Daily Endocrinology Research Analysis
Analyzed 44 papers and selected 3 impactful papers.
Summary
Three impactful studies span precision oncology, perioperative diabetes care, and reproductive endocrinology. A nationwide multi-omic profiling of advanced neuroendocrine neoplasms identified actionable targets with real-world clinical benefit; a SPAQI consensus offers tailored perioperative management of SGLT2 inhibitors; and an EBioMedicine cohort shows that a polygenic score for age at menopause predicts ovarian response in IVF beyond AMH.
Research Themes
- Precision oncology in neuroendocrine neoplasms
- Perioperative safety of SGLT2 inhibitor therapy
- Genomic predictors of ovarian response in IVF
Selected Articles
1. Clinically actionable genomic and transcriptomic landscape of advanced neuroendocrine neoplasms.
In a nationwide precision oncology program, 168 patients with advanced neuroendocrine neoplasms underwent whole-genome/exome and transcriptome sequencing, revealing grade- and tissue-specific heterogeneity and multiple actionable vulnerabilities. Molecularly guided therapies were recommended in 85.7% and implemented in 39.6%, with 69.1% of evaluable treatments showing clinical benefit.
Impact: This work translates comprehensive multi-omics into real-world clinical benefit for advanced NENs, demonstrating the utility of broad profiling in a therapeutically challenging population.
Clinical Implications: Supports routine comprehensive genomic/transcriptomic profiling in advanced NENs to uncover diverse therapeutic options (e.g., ICB, kinase inhibitors, ADCs, PARP inhibitors, platinum) and guide treatment selection.
Key Findings
- Marked molecular heterogeneity across grades and tissues of origin in advanced NENs
- Actionable features included temozolomide-induced high TMB, rare kinase mutations, overexpressed antigens, and homologous recombination deficiency signatures
- Molecularly guided recommendations were provided to 85.7%; 39.6% received such therapies, with 69.1% of evaluable treatments showing clinical benefit
Methodological Strengths
- Nationwide precision oncology framework with whole-genome/exome and transcriptome sequencing
- Linkage of multi-omic profiling to real-world outcomes from molecularly guided interventions
Limitations
- Non-randomized observational design without a control arm limits causal inference
- Heterogeneity across tumor sites and prior treatments may confound outcome attribution
Future Directions: Anatomic site-specific trials validating molecularly guided strategies and prospective studies to refine biomarker–therapy matching are warranted.
BACKGROUND: Epithelial neuroendocrine neoplasms (NENs) are a rare and heterogeneous group of malignancies with limited treatment options. Comprehensive molecular characterization may reveal novel therapeutic opportunities for these clinically challenging tumors. METHODS: Within a nationwide precision oncology program, we performed whole-genome/exome and transcriptome sequencing in 168 patients with a diagnosis of advanced NEN from diverse anatomic origins, followed by evaluation of real-world outcomes associated with molecularly guided interventions. FINDINGS: Our analysis revealed substantial molecular heterogeneity across advanced NENs, including distinct genetic profiles between low-grade and high-grade tumors, as well as alterations specific to particular tissues of origin. Candidate therapeutic targets included elevated tumor mutational burden induced by temozolomide exposure, rare actionable kinase mutations, overexpression of targetable antigens, and signatures of homologous recombination deficiency, providing a rationale for immune checkpoint blockade, kinase inhibitors, antibody-drug conjugates, poly(ADP-ribose) polymerase (PARP) inhibitors, and platinum-based therapies, respectively. Overall, 144 patients (85.7%) received molecularly guided treatment recommendations, of which 85 were implemented in 57 patients (39.6%). Among 68 evaluable therapy outcomes, 47 (69.1%) demonstrated clinical benefit (objective response, n = 25; disease stabilization, n = 22). At the patient level, 34 of the 57 treated (59.6%) experienced clinical benefit from at least one therapy (objective response, n = 18; disease stabilization, n = 16). CONCLUSIONS: Comprehensive genomic and transcriptomic profiling identified distinct molecular alteration patterns and therapeutic vulnerabilities among different classes of epithelial NENs from various tissues, warranting further investigation in anatomic-site-specific studies. Our outcome data underscore the clinical utility of broad molecular profiling in patients with advanced NENs lacking further standard treatment options. FUNDING: Funding for the study was institutional.
2. Perioperative management of patients taking sodium-glucose cotransporter 2 inhibitors: Society for Perioperative Assessment and Quality Improvement (SPAQI) multidisciplinary consensus statement.
Using a systematic review and modified Delphi process, SPAQI convened a multidisciplinary panel to standardize perioperative SGLT2 inhibitor management. The statement advocates a tailored approach based on diabetes status, comorbidities, surgical/dietary factors, and explicit monitoring and prevention for euglycemic DKA.
Impact: Addresses a pressing safety gap with harmonized, evidence-informed recommendations likely to reduce perioperative euglycemic DKA and practice variability.
