Sequencing Capacity in Ireland Technical specifications on the machine runtime and DNA throughput for the Illumina NextSeq and ThermoFisher Ion Torrent platforms were obtained from their respective manufacturer websites. To calculate nominal maximum throughput, the highest throughput configuration of each machine was used (NextSeq 550 High-Output = 100-120 Gb of 120 bp paired-end reads/29 hrs 49 , Ion GeneStudio with Ion 550 Chip = 40-50 Gb of 200 bp paired-end reads per 12 hrs 50 ). DNA sequencing target size was based on paired-end sequencing with a 120x coverage target using the Agilent SureSelect Clinical Research Exome V4 (total design size=51.0 Mb), for a targeted total of 12.24 Gb of genetic material sequenced per sample 126 . Maximum capacity was then calculated to be the total number of exomes able to be sequenced by all 8 machines running at maximum capacity. The lower end of this range represents one run of each instrument using the lower bound of the instruments' stated throughput (one 29-hour run of the NextSeq at 100 Gb = 8 exomes per machine = 32 exomes, plus one 12-hour run of the Ion Torrent at 40 Gb = 3 exomes per machine = 12 exomes, totalling 44 exomes), while the higher end of the range represents the higher bound of the instruments' stated throughput, with two 12-hour runs of the Ion Torrent within the same time frame as one 29-hour NextSeq run (one 29-hour run of the NextSeq at 120 Gb = 9 exomes per machine = 36 exomes, plus two 12-hour runs of the Ion Torrent at 50 Gb = 8 exomes twice per machine = 32 exomes, totalling 68 exomes). Molecular Indications for Clinical Trials Information on clinical trials was obtained from Cancer Trials Ireland 115 . Trials were considered to have a molecular component if the trial eligibility criteria included genetic mutations, aberrant genetic pathways, gene expression, cellular biomarkers, or microsatellite instability status as inclusion or exclusion criteria, or if the trial's purpose was to otherwise collect or analyse genomic data. Trials were evaluated systematically, beginning by prioritising those with explicit mention of these criteria in their short description. Trials without explicit reference to one of the two criteria, but which referenced a disease or treatment known to have a strong or common molecular diagnostic component were also prioritised. Short-listed trials' full trial descriptions were then checked to confirm the nature of the trial. After confirmation of short-listed trials, remaining trial full descriptions were then checked to confirm absence of a molecular diagnostic component. Data availability Underlying data Zenodo: Table of Indications and Regimens from the National Cancer Control Programme, Ireland. https://zenodo.org/doi/10.5281/zenodo.10157939 22 This project contains the following underlying data: NCCP_Indications_and_Regimens.2023-Nov-06.tsv Extended data Zenodo: Table of Indications and Regimens from the National Cancer Control Programme, Ireland. https://zenodo.org/doi/10.5281/zenodo.10157939 22 This project contains the following extended data: nccp_sact_parser.py harmonization.tsv Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). Software availability Analysis code available from: https://github.com/TDMedina/NCCP-SACT-Parser 125 Archived analysis code at time of publication: https://doi.org/10.5281/zenodo.10660553 License: Creative Commons Zero v1.0 Universal (CCO 1.0 Public domain dedication) Faculty Opinions recommended References 1. 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Reference Source Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 26 Mar 2024 ADD YOUR COMMENT Comment Author details Author details 1 School of Mathematical & Statistical Sciences, University of Galway, Galway, County Galway, Ireland 2 SFI Centre for Research Training in Genomics Data Science, Science Foundation Ireland, Dublin, Ireland 3 Discipline of Pathology, School of Medicine, University of Galway, Galway, County Galway, Ireland 4 Division of Anatomical Pathology, University Hospital Galway, Galway, Ireland 5 Trinity St James’s Cancer Institute, St James's Hospital and Trinity College Dublin, Dublin, Ireland 6 CURAM, SFI Research Centre for Medical Devices, University of Galway, Galway, County Galway, Ireland 7 Health Economics and Policy Analysis Centre, Institute for Lifecourse and Society, University of Galway, Galway, County Galway, Ireland 8 Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland 9 Systems Biology Ireland, University College Dublin, Dublin, Ireland Tyler Medina Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Seán O. Hynes Roles: Supervision, Writing – Review & Editing Maeve Lowery Roles: Supervision, Writing – Review & Editing Patrick Gillespie Roles: Supervision, Writing – Review & Editing Walter Kolch Roles: Supervision, Writing – Review & Editing Cathal Seoighe Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing Competing interests Maeve Lowery has a consulting or advisory role in Roche/Genentech, AstraZeneca, and Servier, and receives research funding through her institution from MSD, Exelixis, Basilea, Astellas Pharma, Zymeworks, Legend Biotech, and Genuity Science. Sean Hynes has received honoraria for speaking and meeting support from Roche. All other authors have no conflicts of interest to disclose, including financial interest. Grant information Health Research Board [CES-2023-025], Science Foundation Ireland [18/CRT/6214], Science Foundation Ireland [16/IA/4612], H2020 Marie Skłodowska-Curie Actions, [H2020-MSCA-COFUND-2019-945385]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 09 Jun 2025, 7:16 https://doi.org/10.12688/hrbopenres.13822.2 version 1 Published: 26 Mar 2024, 7:16 https://doi.org/10.12688/hrbopenres.13822.1 Copyright © 2024 Medina T et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics VIEWS $counts.viewCount downloads Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Medina T, Hynes SO, Lowery M et al. Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.12688/hrbopenres.13822.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 26 Mar 2024 Views 0 Cite How to cite this report: Thomas G. Reviewer Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15129.r42367 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-16/v1#referee-response-42367 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 Sep 2024 George Thomas , Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, USA Approved with Reservations VIEWS 0 https://doi.org/10.21956/hrbopenres.15129.r42367 This study provides a comprehensive overview of molecular diagnostics in clinical oncology in Ireland. The authors analyze cancer treatment regimens published by the National Cancer Control Programme (NCCP), identifying 148 regimens with molecular diagnostic components. They estimate that approximately 50% ... Continue reading READ ALL This study provides a comprehensive overview of molecular diagnostics in clinical oncology in Ireland. The authors analyze cancer treatment regimens published by the National Cancer Control Programme (NCCP), identifying 148 regimens with molecular diagnostic components. They estimate that approximately 50% of cancer patients in Ireland could qualify for molecular testing, with about 30% potentially benefiting from molecularly guided therapies. The paper examines the current sequencing capacity in Irish clinical laboratories and discusses the molecular criteria used in ongoing clinical trials. The study aims to establish a baseline understanding of current molecular diagnostic practices in Irish oncology and to inform future planning and implementation of personalized medicine approaches. Strengths: Comprehensive overview of molecular diagnostics in Irish clinical oncology, including genetic and biomarker testing. Detailed analysis of NCCP cancer treatment regimens and associated molecular indications. Estimation of molecular testing needs based on cancer incidence data and literature. Assessment of current sequencing capacity in Irish clinical laboratories. Inclusion of information on molecular criteria in ongoing clinical trials. Clarification and additional input needed: Limited discussion on the uniformity of testing across different centers in Ireland. Minimal exploration of send-out testing practices and their implications. Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment.: Please specify the clones being used for testing, e.g. Dako 22C3 For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. It would help to separate Solid tumor from Hematological malignancies in the tables GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “ Negative for RAS mutations” Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Need to expand on Her2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Please define HRD+, i.e. what genes are considered? Insufficient information on patient outcomes related to molecular testing. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Precision Oncology;Molecular Diagnostics; Cancer Therapeutics: Companion Diagnostics; Pathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Thomas G. Reviewer Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15129.r42367 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-16/v1#referee-response-42367 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 03 Jul 2025 Tyler Medina , School of Mathematical & Statistical Sciences, University of Galway, Galway, Ireland 03 Jul 2025 Author Response Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. ... Continue reading Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. We would like to note that our manuscript was intended to provide an overview of the molecular markers that are described by the Irish National Cancer Control Panel for use in assigning cancer therapy, which limits our scope to the markers that have currently been described in drug regimens and indications by the NCCP. In our new release of the article, we have updated the described indications by reviewing and adding 98 indications that were added between November 2023 and May 2025. However, it should be noted that NCCP indications do not generally describe detailed testing strategies, which are instead described by the National Genomics Test Directory for Cancer, newly released and actively being developed since June 2024. We have now included additional diagnostic criteria for PD-L1 testing as suggested and as prescribed in the new national test directory. While there are also additional genetic tests outlined in the test directory (e.g., DPYD testing for fluoropyrimidine treatment, BRAF in mCRC, Lynch syndrome screening), any tests not yet included in NCCP drug regimens have not been added. In addition, Ireland does not as of today have a centralized electronic health record system, nor are centralized records kept regarding genomics tests ordered. These are matters of current development in the country. Similarly, because the National Genomics Test Directory was only very recently published, records on send-out practice have generally not been standardized or centralized, making them difficult to obtain even for the hospitals themselves. Comment 1: Limited discussion on the uniformity of testing across different centers in Ireland. Response 1: We were unfortunately unable to obtain records specifically detailing the molecular diagnostic practices at individual hospitals in Ireland and so we did not include a discussion on test practices across the country. However, Ireland has few hospitals performing cancer molecular diagnostics, with each generally specializing in particular testing or cancer types. For example, the majority of solid tumour samples in the country requiring NGS are sequenced at a single test center, while many breast cancer samples are sent for IHC at a separate center specializing in breast cancer. As such, testing is not so much uniform across hospitals as it is consolidated. Comment 2: Minimal exploration of send-out testing practices and their implications. Response 2: At the time of writing, no centralized records (or in-hospital records) regarding the number of send-out samples were available, and so these numbers could not be included in the article. Send-out practices were, in fact, an ongoing area of investigation by the new National Genetics and Genomics Office, and by several hospitals as they intended to start or expand NGS testing services. Domestic send-out, as mentioned in the response to point 1, is common, depending on the tissue type and testing required. Comment 3: Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment. Please specify the clones being used for testing, e.g. Dako 22C3 Response 3: Thank you for your comment. We had previously omitted required thresholds for PD-L1 expression for simplicity, but have added them in the revised version in Table 2. While specifications for antibodies were not previously available, the latest version of the National Genomics Test Directory for Cancer does now include this information for some tests for some cancer types, and we have added these to Table 2 where possible. Comment 4: For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. Response 4: Thank you for pointing out the ambiguity in " ALK mutations". This has been corrected in the revised article in Tables 1 and 3 for NSCLC, with "mutation" replaced with "fusion". MET exon 14 was not included in the National Cancer Control Programme published list of drug regimens and indications when the original version of this article was released, but was added in July 2024, and it is now included in the article in Tables 1 and 3 for NSCLC as well. Comment 5: It would help to separate Solid tumor from Hematological malignancies in the tables. Response 5: We have reordered the table entries in Tables 1 and 2 such that haematological malignancies (leukaemia/lymphoma) are at the bottom of each table. However, Tables 3 and 4 are grouped and sorted by incidence rates in Ireland, so we have elected to leave leukaemia and lymphoma in place to indicate their rank in total cancer cases. Comment 6: GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex Response 6: At this time, NCCP guidelines on GIST testing for treatment are limited to c-KIT , and as such we have not included other genetic testing criteria, given the scope of the article, as outlined above. Comment 7: RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “Negative for RAS mutations” Response 7: Thank you for suggesting that this should be clarified. We have changed "normal RAS " to "wild-type KRAS and NRAS " for colorectal cancer in Tables 1 and 3 to avoid ambiguity and to be in line with the European Medicines Agency text regarding cetuximab and panitumumab indications. Comment 8: Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Response 8: As of May 2025, BRAF V600 is the only codon currently listed under NCCP indications, and so other testing candidates are not listed. However, the national test directory as of April 2025 does now list testing for BRAF , NRAS , and KIT , with suggestions for test expansion to include ALK and ROS , and we anticipate that these genes will be added to NCCP indications if/when approved for targeted treatment. Comment 9: Need to expand on HER2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Response 9: An indication for HER2-low in breast cancer was added to the NCCP indications in July 2024, and