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PubMed2025

Newborn screening for common genetic variants associated with permanent hearing loss: Implementation in Ontario and review of the first 3 years.

PURPOSE: Early hearing detection and intervention (EHDI) programs using audiometric screening techniques alone have a limited ability to detect noncongenital childhood permanent hearing loss (PHL). In 2019, Ontario launched universal newborn screening (NBS) for PHL risk factors, including congenital cytomegalovirus and 22 common variants in GJB2 and SLC26A4. Here, we describe our experience in screening for genetic risk factors. METHODS: Ontario newborns who participated in universal newborn hearing screening (UNHS) were offered risk factor screening using dried blood spots (DBS) collected for conventional newborn screening. The screening was conducted using a custom MassArray assay, and positive results were confirmed by Sanger sequencing or polymerase chain reaction. Diagnostic audiological assessments were performed for all screen-positive infants. RESULTS: Of the 412,424 infants screened, 93 had 2 variants in GJB2 or SLC26A4. Of these, 72 had confirmed PHL, 20 had normal hearing, and 1 declined follow-up. Thirteen infants with PHL (1 in 31,724; 11.8% of screen positives) were not identified through audiometric testing as they passed (3) or missed (10) the screening. Importantly, among infants who ultimately received cochlear implants, the detection of genetic etiology through NBS led to an accelerated time to diagnosis, assessment, and intervention. CONCLUSION: Genetic screening has strengthened UNHS and care for infants with or at risk of PHL in Ontario. This study is a step toward the broader inclusion of genomic testing in NBS.

Humans↗
PubMed2026

Aligning awareness, systems and policy to increase equitable access to genomically driven cancer care.

Genomic testing has the potential to transform cancer care across the patient pathway. However, its benefits remain unevenly realised across populations and health systems. Precision oncology is characterised by a strong promissory discourse, with expectations of improved outcomes and cost-effectiveness, yet real-world implementation remains variable and context dependent. This review examines how patient and public awareness interacts with, and is constrained by, structural, organisational and political-economic factors that shape equitable access to genomically driven cancer care across five themes: (1) the power of patient and public advocacy; (2) learning from the patient perspective; (3) culturally responsive communication; (4) structural and personal barriers and facilitators and (5) political economy of health. Examples are mapped across global regions to highlight how health system, structural and societal factors continue to limit the universal realisation of genomic medicine's benefits. We present four recommendations to strengthen the translation of awareness into equitable access and clinical impact: (1) expand and adequately power genomic studies in underserved populations; (2) improve risk communication and decision-making across the cancer pathway; (3) equitable validation and interpretation of emerging genomic technologies and (4) generate real-world evidence on access, uptake and outcomes of genome-matched therapies. Embedding awareness, trust, access and equity in future initiatives is imperative to realise the promise of precision medicine for all patients.

Biomarkers↗
PubMed2026

Immune dysregulatory disorders: perspective from solving a diagnostic odyssey.

PURPOSE OF REVIEW: Inborn errors of immunity (IEIs), once considered rare disorders characterized primarily by recurrent infections, are now recognized as a rapidly expanding group of diseases encompassing autoimmunity, autoinflammation, allergy, malignancy, and immune dysregulation. Advances in next-generation sequencing, functional immunology, and systems biology have revealed overlap between traditionally distinct disease categories and highlighted the complexity of genotype-phenotype relationships. RECENT FINDINGS: While this evolution has led to the discovery of hundreds of previously unrecognized disorders, it has also challenged conventional diagnostic paradigms and demonstrated how patients may have care spread across multiple specialties, without a clear medical home. These discoveries have also highlighted ongoing challenges translating scientific findings to the clinic including difficulties in accessing genomic testing, interpretation of variants of uncertain significance, impacts of incomplete penetrance and somatic mosaicism, and limited availability of specialized functional assays. Emerging computational approaches, including artificial intelligence, offer opportunities to accelerate diagnosis but cannot replace comprehensive clinical evaluation or longitudinal physician-patient relationships. SUMMARY: This perspective examines how the diagnostic odyssey for immune dysregulatory disorders has evolved, side-by-side with the changing framework for diagnosing rare immune diseases. We propose an integrated approach combining clinical phenotyping, genomics, functional validation, and multidisciplinary expertise to unite ongoing discovery between clinicians and scientists, diagnostics, and patient outcomes.

diagnostic odyssey↗
PubMed2026

Synergistic engineering of Casδ nuclease for robust genome editing.

