The Challenge of Predicting Aggressiveness in Endometrial Cancer
Endometrial cancer is one of the most molecularly heterogeneous malignancies in oncology.
Its four recognised molecular subtypes, defined by replicative polymerase mutations, microsatellite stability, copy number high/serous-like profiles, and microsatellite instability, reflect a diverse landscape of genomic aberrations that drive vastly different clinical behaviours.
Yet despite this complexity, predicting which patients will develop aggressive, progressive, or metastatic disease remains one of the most difficult challenges in endometrial cancer management. Conventional clinical and pathological assessments often fall short of capturing the full molecular picture, leaving oncologists without the precision they need to make early, proactive treatment decisions.
This study demonstrates how comprehensive genomic profiling using our OncoIndx CGP assay can bridge that gap:- mapping the mutational landscape of endometrial cancer and establishing clear molecular correlates of disease aggressiveness.
Our Study: 40 Endometrial Cancer Patients
In a retrospective analysis of 40 endometrial cancer patients, we investigated the association between comprehensive genomic mutational profiles generated using our OncoIndx CGP assay; and clinical disease status determined from PET scans and histopathological examination (HPE) reports.
This dual-evidence approach allowed us to directly correlate molecular findings with clinical disease behaviour; establishing whether specific genomic pathway alterations could serve as early predictors of progression and metastasis.
What We Found
The findings reveal a clear and clinically significant relationship between genomic pathway alterations and disease aggressiveness in endometrial cancer:
- 65% of patients (n=26/40) had progressive or metastatic disease confirmed by PET scans and HPE, reflecting the high prevalence of aggressive disease in this cohort
- Of those with aggressive disease, 80% (n=20/26) carried at least one genomic alteration, establishing a strong molecular footprint of disease aggressiveness
- Across the full cohort, 83 genomic alterations were detected spanning five key pathways:- cell proliferation, cell progression, dsDNA repair, MMR, and tumour suppression
- Cell proliferation pathway alterations carried the highest mutational load at 57.8% (n=48/83): confirming their central role as drivers of aggressive endometrial cancer biology
- dsDNA repair pathway alterations were the second most frequent at 14.5% (n=12/83): a finding with direct implications for PARP inhibitor eligibility
- Tumour suppressor alterations constituted the lowest frequency at just 6% , suggesting their role as secondary rather than primary drivers in this cohort
- Five patients showed high MSI scores and one showed an intermediate MSI score, with two MSI-high patients also harbouring classical MMR gene mutations in MSH3 and MSH6
Critically, high MSI scores were not always concordant with mutations in classical MMR genes and vice versa, a finding with profound implications for how MSI testing and MMR mutation profiling should be interpreted together in clinical practice
Why This Matters
This study makes two important contributions to endometrial cancer management.
First, it establishes that cell proliferation and dsDNA repair pathway alterations:- detectable through comprehensive genomic profiling correlate strongly with clinically confirmed aggressive disease, and therefore have the potential to serve as early molecular predictors of progression and metastasis. Identifying these alterations at diagnosis could allow oncologists to escalate surveillance and treatment for high-risk patients far earlier than current clinical tools allow.
Second, the discordance between MSI scores and classical MMR gene mutations in a subset of patients highlights a critical nuance that has direct implications for immunotherapy eligibility. If MSI status and MMR mutations are assessed independently rather than together, patients may be incorrectly classified:- either missing out on immunotherapy they would benefit from, or being assigned to it inappropriately.
Our OncoIndx CGP assay captures both simultaneously: ensuring that no clinically critical signal is missed.
Published at the ASCO Annual Meeting 2025 | DOI: 10.1200/JCO.2025.43.16_suppl.e15034
Presented by Aarthi Ramesh | OneCell Dx | Publication Only: Developmental Therapeutics:- Molecularly Targeted Agents and Tumor Biology
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