has now been added to the revised article (Tables 2 and 4). We have also further provided the distinguishing thresholds for HER2+ versus HER2-low in breast cancer in Table 2. However, a threshold for HER2+ in gastric cancers has not been officially published by the NCCP, and so is not included. Comment 10: Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Response 10: We have expanded on the genes indicated for dMMR testing (Table 1: endometrial and colorectal cancer) as per the national test directory, which now include MLH1 promoter hypermethylation, PMS2 , MSH2 , and MSH6 . While BRAF is also included in the test directory for colon cancer, it is not yet included in any NCCP indication. Comment 11: Please define HRD+, i.e. what genes are considered? Response 11: The European Medicines Agency indication for the use of olaparib and bevacizumab in HRD+ gynaecological cancers bases its definition of HRD+ on the PAOLA-1 phase III clinical trial, which classified HRD+ patients as having either BRCA1/2 tumour mutations or a sufficient genomic instability score (GIS). GIS was produced through the Myriad Genetics MyChoice CDx Plus assay, which considered factors such as genome-wide loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. The assay also includes 15 homologous repair pathway genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L ), though the assay and study both consider BRCA1/2 mutations alone to be sufficient for HRD+ classification in the study. Though the same Myriad assay has been considered for use in Ireland, the actual test implementation has not yet been officially established in the national test directory. However, as HRD+ and GIS refer to the EMA indication, we have now included their description of GIS as an explanatory note in the caption for Table 1, though we have not included the specific lists of genes used in the Myriad test, aside from BRCA1/2 . Comment 12: Insufficient information on patient outcomes related to molecular testing. Response 12: This was a question that was initially considered as part of our investigation, as it would also greatly help contextualize the requirement for and benefit of molecular medicine in Ireland. Unfortunately, this data was not available to us as part of this study, but would be of great importance for future work. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Response: Clinical implementation and results, including comparing testing practices, turnaround times, send-out practices, and patient outcomes, are certainly of interest to us, but were unfortunately out of scope for this current work. We expect that work regarding these matters will be more feasible in the coming years as national genomics initiatives in Ireland continue to progress and as data regarding these aspects of genomics are made more readily available. Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. We would like to note that our manuscript was intended to provide an overview of the molecular markers that are described by the Irish National Cancer Control Panel for use in assigning cancer therapy, which limits our scope to the markers that have currently been described in drug regimens and indications by the NCCP. In our new release of the article, we have updated the described indications by reviewing and adding 98 indications that were added between November 2023 and May 2025. However, it should be noted that NCCP indications do not generally describe detailed testing strategies, which are instead described by the National Genomics Test Directory for Cancer, newly released and actively being developed since June 2024. We have now included additional diagnostic criteria for PD-L1 testing as suggested and as prescribed in the new national test directory. While there are also additional genetic tests outlined in the test directory (e.g., DPYD testing for fluoropyrimidine treatment, BRAF in mCRC, Lynch syndrome screening), any tests not yet included in NCCP drug regimens have not been added. In addition, Ireland does not as of today have a centralized electronic health record system, nor are centralized records kept regarding genomics tests ordered. These are matters of current development in the country. Similarly, because the National Genomics Test Directory was only very recently published, records on send-out practice have generally not been standardized or centralized, making them difficult to obtain even for the hospitals themselves. Comment 1: Limited discussion on the uniformity of testing across different centers in Ireland. Response 1: We were unfortunately unable to obtain records specifically detailing the molecular diagnostic practices at individual hospitals in Ireland and so we did not include a discussion on test practices across the country. However, Ireland has few hospitals performing cancer molecular diagnostics, with each generally specializing in particular testing or cancer types. For example, the majority of solid tumour samples in the country requiring NGS are sequenced at a single test center, while many breast cancer samples are sent for IHC at a separate center specializing in breast cancer. As such, testing is not so much uniform across hospitals as it is consolidated. Comment 2: Minimal exploration of send-out testing practices and their implications. Response 2: At the time of writing, no centralized records (or in-hospital records) regarding the number of send-out samples were available, and so these numbers could not be included in the article. Send-out practices were, in fact, an ongoing area of investigation by the new National Genetics and Genomics Office, and by several hospitals as they intended to start or expand NGS testing services. Domestic send-out, as mentioned in the response to point 1, is common, depending on the tissue type and testing required. Comment 3: Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment. Please specify the clones being used for testing, e.g. Dako 22C3 Response 3: Thank you for your comment. We had previously omitted required thresholds for PD-L1 expression for simplicity, but have added them in the revised version in Table 2. While specifications for antibodies were not previously available, the latest version of the National Genomics Test Directory for Cancer does now include this information for some tests for some cancer types, and we have added these to Table 2 where possible. Comment 4: For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. Response 4: Thank you for pointing out the ambiguity in " ALK mutations". This has been corrected in the revised article in Tables 1 and 3 for NSCLC, with "mutation" replaced with "fusion". MET exon 14 was not included in the National Cancer Control Programme published list of drug regimens and indications when the original version of this article was released, but was added in July 2024, and it is now included in the article in Tables 1 and 3 for NSCLC as well. Comment 5: It would help to separate Solid tumor from Hematological malignancies in the tables. Response 5: We have reordered the table entries in Tables 1 and 2 such that haematological malignancies (leukaemia/lymphoma) are at the bottom of each table. However, Tables 3 and 4 are grouped and sorted by incidence rates in Ireland, so we have elected to leave leukaemia and lymphoma in place to indicate their rank in total cancer cases. Comment 6: GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex Response 6: At this time, NCCP guidelines on GIST testing for treatment are limited to c-KIT , and as such we have not included other genetic testing criteria, given the scope of the article, as outlined above. Comment 7: RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “Negative