THE MOLECULAR CLASSIFICATION OF ENDOMETRIAL CARCINOMA: ADVANCEMENTS IN DIAGNOSIS, PROGNOSTICATION, AND THERAPEUTIC STRATIFICATION

ABSTRACT

Endometrial carcinoma (EC) presents a complex diagnostic and therapeutic challenge, necessitating innovative approaches. Recent molecular classification advancements, facilitated by The Cancer Genome Atlas (TCGA), have identified four distinct subtypes: POLE ultramutated, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP). These subtypes reveal tumor biology intricacies and enable personalized treatment strategies, enhancing patient outcomes. Notably, patients with POLE ultramutated tumors may benefit from de-escalated treatments, while those with MMRd may respond favorably to immunotherapies.

However, high costs and limited access to molecular testing hinder widespread adoption, particularly in resource-constrained settings. Future directions include integrating innovative technologies, such as liquid biopsy, to enhance early detection and treatment monitoring. Ensuring equitable access to these advancements is crucial for improving outcomes for all EC patients.

АННОТАЦИЯ

Рак эндометрия представляет собой сложную диагностическую и терапевтическую проблему, требующую инновационных подходов. Недавние достижения в молекулярной классификации, обеспеченные проектом "Атлас рака" (The Cancer Genome Atlas, TCGA), позволили выявить четыре основных подтипа: гипермутированные POLE, дефектные по репарации несоответствий (MMRd), аномальные p53 (p53abn) и без специфического молекулярного профиля (NSMP). Эти подтипы не только раскрывают сложности биологии опухоли, но и позволяют разрабатывать индивидуализированные стратегии лечения, улучшающие результаты для пациентов. В частности, пациенты с гипермутированными опухолями POLE могут получить менее агрессивное лечение, а пациенты с MMRd могут ответить на иммунотерапию.

Однако высокие затраты и ограниченный доступ к молекулярному тестированию являются значительными барьерами, особенно в условиях ограниченных ресурсов. В будущем перспективными направлениями являются интеграция инновационных технологий, таких как ликвидная биопсия, для улучшения раннего выявления и мониторинга лечения. Обеспечение равного доступа к этим достижениям будет критически важным для улучшения результатов для всех пациентов с раком эндометрия.

Keywords: endometrial carcinoma, endometrial cancer, uterin cancer, p53, molecular classification liquid biopsy.

Ключевые слова: рак эндометрия, эндометриоидная карцинома, молекулярная классификация, p53, иммунотерапия, жидкостная биопсия.

Endometrial carcinoma (EC) is one of the most prevalent gynecological malignancies, with significant implications for global healthcare. Over the last decade, advancements in molecular biology and genomics have substantially transformed the understanding of EC, leading to the development of molecular classification systems. These systems are pivotal in improving diagnostic accuracy, prognostic predictions, and therapeutic strategies. Among the most notable advancements is the classification proposed by The Cancer Genome Atlas (TCGA), which divides EC into four molecular subtypes: POLE ultramutated, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP). These subtypes offer critical insights into the tumor biology of EC, guiding personalized treatment approaches. This review aims to provide a comprehensive exploration of the molecular classification of EC, focusing on its historical context, theoretical development, diagnostic implications, and future perspectives.
The practice of classification, a fundamental aspect of scientific inquiry, has a long history that dates back to ancient philosophy. Early thinkers such as Aristotle categorized knowledge into distinct domains like theoretical, practical, and productive sciences [7]. These early classification efforts were not limited to philosophy but also extended to the natural sciences, including medicine. Over time, the need to categorize complex phenomena became increasingly important, particularly in fields such as biology and medicine. The classification of diseases, including cancers, reflects this broader intellectual effort to impose order on the natural world.

