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Deep Dive into Predictive Markers and Endometrial Cancer Therapy
Welcome to an in-depth presentation exploring the critical role of predictive markers in guiding the treatment of endometrial cancer. This session will provide you with a comprehensive understanding of how molecular profiles are transforming therapeutic approaches and improving patient outcomes. You will discover the latest insights into identifying patients who will benefit most from targeted therapies, particularly PARP inhibitors and primary chemo-immunotherapy.
Understanding Homologous Recombination Deficiency (HRD)
The presentation begins by detailing Homologous Recombination Deficiency (HRD), a key genomic instability that influences treatment response. You will learn about:
- The different components of HRD testing, including BRCA mutation tests and genomic instability scores (GIS).
- How HRD functional status is assessed through tests like the nuclear RAD51 test.
- Commercially available HRD tests and the types of genomic information they provide, such as BRCA mutations and genomic scars.
- The importance of assessing the cause and effect of HRR pathway defects in guiding therapeutic decisions.
Molecular Classification of Endometrial Cancer
A significant portion of this discussion is dedicated to the molecular classification of endometrial cancer, which is crucial for personalized treatment strategies. You will explore the distinct molecular subgroups:
- POLE ultramutated (POLEmut): Characterized by a high number of mutations.
- Microsatellite unstable (MSI-H or dMMR): Showing hypermutation and specific substitution frequencies.
- Copy-number low (endometrioid) or no specific molecular profile (NSMP): Representing a large proportion of cases with varying mutation patterns.
- Copy-number high (serous-like) or p53 abnormal (p53abn): Often associated with specific genomic alterations.
You will learn how immunohistochemistry for p53 and mismatch repair proteins, along with DNA sequencing for POLE exonuclease domain mutations, contribute to this classification. This molecular understanding is essential because "endometrial cancer is not one disease" and "one size (treatment) does not fit all".
Primary Chemo-Immunotherapy and PARP Inhibitors
The presentation delves into the rationale and impact of combining immune checkpoint inhibitors (ICI) with chemotherapy, potentially including PARP inhibitors, for advanced or recurrent endometrial cancer. Key benefits of this combination include:
- Enhanced immunogenic cell death and reduced immunosuppression within the tumor microenvironment.
- Broad clinical activity observed across several cancer types.
- The potential of adding a PARP inhibitor to further improve outcomes, even in patients with proficient mismatch repair (MMRp) disease.
You will explore data indicating a substantial benefit of ICI plus chemotherapy in mismatch repair deficient (dMMR) endometrial cancer. However, it is noted that there might be no additional benefit of PARP inhibitors on top of ICI in dMMR endometrial cancer, suggesting the effect is predominantly driven by anti-PD-(L)1 agents. Conversely, for MMRp endometrial cancer, a clinically meaningful benefit of ICI plus chemotherapy is observed, with further analysis needed to identify which subgroups benefit most from PARP inhibitor addition.
Challenges and Future Directions in Biomarker Research
The discussion also addresses critical questions and challenges in validating predictive markers for PARP inhibitors and combination therapies. Key takeaways include:
- Data is currently derived from limited subgroup analyses.
- Changes in HRR genes are linked to HRD, but HRD cut-off values may not be universally applicable across all tumor types.
- Validation studies are necessary to confirm findings across diverse patient populations.
- Access to PARP inhibitor treatment should not be restricted based solely on HRR alterations or HRD scores without further evidence.
The presentation emphasizes the need for continued collaboration among study groups and pooling data from clinical trials to gain a more comprehensive understanding. Future research aims to address crucial questions such as identifying dMMR patients who may not benefit from ICI plus chemotherapy, exploring whether chemotherapy can be replaced by ICI-only treatment in certain dMMR patients, and determining how to treat patients who experience relapse after chemo-immunotherapy. The ongoing quest for predictive biomarkers is vital to identify patients who will derive the most benefit from PARP inhibitor addition to ICI in MMRp endometrial cancer. Molecular profiling has completely transformed the therapeutic approach, marking the beginning of an unprecedented improvement in patient outcomes.