for RAS mutations” Response 7: Thank you for suggesting that this should be clarified. We have changed "normal RAS " to "wild-type KRAS and NRAS " for colorectal cancer in Tables 1 and 3 to avoid ambiguity and to be in line with the European Medicines Agency text regarding cetuximab and panitumumab indications. Comment 8: Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Response 8: As of May 2025, BRAF V600 is the only codon currently listed under NCCP indications, and so other testing candidates are not listed. However, the national test directory as of April 2025 does now list testing for BRAF , NRAS , and KIT , with suggestions for test expansion to include ALK and ROS , and we anticipate that these genes will be added to NCCP indications if/when approved for targeted treatment. Comment 9: Need to expand on HER2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Response 9: An indication for HER2-low in breast cancer was added to the NCCP indications in July 2024, and has now been added to the revised article (Tables 2 and 4). We have also further provided the distinguishing thresholds for HER2+ versus HER2-low in breast cancer in Table 2. However, a threshold for HER2+ in gastric cancers has not been officially published by the NCCP, and so is not included. Comment 10: Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Response 10: We have expanded on the genes indicated for dMMR testing (Table 1: endometrial and colorectal cancer) as per the national test directory, which now include MLH1 promoter hypermethylation, PMS2 , MSH2 , and MSH6 . While BRAF is also included in the test directory for colon cancer, it is not yet included in any NCCP indication. Comment 11: Please define HRD+, i.e. what genes are considered? Response 11: The European Medicines Agency indication for the use of olaparib and bevacizumab in HRD+ gynaecological cancers bases its definition of HRD+ on the PAOLA-1 phase III clinical trial, which classified HRD+ patients as having either BRCA1/2 tumour mutations or a sufficient genomic instability score (GIS). GIS was produced through the Myriad Genetics MyChoice CDx Plus assay, which considered factors such as genome-wide loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. The assay also includes 15 homologous repair pathway genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L ), though the assay and study both consider BRCA1/2 mutations alone to be sufficient for HRD+ classification in the study. Though the same Myriad assay has been considered for use in Ireland, the actual test implementation has not yet been officially established in the national test directory. However, as HRD+ and GIS refer to the EMA indication, we have now included their description of GIS as an explanatory note in the caption for Table 1, though we have not included the specific lists of genes used in the Myriad test, aside from BRCA1/2 . Comment 12: Insufficient information on patient outcomes related to molecular testing. Response 12: This was a question that was initially considered as part of our investigation, as it would also greatly help contextualize the requirement for and benefit of molecular medicine in Ireland. Unfortunately, this data was not available to us as part of this study, but would be of great importance for future work. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Response: Clinical implementation and results, including comparing testing practices, turnaround times, send-out practices, and patient outcomes, are certainly of interest to us, but were unfortunately out of scope for this current work. We expect that work regarding these matters will be more feasible in the coming years as national genomics initiatives in Ireland continue to progress and as data regarding these aspects of genomics are made more readily available. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 03 Jul 2025 Tyler Medina , School of Mathematical & Statistical Sciences, University of Galway, Galway, Ireland 03 Jul 2025 Author Response Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. ... Continue reading Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. We would like to note that our manuscript was intended to provide an overview of the molecular markers that are described by the Irish National Cancer Control Panel for use in assigning cancer therapy, which limits our scope to the markers that have currently been described in drug regimens and indications by the NCCP. In our new release of the article, we have updated the described indications by reviewing and adding 98 indications that were added between November 2023 and May 2025. However, it should be noted that NCCP indications do not generally describe detailed testing strategies, which are instead described by the National Genomics Test Directory for Cancer, newly released and actively being developed since June 2024. We have now included additional diagnostic criteria for PD-L1 testing as suggested and as prescribed in the new national test directory. While there are also additional genetic tests outlined in the test directory (e.g., DPYD testing for fluoropyrimidine treatment, BRAF in mCRC, Lynch syndrome screening), any tests not yet included in NCCP drug regimens have not been added. In addition, Ireland does not as of today have a centralized electronic health record system, nor are centralized records kept regarding genomics tests ordered. These are matters of current development in the country. Similarly, because the National Genomics Test Directory was only very recently published, records on send-out practice have generally not been standardized or centralized, making them difficult to obtain even for the hospitals themselves. Comment 1: Limited discussion on the uniformity of testing across different centers in Ireland. Response 1: We were unfortunately unable to obtain records specifically detailing the molecular diagnostic practices at individual hospitals in Ireland and so we did not include a discussion on test practices across the country. However, Ireland has few hospitals performing cancer molecular diagnostics, with each generally specializing in particular testing or cancer types. For example, the majority of solid tumour samples in the country requiring NGS are sequenced at a single test center, while many breast cancer samples are sent for IHC at a separate center specializing in breast cancer. As such, testing is not so much uniform across hospitals as it is consolidated. Comment 2: Minimal exploration of send-out testing practices and their implications. Response 2: At the time of writing, no centralized records (or in-hospital records) regarding the number of send-out samples were available, and so these numbers could not be included in the article. Send-out practices were, in fact, an ongoing area of investigation by the new National Genetics and Genomics Office, and by several hospitals as they intended to start or expand NGS testing services. Domestic send-out, as mentioned in the response to point 1, is common, depending on the tissue type and testing required. Comment 3: Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment. Please specify the clones being used for testing, e.g. Dako 22C3 Response 3: Thank you for your comment. We had previously omitted required thresholds for PD-L1 expression for simplicity, but have added them in the revised version in Table 2. While specifications for antibodies were not previously available, the latest version of the National Genomics Test Directory for Cancer does now include this information for some tests for some cancer types, and we have added these to Table 2 where possible. Comment 4: For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. Response 4: Thank you for pointing out the ambiguity in " ALK mutations". This has been corrected in the revised article in Tables 1 and 3 for NSCLC, with "mutation" replaced with "fusion". MET exon 14 was not included in the National Cancer Control Programme published list of drug regimens and indications when the original version of this article was released, but was added in July 2024, and it is now included in the article in Tables 1 and 3 for NSCLC as well. Comment 5: It would help to separate Solid tumor from Hematological malignancies in the tables. Response 5: We have reordered the table entries in Tables 1 and 2 such that haematological malignancies (leukaemia/lymphoma) are at the bottom of each table. However, Tables 3 and 4 are grouped and sorted by incidence rates in Ireland, so we have elected to leave leukaemia and lymphoma in place to indicate their rank in total cancer cases. Comment 6: GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex Response 6: At this time, NCCP guidelines on GIST testing for treatment are limited to c-KIT , and as such we have not included other genetic testing criteria, given the scope of the article, as outlined above. Comment 7: RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “Negative for RAS mutations” Response 7: Thank you for suggesting that this should be clarified. We have changed "normal RAS " to "wild-type KRAS and NRAS " for colorectal cancer in Tables 1 and 3 to avoid ambiguity and to be in line with the European Medicines Agency text regarding cetuximab and panitumumab indications. Comment 8: Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Response 8: As of May 2025, BRAF V600 is the only codon currently listed under NCCP indications, and so other testing candidates are not listed. However, the national test directory as of April 2025 does now list testing for BRAF , NRAS , and KIT , with suggestions for test expansion to include ALK and ROS , and we anticipate that these genes will be added to NCCP indications if/when approved for targeted treatment. Comment 9: Need to expand on HER2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Response 9: An indication for HER2-low in breast cancer was added to the NCCP indications in July 2024, and has now been added to the revised article (Tables 2 and 4). We have also further provided the distinguishing thresholds for HER2+ versus HER2-low in breast cancer in Table 2. However, a threshold for HER2+ in gastric cancers has not been officially published by the NCCP, and so is not included. Comment 10: Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Response 10: We have expanded on the genes indicated for dMMR testing (Table 1: endometrial and colorectal cancer) as per the national test directory, which now include MLH1 promoter hypermethylation, PMS2 , MSH2 , and MSH6 . While BRAF is also included in the test directory for colon cancer, it is not yet included in any NCCP indication. Comment 11: Please define HRD+, i.e. what genes are considered? Response 11: The European Medicines Agency indication for the use of olaparib and bevacizumab in HRD+ gynaecological cancers bases its definition of HRD+ on the PAOLA-1 phase III clinical trial, which classified HRD+ patients as having either BRCA1/2 tumour mutations or a sufficient genomic instability score (GIS). GIS was produced through the Myriad Genetics MyChoice CDx Plus assay, which considered factors such as genome-wide loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. The assay also includes 15 homologous repair pathway genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L ), though the assay and study both consider BRCA1/2 mutations alone to be sufficient for HRD+ classification in the study. Though the same Myriad assay has been considered for use in Ireland, the actual test implementation has not yet been officially established in the national test directory. However, as HRD+ and GIS refer to the EMA indication, we have now included their description of GIS as an explanatory note in the caption for Table 1, though we have not included the specific lists of genes used in the Myriad test, aside from BRCA1/2 . Comment 12: Insufficient information on patient outcomes related to molecular testing. Response 12: This was a question that was initially considered as part of our investigation, as it would also greatly help contextualize the requirement for and benefit of molecular medicine in Ireland. Unfortunately, this data was not available to us as part of this study, but would be of great importance for future work. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Response: Clinical implementation and results, including comparing testing practices, turnaround times, send-out practices, and patient outcomes, are certainly of interest to us, but were unfortunately out of scope for this current work. We expect that work regarding these matters will be more feasible in the coming years as national genomics initiatives in Ireland continue to progress and as data regarding these aspects of genomics are made more readily available. Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. We would like to note that our manuscript was intended to provide an overview of the molecular markers that are described by the Irish National Cancer Control Panel for use in assigning cancer therapy, which limits our scope to the markers that have currently been described in drug regimens and indications by the NCCP. In our new release of the article, we have updated the described indications by reviewing and adding 98 indications that were added between November 2023 and May 2025. However, it should be noted that NCCP indications do not generally describe detailed testing strategies, which are instead described by the National Genomics Test Directory for Cancer, newly released and actively being developed since June 2024. We have now included additional diagnostic criteria for PD-L1 testing as suggested and as prescribed in the new national test directory. While there are also additional genetic tests outlined in the test directory (e.g., DPYD testing for fluoropyrimidine treatment, BRAF in mCRC, Lynch syndrome screening), any tests not yet included in NCCP drug regimens have not been added. In addition, Ireland does not as of today have a centralized electronic health record system, nor are centralized records kept regarding genomics tests ordered. These are matters of current development in the country. Similarly, because the National Genomics Test Directory was only very recently published, records on send-out practice have generally not been standardized or centralized, making them difficult to obtain even for the hospitals themselves. Comment 1: Limited discussion on the uniformity of testing across different centers in Ireland. Response 1: We were unfortunately unable to obtain records specifically detailing the molecular diagnostic practices at individual hospitals in Ireland and so we did not include a discussion on test practices across the country. However, Ireland has few hospitals performing cancer molecular diagnostics, with each generally specializing in particular testing or cancer types. For example, the majority of solid tumour samples in the country requiring NGS are sequenced at a single test center, while many breast cancer samples are sent for IHC at a separate center specializing in breast cancer. As such, testing is not so much uniform across hospitals as it is consolidated. Comment 2: Minimal exploration of send-out testing practices and their implications. Response 2: At the time of writing, no centralized records (or in-hospital records) regarding the number of send-out