Casδ is a recently identified evolutionary transitional CRISPR system characterized by its compact size (~900 amino acids), broad temperature tolerance, and guidance by a short crRNA without the requirement of a tracrRNA. However, the low editing efficiency of Casδ in eukaryotic cells limits its application. Here, we have developed a hierarchical engineering strategy to improve the genome editing activity of Casδ-1, with optimization focused on enhancing its interactions with the crRNA, the protospacer adjacent motif (PAM) duplex, the single-stranded DNA substrate, and the RNA-DNA heteroduplex. Through this strategy, we successfully generated an activity-enhanced Casδ-1 variant, designated enCasδ, which harbors 9 amino acid substitutions that synergistically augment its editing efficiency. In human cell lines, enCasδ showed 1.3- to 29.3-fold higher editing activity than the wild-type Casδ-1 across ten tested genomic loci, with an average editing efficiency of 54.6%. In addition, enCasδ also mediated robust genome editing in maize; its editing efficiency increased by an average of 5.3-fold relative to Casδ-1, and reached up to an average of 80% at the TS4 and PSY1 loci in stable transgenic lines. The overall editing performance of enCasδ was comparable to that of Streptococcus pyogenes Cas9 (SpCas9) and other Cas12 nucleases. Collectively, enCasδ represents a highly optimized Casδ-1 variant that broadens the applicability of the Casδ CRISPR system and facilitates robust genome editing in both animal cells and plants.

Gene Editing↗
PubMed2026

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

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

Humans↗
PubMed2026

Whole genome sequencing reveals a specific microbiota in subglottic stenosis C. acnes may contribute to inflammation.

PURPOSE: Subglottic stenosis (SGS) progressively reduces the airway below the vocal folds. The cause is not known and there is a recurrent need of surgical treatment. Including all phenotypes, SGS affects 1/400 000/yr, with a female dominance. Previous studies have revealed a possible role of the Mycobacterium complex in SGS development. Our hypothesis is that microbiota is associated with the inflammation in SGS, if true it might affect the prevailing treatment options. METHODS: This prospective cross-sectional study included biopsies from 34 patients with subglottic stenosis, collected between 2020 and 2023. Nucleic acids were extracted from the tissue samples and analysed using whole genome sequencing. Microbial composition was characterized using taxonomic profiling of sequencing data. Species with sufficient read counts were selected for further validation using sequence alignment methods to ensure accuracy of identification. RESULTS: Using the most comprehensive form of genomic testing currently in clinical use, we present curated and stable data on the presence of Cutibacterium acnes in 28 out of the 34 cases. CONCLUSION: Cutibacterium acnes may serve as a driver of the inflammation characterizing SGS and should be considered in therapeutically oriented future studies.

Cutibacterium acnes↗
PubMed2025

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

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

Humans↗
PubMed2026

Latin American consensus on the medical oncologic management of early-stage HR+/HER2- breast cancer: Addressing regional disparities in Spanish-speaking countries.

PURPOSE: Substantial disparities persist in managing early-stage hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer across Spanish-speaking Latin America, including limited access to genomic testing, systemic therapies, and fertility preservation. The Latin American Breast Cancer Association (LABCA) convened an expert panel to produce the first consensus tailored to Spanish-speaking countries. METHODS: A literature review (Embase, PubMed, Scopus, ClinicalKey, LILACS; 2014-2025), informed by ESMO/ASCO/NCCN/SEOM guidelines and registered in PROSPERO (CRD42024565706), supported statement development. A steering committee of three experts of Spanish nationality supervised the process. Twenty-one specialists from 11 countries participated in a modified Delphi process; 31 items were voted in Round 1 and 25 statements were retained within scope. Consensus was pre-defined as ≥80% agreement (or median 7-9), with a mean/outlier rule reported alongside. RESULTS: Applying the ≥80% rule, 22 of 25 statements (88%) reached full consensus; three (1.3, 2.4, 3.3; 75-76%) were near-consensus and retained with caveats. Recommendations integrated clinicopathologic and molecular factors to guide risk stratification; genomic assays were reserved for selected scenarios and discouraged in very low-risk tumors or ≥4 positive lymph nodes. Consensus also covered ovarian suppression plus endocrine therapy, fertility preservation, sexual-health and genetic evaluation, and adjuvant CDK4/6 and PARP inhibitors when accessible. Marked heterogeneity in access was documented by country and sector. CONCLUSION: This consensus provides the first region-specific, evidence-based, resource-adapted recommendations for early-stage HR+/HER2- breast cancer in Spanish-speaking Latin America, aiming to reduce disparities and strengthen equitable oncology care.

Humans↗
PubMed2026

Prenatal SNP-array chromosomal microarray analysis in 3,549 pregnancies: indication-specific yields and clinical implications.