Clinical Implications: Adopt a risk-stratified perioperative plan for SGLT2 inhibitors incorporating diabetes status, comorbidities, procedural fasting/diet, and proactive monitoring to prevent euglycemic DKA rather than a blanket stop interval.
Key Findings
- Perioperative guidance for SGLT2 inhibitors varies widely across societies and settings
- SPAQI used a systematic review and modified Delphi to produce updated, multidisciplinary recommendations
- Recommendations emphasize tailored management and monitoring/prevention strategies for euglycemic DKA
Methodological Strengths
- Modified Delphi consensus methodology with multidisciplinary expertise
- Recommendations grounded in a systematic review of the literature
Limitations
- Consensus-based guidance without prospective interventional validation
- Evidence gaps persist regarding optimal timing across diverse procedures and populations
Future Directions: Prospective studies to evaluate safety/efficacy of tailored perioperative SGLT2i protocols and to refine risk stratification algorithms.
The perioperative management of patients using sodium-glucose cotransporter 2 inhibitors (SGLT2is) remains controversial. The US Food and Drug Administration currently recommends stopping SGLT2is for 3-4 days before surgery, irrespective of a diagnosis of diabetes mellitus. Other multisociety recommendations vary significantly in terms of SGLT2i management, perioperative monitoring, and mitigating strategies for euglycaemic diabetic ketoacidosis. This multidisciplinary consensus statement led by the Society for Perioperative Assessment and Quality Improvement (SPAQI) provides updated recommendations based on a modified Delphi process and supported by a systematic review of the literature. The recommendations include a tailored approach to management of SGLT2is perioperatively based on the presence of diabetes mellitus and other comorbidities, surgical and periprocedural dietary considerations, as well as monitoring and prevention strategies for euglycaemic diabetic ketoacidosis.
3. The polygenic score for age at menopause is independently associated with the response of controlled ovarian hyperstimulation in women undergoing IVF.
In 435 IVF patients, a higher polygenic score for age at natural menopause correlated with more pre-retrieval follicles, while a lower score was linked to suboptimal response, independent of age and largely beyond AMH. Mediation analysis showed AMH accounts for 31% of the genetic effect, and no association with ongoing pregnancy was observed.
Impact: Introduces a clinically accessible genomic predictor that augments AMH for anticipating ovarian responsiveness, enabling more precise, risk-adapted stimulation strategies.
Clinical Implications: Incorporating ANM-related polygenic scores could refine ovarian stimulation planning, especially in patients at risk for suboptimal response, while recognizing that pregnancy outcomes were not predicted.
Key Findings
- Each 1 SD increase in ANM polygenic score associates with +0.950 follicles two days pre-OPU (p < 0.001)
- Lower ANM-PGS in <8 follicles retrieved vs optimal response (mean difference −0.33, p < 0.01); no association with ongoing pregnancy
- AMH mediates 31% of the PGS effect on follicle number (p = 0.002)
Methodological Strengths
- Standardized IVF stimulation with genotype-based PGS and adjustment for genomic components and age
- Causal mediation analysis quantifying AMH's contribution to genetic effects
Limitations
- Observational cohort design limits causal inference and external generalizability
- No predictive value for ongoing pregnancy; industry funding (Ferring) may introduce bias
Future Directions: External validation and randomized adaptive stimulation trials using PGS-informed protocols to test clinical utility and cost-effectiveness.
BACKGROUND: While Anti-Müllerian hormone (AMH) helps personalise In Vitro Fertilization (IVF) stimulation protocols, a significant number of women still do not achieve an optimal ovarian response. To address this, we explore the utility of a polygenic score for age at natural menopause (ANM) as a predictor for ovarian response during IVF. METHODS: This cohort study included 435 women who underwent standardised IVF stimulation, and they were genotyped to calculate a polygenic score (PGS) for ANM. Linear regression and ANCOVA models were used to assess the associations between the PGS and ovarian response, oocyte and embryo quality and pregnancy rates, adjusting for genomic components and age. FINDINGS: A one standard deviation increase in the PGS for ANM was associated with 0.950 (p < 0.001) additional follicles two days before ovum pick-up. While the PGS did not significantly associate with the overall diminished ovarian response (DOR), a mean difference of -0.33 (p < 0.01) in PGS was observed when comparing individuals with fewer than 8 follicles retrieved to those with an optimal ovarian response. No association was found between the PGS and ongoing pregnancy. Causal mediation revealed that the effect of the PGS onto the number of follicles was partly mediated by AMH levels (proportion mediated = 31%, p = 0.002). INTERPRETATION: A lower PGS for ANM, indicative for earlier menopause, is independently associated with a reduced ovarian response during IVF stimulation, specifically fewer follicles retrieved and mostly independent of AMH levels. This highlights the potential of ANM-related genetic variants to inform personalised IVF protocols by predicting ovarian responsiveness. FUNDING: This study was supported by Ferring Pharmaceuticals.