samples were available, and so these numbers could not be included in the article. Send-out practices were, in fact, an ongoing area of investigation by the new National Genetics and Genomics Office, and by several hospitals as they intended to start or expand NGS testing services. Domestic send-out, as mentioned in the response to point 1, is common, depending on the tissue type and testing required. Comment 3: Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment. Please specify the clones being used for testing, e.g. Dako 22C3 Response 3: Thank you for your comment. We had previously omitted required thresholds for PD-L1 expression for simplicity, but have added them in the revised version in Table 2. While specifications for antibodies were not previously available, the latest version of the National Genomics Test Directory for Cancer does now include this information for some tests for some cancer types, and we have added these to Table 2 where possible. Comment 4: For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. Response 4: Thank you for pointing out the ambiguity in " ALK mutations". This has been corrected in the revised article in Tables 1 and 3 for NSCLC, with "mutation" replaced with "fusion". MET exon 14 was not included in the National Cancer Control Programme published list of drug regimens and indications when the original version of this article was released, but was added in July 2024, and it is now included in the article in Tables 1 and 3 for NSCLC as well. Comment 5: It would help to separate Solid tumor from Hematological malignancies in the tables. Response 5: We have reordered the table entries in Tables 1 and 2 such that haematological malignancies (leukaemia/lymphoma) are at the bottom of each table. However, Tables 3 and 4 are grouped and sorted by incidence rates in Ireland, so we have elected to leave leukaemia and lymphoma in place to indicate their rank in total cancer cases. Comment 6: GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex Response 6: At this time, NCCP guidelines on GIST testing for treatment are limited to c-KIT , and as such we have not included other genetic testing criteria, given the scope of the article, as outlined above. Comment 7: RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “Negative for RAS mutations” Response 7: Thank you for suggesting that this should be clarified. We have changed "normal RAS " to "wild-type KRAS and NRAS " for colorectal cancer in Tables 1 and 3 to avoid ambiguity and to be in line with the European Medicines Agency text regarding cetuximab and panitumumab indications. Comment 8: Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Response 8: As of May 2025, BRAF V600 is the only codon currently listed under NCCP indications, and so other testing candidates are not listed. However, the national test directory as of April 2025 does now list testing for BRAF , NRAS , and KIT , with suggestions for test expansion to include ALK and ROS , and we anticipate that these genes will be added to NCCP indications if/when approved for targeted treatment. Comment 9: Need to expand on HER2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Response 9: An indication for HER2-low in breast cancer was added to the NCCP indications in July 2024, and has now been added to the revised article (Tables 2 and 4). We have also further provided the distinguishing thresholds for HER2+ versus HER2-low in breast cancer in Table 2. However, a threshold for HER2+ in gastric cancers has not been officially published by the NCCP, and so is not included. Comment 10: Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Response 10: We have expanded on the genes indicated for dMMR testing (Table 1: endometrial and colorectal cancer) as per the national test directory, which now include MLH1 promoter hypermethylation, PMS2 , MSH2 , and MSH6 . While BRAF is also included in the test directory for colon cancer, it is not yet included in any NCCP indication. Comment 11: Please define HRD+, i.e. what genes are considered? Response 11: The European Medicines Agency indication for the use of olaparib and bevacizumab in HRD+ gynaecological cancers bases its definition of HRD+ on the PAOLA-1 phase III clinical trial, which classified HRD+ patients as having either BRCA1/2 tumour mutations or a sufficient genomic instability score (GIS). GIS was produced through the Myriad Genetics MyChoice CDx Plus assay, which considered factors such as genome-wide loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. The assay also includes 15 homologous repair pathway genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L ), though the assay and study both consider BRCA1/2 mutations alone to be sufficient for HRD+ classification in the study. Though the same Myriad assay has been considered for use in Ireland, the actual test implementation has not yet been officially established in the national test directory. However, as HRD+ and GIS refer to the EMA indication, we have now included their description of GIS as an explanatory note in the caption for Table 1, though we have not included the specific lists of genes used in the Myriad test, aside from BRCA1/2 . Comment 12: Insufficient information on patient outcomes related to molecular testing. Response 12: This was a question that was initially considered as part of our investigation, as it would also greatly help contextualize the requirement for and benefit of molecular medicine in Ireland. Unfortunately, this data was not available to us as part of this study, but would be of great importance for future work. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Response: Clinical implementation and results, including comparing testing practices, turnaround times, send-out practices, and patient outcomes, are certainly of interest to us, but were unfortunately out of scope for this current work. We expect that work regarding these matters will be more feasible in the coming years as national genomics initiatives in Ireland continue to progress and as data regarding these aspects of genomics are made more readily available. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Nagy B. Reviewer Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15129.r41155 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-16/v1#referee-response-41155 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 Jul 2024 Bálint Nagy , Department of Human Genetics, Faculty of Medicine,, University of Debrecen, H-4032 Debrecen, Hungary Approved VIEWS 0 https://doi.org/10.21956/hrbopenres.15129.r41155 The submitted manuscripts is interesting and it is in the focus of clinical interest. The Abstract is too general, please provide more concrete data and conclusion. I miss liquid biopsy and cell-free nucleic acids, are they in use in ... Continue reading READ ALL The submitted manuscripts is interesting and it is in the focus of clinical interest. The Abstract is too general, please provide more concrete data and conclusion. I miss liquid biopsy and cell-free nucleic acids, are they in use in the clinical practice in Ireland? You should mention this possibility, even if it is not used in Ireland. The Methods section has to be more detailed. There is a "personalized medicine" keyword, you should discuss it in more details. Somehow you should give a perspective about the use of molecular genetics in the clinical practice, diagnosis, treatment and follow up of the cases. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: molecular genetics, molecular diagnostics, non.invasive diagnostics, cell-free nucleic acids, liquid biopsy, cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Nagy B. Reviewer Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15129.r41155 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-16/v1#referee-response-41155 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 26 Mar 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 09 Jun 25 read Version 1 26 Mar 24 read read Bálint Nagy , University of Debrecen, H-4032 Debrecen, Hungary George Thomas , Knight Cancer Institute, Oregon Health & Science University, Portland, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Thomas G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Jul 2025 | for Version 2 George Thomas , Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, USA 0 Views copyright © 2025 Thomas G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This is fine, Thank you, G Competing Interests No competing interests were disclosed. Reviewer Expertise Precision Oncology;Molecular Diagnostics; Cancer Therapeutics: Companion Diagnostics; Pathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Thomas G. Peer Review Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15601.r47685) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://hrbopenresearch.org/articles/7-16/v2#referee-response-47685 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Thomas G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Sep 2024 | for Version 1 George Thomas , Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, USA 0 Views copyright © 2024 Thomas G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This study provides a comprehensive overview of molecular diagnostics in clinical oncology in Ireland. The authors analyze cancer treatment regimens published by the National Cancer Control Programme (NCCP), identifying 148 regimens with molecular diagnostic components. They estimate that approximately 50% of cancer patients in Ireland could qualify for molecular testing, with about 30% potentially benefiting from molecularly guided therapies. The paper examines the current sequencing capacity in Irish clinical laboratories and discusses the molecular criteria used in ongoing clinical trials. The study aims to establish a baseline understanding of current molecular diagnostic practices in Irish oncology and to inform future planning and implementation of personalized medicine approaches. Strengths: Comprehensive overview of molecular diagnostics in Irish clinical oncology, including genetic and biomarker testing. Detailed analysis of NCCP cancer treatment regimens and associated molecular indications. Estimation of molecular testing needs based on cancer incidence data and literature. Assessment of current sequencing capacity in Irish clinical laboratories. Inclusion of information on molecular criteria in ongoing clinical trials. Clarification and additional input needed: Limited discussion on the uniformity of testing across different centers in Ireland. Minimal exploration of send-out testing practices and their implications. Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment.: Please specify the clones being used for testing, e.g. Dako 22C3 For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. It would help to separate Solid tumor from Hematological malignancies in the tables GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “ Negative for RAS mutations” Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Need to expand on Her2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Please define HRD+, i.e. what genes are considered? Insufficient information on patient outcomes related to molecular testing. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Precision Oncology;Molecular Diagnostics; Cancer Therapeutics: Companion Diagnostics; Pathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 03 Jul 2025 Tyler Medina, School of Mathematical & Statistical Sciences, University of Galway, Galway, Ireland Thank you, Prof. Thomas, for taking the time to review our manuscript and for providing valuable feedback. We have gone through your suggestions, and we have outlined our responses below. We would like to note that our manuscript was intended to provide an overview of the molecular markers that are described by the Irish National Cancer Control Panel for use in assigning cancer therapy, which limits our scope to the markers that have currently been described in drug regimens and indications by the NCCP. In our new release of the article, we have updated the described indications by reviewing and adding 98 indications that were added between November 2023 and May 2025. However, it should be noted that NCCP indications do not generally describe detailed testing strategies, which are instead described by the National Genomics Test Directory for Cancer, newly released and actively being developed since June 2024. We have now included additional diagnostic criteria for PD-L1 testing as suggested and as prescribed in the new national test directory. While there are also additional genetic tests outlined in the test directory (e.g., DPYD testing for fluoropyrimidine treatment, BRAF in mCRC, Lynch syndrome screening), any tests not yet included in NCCP drug regimens have not been added. In addition, Ireland does not as of today have a centralized electronic health record system, nor are centralized records kept regarding genomics tests ordered. These are matters of current development in the country. Similarly, because the National Genomics Test Directory was only very recently published, records on send-out practice have generally not been standardized or centralized, making them difficult to obtain even for the hospitals themselves. Comment 1: Limited discussion on the uniformity of testing across different centers in Ireland. Response 1: We were unfortunately unable to obtain records specifically detailing the molecular diagnostic practices at individual hospitals in Ireland and so we did not include a discussion on test practices across the country. However, Ireland has few hospitals performing cancer molecular diagnostics, with each generally specializing in particular testing or cancer types. For example, the majority of solid tumour samples in the country requiring NGS are sequenced at a single test center, while many breast cancer samples are sent for IHC at a separate center specializing in breast cancer. As such, testing is not so much uniform across hospitals as it is consolidated. Comment 2: Minimal exploration of send-out testing practices and their implications. Response 2: At the time of writing, no centralized records (or in-hospital records) regarding the number of send-out samples were available, and so these numbers could not be included in the article. Send-out practices were, in fact, an ongoing area of investigation by the new National Genetics and Genomics Office, and by several hospitals as they intended to start or expand NGS testing services. Domestic send-out, as mentioned in the response to point 1, is common, depending on the tissue type and testing required. Comment 3: Lack of detailed analysis on PD-L1 IHC testing and interpretation, despite its growing importance in oncology as a tumor agnostic biomarker for treatment. Please specify the clones being used for testing, e.g. Dako 22C3 Response 3: Thank you for your comment. We had previously omitted required thresholds for PD-L1 expression for simplicity, but have added them in the revised version in Table 2. While specifications for antibodies were not previously available, the latest version of the National Genomics Test Directory for Cancer does now include this information for some tests for some cancer types, and we have added these to Table 2 where possible. Comment 4: For NSCLC, the testing of RNA for ALK fusions should be