BACKGROUND: SNP-based chromosomal microarray analysis (CMA) is widely used in invasive prenatal diagnosis, yet real-world performance across contemporary referral pathways, especially in the NIPT era, remains incompletely characterized. METHODS: We retrospectively analyzed 3,549 prenatal invasive samples tested by SNP array, and evaluated diagnostic yield overall and by referral indication and ultrasound phenotype. RESULTS: In total, we identified 398 pathogenic or likely pathogenic (P/LP) variants across 386 fetuses, resulting in an overall diagnostic yield of 10.9% (386/3,549). These findings comprised 223 aneuploidies and 175 pathogenic CNVs. In contrast, variants of uncertain significance (VOUS) were detected in 12.0% (426/3,549) of cases. Diagnostic yields were heavily stratified by indication: yields peaked in NIPT high-risk referrals (38.9%) and were intermediate in ultrasound-based cases (~ 11%), but dropped significantly in the advanced maternal age (AMA; 4.2%) and serum screening (~ 5-6%) groups. Conversely, VOUS rates remained remarkably stable across all referral categories. Sub-analysis of ultrasound abnormalities revealed that multisystem anomalies conferred the highest risk (27.3%), driven predominantly by aneuploidies; among soft markers, increased nuchal translucency (NT) emerged as the strongest predictor of chromosomal pathology. CONCLUSIONS: In our cohort, SNP-array identified clinically actionable findings in 10.9% of cases. NIPT enriched diagnostic yields, particularly for aneuploidies, and NT thickness was strongly associated with pathogenic findings. These results support an indication-based approach to genomic testing, with NIPT as a triage tool for aneuploidy and CMA for high-risk populations, while improving VOUS counseling.

Humans↗
PubMed2026

Impact of Somatic Mutations on Treatment Response and Resistance in Chronic Myeloid Leukemia.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML); yet, diverse molecular responses and resistance persist. BCR::ABL1 kinase-domain (TKD) mutations constitute just a fraction of this resistance, and the impact of additional somatic mutations on disease progression and early molecular response remains incompletely defined. METHODS: This single-centre cohort study analyzed 109 NGS-tested patients with CML, comprising 44 with TKI-resistant disease and 65 newly diagnosed patients. Targeted next-generation sequencing using a 135-gene myeloid panel was performed on 109 patients. An additional pilot subgroup of 30 TKI-resistant patients underwent BCR::ABL1 kinase-domain analysis by PCR/Sanger sequencing and was analyzed separately. Molecular response was assessed using BCR::ABL1 transcript levels on the International Scale and interpreted according to ELN 2020 recommendations. RESULTS: Somatic mutations were identified in 52.3% of TKI-resistant and 29.2% of newly diagnosed patients. All Cohort 1 blast-crisis patients were mutation-positive, and several concurrent abnormalities were more common in Cohort 1 than in Cohort 2, indicating clonal complexity. In Cohort 2, MMR was achieved in 28/39 (71.8%) mutation-negative and 6/13 (46.2%) mutation-positive patients. Mutation-positivity at baseline was associated with reduced MMR chances but not statistically significant (odds ratio 0.34; 95% confidence interval 0.09-1.23; p = 0.099). ASXL1 emerged as the most common non-ABL1 mutation but was not statistically significant. CONCLUSIONS: In this Indian CML cohort, somatic mutations were prevalent in TKI-resistant disease, linked to advanced phase and clonal complexity, and demonstrated a non-significant trend toward lower early MMR at diagnosis, highlighting the importance of genomic testing in this context.

Humans↗
PubMed2026

Epilepsy of infancy with migrating focal seizures: A scoping review of clinical features, diagnostic testing including genetics, long-term outcomes, mortality, and current and emerging therapeutic strategies.

BACKGROUND: Epilepsy of infancy with migrating focal seizures (EIMFS) is among the most severe developmental and epileptic encephalopathies (DEEs), marked by intractable multifocal seizures migrating across both hemispheres, profound developmental arrest, and high early mortality. Advances in next-generation sequencing have revealed a heterogeneous genetic architecture dominated by KCNT1 gain-of-function variants across more than 30 implicated genes, creating opportunities for precision therapeutics. OBJECTIVE: To systematically map published evidence on the clinical, electrophysiological, neuroimaging, genetic, and therapeutic landscape of EIMFS, and to delineate critical knowledge gaps and future research priorities. METHODS: A scoping review was conducted following the Arksey and O'Malley framework, searching PubMed, Ovid MEDLINE, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov. RESULTS: Of 643 articles screened, 89 met inclusion criteria. Beyond confirmation of the canonical electroclinical phenotype, several gaps emerged: neonatal versus post-neonatal onset stratification by genetic etiology remains largely uncharacterized; genotype-specific EEG biomarkers are lacking except for a single small KCNT1 study; and the clinical significance of atypical EEG features-including burst suppression and hypsarrhythmia-is undefined. Neuroimaging literature documents progressive cerebral atrophy and myelination abnormalities without quantitative volumetry, diffusion tractography markers, or attribution to seizure burden, medication effects, or underlying etiology. Genetic diagnostic yield was 70-80%, with KCNT1 accounting for 30-50% of solved cases; however, genotype-outcome stratification is limited. Seizures were broadly refractory; potassium bromide, ketogenic diet, cannabidiol, and quinidine (in KCNT1-confirmed cases) showed partial efficacy. Emerging precision approaches include sodium channel blockers for SCN2A gain-of-function variants, novel small molecules, fluoxetine, antisense oligonucleotides, and divalent siRNA targeting KCNT1. Systemic-to-pulmonary collateral circulation causing severe cardiopulmonary complications was reported across multiple cases, yet no consensus screening protocol exists. CONCLUSIONS: EIMFS remains one of the most refractory epilepsy syndromes of infancy. Precision genetic diagnosis is essential to guide targeted therapy. International collaborative registries, standardized outcome measures, genotype-stratified biomarker studies, and rapid point-of-care genomic testing are urgently needed to advance evidence-based care for this highly vulnerable population.

Humans↗
PubMed2026

Development and Validation of a Multimodal Clinical, Pathologic, and Genomic Model for Breast Cancer Recurrence.

PURPOSE: To develop and validate a multimodal recurrence-risk model integrating histology, genomic testing, and clinical variables. METHODS: We developed AI-Path, a whole-slide image biomarker for recurrence prediction trained in CALGB 9344, and validated it in three independent cohorts: TAILORx, a multi-site Chicago cohort, and the MDX-BRCA cohort. We then integrated AI-Path with Oncotype DX Recurrence Score (RS), tumor size, and nodal status into a Cox model, PathClinRS, fit using 60% of cases from TAILORx, with the remaining 40% held out for validation. The primary end point was distant recurrence-free interval. Performance was assessed using Harrell's concordance index (C-index) and Kaplan-Meier analyses. RESULTS: A total of 12,418 patients were included. In TAILORx, AI-Path outperformed RS for distant recurrence (C-index, 0.682 vs 0.647; P = .038), driven by superior prediction of late recurrence (0.656 vs 0.567; P < .001). In node-negative disease, PathClinRS outperformed RSClin in the TAILORx fitting (0.72 vs 0.70; P = .016) and validation sets (0.74 vs 0.70; P = .004). In node-positive disease, PathClinRS outperformed RSClinN+ in Chicago (0.94 vs 0.74; P < .001) and MDX-BRCA (0.71 vs 0.66; P = .004) cohorts. Compared with NATALEE eligibility, PathClinRS identified nearly twice as many high-risk node-negative patients while maintaining a comparable 10-year distant recurrence risk (16.7% vs 16.6% per NATALEE eligibility in TAILORx fitting; 21.0% vs 19.4% in TAILORx validation). PathClinRS identified 68% of intermediate risk premenopausal patients as low-risk with no evidence of chemotherapy benefit, compared to only 36% identified as low risk by standard clinicopathologic criteria. CONCLUSION: Digital histopathology provides prognostic information complementary to genomic assays and has the potential to personalize therapy beyond existing clinicogenomic tools.

Journal Article↗
PubMed2026

Multi-Omics Biomarker Signatures for Precision Diagnosis and Prognosis in Primary Liver Cancer: A Literature Review.

Primary liver cancer (PLC) is a biologically heterogeneous group of malignancies dominated by hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and a smaller subset of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and its clinical burden remains high because current diagnostic and prognostic tools do not adequately capture molecular diversity. Conventional imaging, serum markers, and histopathological assessment remain insufficient for precise early diagnosis, subtype-resolved classification, and outcome stratification, while tissue and liquid biopsy approaches have expanded the range of analytes available for clinical assessment. Recent studies have identified candidate biomarker signatures across genomic, epigenomic, transcriptomic, proteomic, metabolomic, and circulating layers, suggesting that integrated multi-omics profiling may better represent tumor lineage, clonal evolution, immune context, and therapeutic vulnerability than isolated molecular readouts. However, these layers are not equally mature for clinical use: genomic testing is closest to routine therapeutic application in iCCA, plasma methylation assays are advancing for HCC surveillance augmentation, and many proteomic or metabolomic panels remain validation-stage tools. Their clinical value remains constrained by sampling bias, biospecimen-dependent signal loss, assay standardization, cost, and the need for prospective validation across clinically diverse populations. This narrative review critically synthesizes current evidence on multi-omics biomarker signatures for precision diagnosis and prognosis in primary liver cancer and argues that clinically useful signatures should be question-specific, stage-aware, and specimen-aware rather than universal multi-analyte panels.