described (ALK mutations suggest that this is not an RNA fusion event); also MET exon 14 skipping lesion, amplifications, etc. Response 4: Thank you for pointing out the ambiguity in " ALK mutations". This has been corrected in the revised article in Tables 1 and 3 for NSCLC, with "mutation" replaced with "fusion". MET exon 14 was not included in the National Cancer Control Programme published list of drug regimens and indications when the original version of this article was released, but was added in July 2024, and it is now included in the article in Tables 1 and 3 for NSCLC as well. Comment 5: It would help to separate Solid tumor from Hematological malignancies in the tables. Response 5: We have reordered the table entries in Tables 1 and 2 such that haematological malignancies (leukaemia/lymphoma) are at the bottom of each table. However, Tables 3 and 4 are grouped and sorted by incidence rates in Ireland, so we have elected to leave leukaemia and lymphoma in place to indicate their rank in total cancer cases. Comment 6: GIST: Expand these to discuss whether in addition to c-KIT, testing also includes PDGFR, BRAF, NF1 and SDH complex Response 6: At this time, NCCP guidelines on GIST testing for treatment are limited to c-KIT , and as such we have not included other genetic testing criteria, given the scope of the article, as outlined above. Comment 7: RAS mutations: please expand to include which genes, e.g. KRAS, NRAS, BRAF, etc. Substitute “normal RAS” with “Negative for RAS mutations” Response 7: Thank you for suggesting that this should be clarified. We have changed "normal RAS " to "wild-type KRAS and NRAS " for colorectal cancer in Tables 1 and 3 to avoid ambiguity and to be in line with the European Medicines Agency text regarding cetuximab and panitumumab indications. Comment 8: Melanoma: while BRAF V600E is most common, there are several other mutated codons that are present; also, NRAS and C-KIT mutations. Response 8: As of May 2025, BRAF V600 is the only codon currently listed under NCCP indications, and so other testing candidates are not listed. However, the national test directory as of April 2025 does now list testing for BRAF , NRAS , and KIT , with suggestions for test expansion to include ALK and ROS , and we anticipate that these genes will be added to NCCP indications if/when approved for targeted treatment. Comment 9: Need to expand on HER2 IHC testing results, i.e. Her-2 low; amplification, etc. and in different cancers Response 9: An indication for HER2-low in breast cancer was added to the NCCP indications in July 2024, and has now been added to the revised article (Tables 2 and 4). We have also further provided the distinguishing thresholds for HER2+ versus HER2-low in breast cancer in Table 2. However, a threshold for HER2+ in gastric cancers has not been officially published by the NCCP, and so is not included. Comment 10: Expand on MSI testing, MLH1 methylation, BRAF mutations in the setting of colon cancer Response 10: We have expanded on the genes indicated for dMMR testing (Table 1: endometrial and colorectal cancer) as per the national test directory, which now include MLH1 promoter hypermethylation, PMS2 , MSH2 , and MSH6 . While BRAF is also included in the test directory for colon cancer, it is not yet included in any NCCP indication. Comment 11: Please define HRD+, i.e. what genes are considered? Response 11: The European Medicines Agency indication for the use of olaparib and bevacizumab in HRD+ gynaecological cancers bases its definition of HRD+ on the PAOLA-1 phase III clinical trial, which classified HRD+ patients as having either BRCA1/2 tumour mutations or a sufficient genomic instability score (GIS). GIS was produced through the Myriad Genetics MyChoice CDx Plus assay, which considered factors such as genome-wide loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. The assay also includes 15 homologous repair pathway genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L ), though the assay and study both consider BRCA1/2 mutations alone to be sufficient for HRD+ classification in the study. Though the same Myriad assay has been considered for use in Ireland, the actual test implementation has not yet been officially established in the national test directory. However, as HRD+ and GIS refer to the EMA indication, we have now included their description of GIS as an explanatory note in the caption for Table 1, though we have not included the specific lists of genes used in the Myriad test, aside from BRCA1/2 . Comment 12: Insufficient information on patient outcomes related to molecular testing. Response 12: This was a question that was initially considered as part of our investigation, as it would also greatly help contextualize the requirement for and benefit of molecular medicine in Ireland. Unfortunately, this data was not available to us as part of this study, but would be of great importance for future work. Additional areas that can be expanded on to strengthen this report: Analyze the uniformity of testing practices across different Irish hospitals and laboratories. Explore the extent and implications of germline testing especially for breast, ovarian and prostate cancers Incorporate data on patient outcomes related to molecular-guided therapies, if available. Discuss challenges in standardizing molecular testing across different centers. Examine the turnaround times for different tests and their impact on treatment decisions. Response: Clinical implementation and results, including comparing testing practices, turnaround times, send-out practices, and patient outcomes, are certainly of interest to us, but were unfortunately out of scope for this current work. We expect that work regarding these matters will be more feasible in the coming years as national genomics initiatives in Ireland continue to progress and as data regarding these aspects of genomics are made more readily available. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Thomas G. Peer Review Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15129.r42367) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://hrbopenresearch.org/articles/7-16/v1#referee-response-42367 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Nagy B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 15 Jul 2024 | for Version 1 Bálint Nagy , Department of Human Genetics, Faculty of Medicine,, University of Debrecen, H-4032 Debrecen, Hungary 0 Views copyright © 2024 Nagy B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The submitted manuscripts is interesting and it is in the focus of clinical interest. The Abstract is too general, please provide more concrete data and conclusion. I miss liquid biopsy and cell-free nucleic acids, are they in use in the clinical practice in Ireland? You should mention this possibility, even if it is not used in Ireland. The Methods section has to be more detailed. There is a "personalized medicine" keyword, you should discuss it in more details. Somehow you should give a perspective about the use of molecular genetics in the clinical practice, diagnosis, treatment and follow up of the cases. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise molecular genetics, molecular diagnostics, non.invasive diagnostics, cell-free nucleic acids, liquid biopsy, cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Nagy B. Peer Review Report For: Overview of Molecular Diagnostics in Irish Clinical Oncology [version 1; peer review: 1 approved, 1 approved with reservations] . HRB Open Res 2024, 7 :16 ( https://doi.org/10.21956/hrbopenres.15129.r41155) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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