Humans↗
PubMed2025

The first case of GOLGA5-RET fusion-positive malignant spindle cell sarcoma of the head and neck responsive to selpercatinib.

Soft-tissue sarcoma (STS) is a rare malignancy that accounts for less than 1% of all cancers, and recent advances in molecular biology have led to its classification based on genomic information. Some RET-rearranged neoplasms have been reported to present pathological features similar to Neurotrophic Tyrosine Kinase Receptor-rearranged spindle cell neoplasms. Here, we report the first case of head and neck spindle cell sarcoma with a GOLGA5-RET fusion that demonstrated a sustained clinical response to selpercatinib, identified through targeted next-generation sequencing (NGS). The patient was a 43&#xa0;year-old man with a tumor in the arytenoid region that was resected and diagnosed as a malignant spindle cell tumor. Despite initial treatment with surgical resection alone, local recurrence was confirmed, requiring salvage therapy with total laryngectomy and bilateral cervical dissection. Surgical specimen revealed a spindle tumor with a patternless pattern and collagenous stroma. Immunohistochemistry (IHC) with positivity for CD34, bcl-2 (focally), S100, and weak nuclear staining for STAT6, with absence of expression of CK AE1/3, desmin, c-kit, smooth muscle actin, myogenin, synaptophysin, and SOX10. Trk A/B/C were also negative on IHC. Following confirmation of multiple lung metastases, the patient was treated with doxorubicin monotherapy. Targeted NGS identified GOLGA5-RET rearrangement, FGF14 amplification (equivocal), CDKN2B loss, and CDKN2A loss. GOLGA5-RET rearrangements were validated through fluorescence in situ hybridization. The patient subsequently was enrolled in a phase 1/2 trial for the selective RET inhibitor selpercatinib, resulting in a sustained partial response over 5&#xa0;years. Although solitary fibrous tumor (SFT) was initially considered as a differential diagnosis based on immunohistochemical findings, the lack of strong and diffuse STAT6 expression made this diagnosis unlikely. Subsequent next-generation sequencing (NGS) revealed a RET fusion, leading to the diagnosis of an RET-rearranged spindle cell neoplasm. This case highlights the importance of genomic testing for certain spindle cell sarcomas and the potential benefit of RET-specific inhibitors against RET-altered sarcomas.

Next-generation sequencing↗
PubMed2026

Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/HER2- Advanced Breast Cancer.

Hormone receptor-positive&#xa0;(HR+), human epidermal growth factor receptor 2-negative (HER2-)&#xa0;breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors&#xa0;(CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin&#xa0;(mTOR) pathway. Genetic alterations such as&#xa0;PIK3CA&#xa0;mutations (present in ~ 45% of HR+/HER2-&#xa0;tumors),&#xa0;AKT1&#xa0;mutations, and&#xa0;PTEN&#xa0;loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in&#xa0;PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3K&#x3b1; inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras&#xa0;(PROTACs). Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2- metastatic breast cancer.

Humans↗
PubMed2025

Mainstreaming of clinical genetic testing: A conceptual framework.

PURPOSE: Demand for genetic testing is increasing across medicine, whereas the genetics workforce remains stable. In response, mainstreaming models are being introduced, in which nongeneticist clinicians are increasingly involved in the genetic testing pathway. Because a standardized approach would facilitate evaluation and optimal patient care, a unified framework is warranted. METHODS: Through a focus group with clinical genetics experts, a conceptual framework for the mainstreaming of clinical genetic testing is proposed. Through a consensus process, experts elucidated the steps in the diagnostic care pathway and defined a set of variables that influence which mainstreaming model is best suited to specific patient care scenarios. RESULTS: A total of 35 individuals representing 20 distinct clinical genetics services and all Canadian provinces participated in the development of the framework. The framework describes 4 generalizable mainstreaming models of care, each with varying levels of involvement of the clinical genetics service in the diagnostic care pathway. CONCLUSION: This framework will help guide clinical teams in the design and evaluation of mainstreaming efforts. It is critical that these programs are evaluated and shared in a standardized way so that we can implement strategies that allow optimal utilization of genetics resources and improve patient care.

Humans↗