In medicine, early classification efforts were heavily influenced by broader philosophical trends. For instance, in the 19th century, positivistic and holistic approaches emerged, shaping medical classification systems [14]. These early systems often focused on observable symptoms and clinical syndromes rather than underlying biological mechanisms. As medical knowledge advanced, classification systems became more refined, evolving from broad categories to more specific diagnostic criteria.
The evolution of medical classification systems has been a gradual process, shaped by advancements in scientific knowledge and technology. In psychiatry, for example, early classifications were based on broad syndromes, influenced by the practical need to categorize large numbers of patients in asylums [9]. Over time, as knowledge of mental health disorders improved, classifications became more precise, reflecting a deeper understanding of the underlying causes of psychiatric conditions.

Similarly, the classification of cancers, including endometrial carcinoma, has evolved significantly. Early cancer classifications were largely based on histological features, such as the appearance of tumor cells under a microscope. However, with the advent of molecular biology, it became clear that many cancers, including EC, are heterogeneous diseases with distinct molecular subtypes. This realization led to the development of molecular classification systems, which classify cancers based on their genetic and molecular characteristics rather than just their histological appearance.

The molecular classification of endometrial carcinoma represents a significant shift in how cancers are understood and treated. Molecular classification systems are more precise than traditional histological classifications, allowing for a deeper understanding of the genetic and molecular mechanisms driving tumor development. In the case of EC, the TCGA classification system identifies four distinct molecular subtypes, each with unique prognostic and therapeutic implications.

POLE Ultramutated Subtype: This subtype is characterized by mutations in the DNA polymerase epsilon (POLE) gene, leading to an extremely high mutation rate. Despite the high mutation burden, patients with POLE ultramutated tumors generally have an excellent prognosis, with low recurrence rates and high overall survival [8, 16]. The identification of POLE mutations has become a key factor in determining prognosis and guiding treatment decisions.

Mismatch repair deficient subtype (MMRd) is defined by defects in the DNA mismatch repair system, leading to microsatellite instability (MSI). These tumors are often associated with Lynch syndrome and have a higher risk of recurrence compared to other subtypes [1]. Immune checkpoint inhibitors (ICIs), such as pembrolizumab and dostarlimab, have shown significant efficacy in treating MMRd tumors, making this subtype particularly important for therapeutic decision-making [15].

p53 Abnormal (p53abn) subtype is characterized by mutations in the TP53 gene, commonly found in high-grade serous carcinomas. The p53abn subtype is associated with a poor prognosis and is often linked to more aggressive disease courses [8]. Trastuzumab, a HER2-targeted therapy, has shown promise in treating HER2-positive serous carcinomas within this subtype, highlighting the importance of molecular classification in guiding targeted therapies [6].

The most common subtype, non-specific molecula classification (NSMP), accounts for approximately 50% of EC cases and lacks the specific molecular alterations seen in the other subtypes [3]. NSMP tumors generally have an intermediate prognosis, but their heterogeneity presents challenges in treatment planning, underscoring the need for ongoing research to better stratify these cases [4].

Conceptual and Methodological Considerations

The molecular classification of EC is not without its challenges. One of the key conceptual issues is the dynamic nature of classification systems themselves. As scientific knowledge advances, classification systems evolve, reflecting new insights into the molecular and genetic mechanisms underlying disease. This is particularly true in oncology, where the rapid pace of technological innovation has led to the continuous refinement of molecular classification systems.

Methodologically, the classification of diseases like EC involves integrating diverse types of data, including genetic, molecular, and clinical information. This interdisciplinary approach is essential for developing robust classification systems that are both clinically useful and scientifically accurate [14]. However, this approach also presents challenges, particularly in terms of standardizing methodologies across different research and clinical settings.

Furthermore, the cultural and historical contexts in which classification systems are developed play a crucial role in shaping their structure and application [2]. Understanding these contexts is essential for appreciating the complexities involved in classifying diseases at the molecular level.

Diagnostic and Prognostic Advancements

The molecular classification of EC has led to significant advancements in both diagnostic and prognostic accuracy. Traditional histopathological classifications, while useful, are limited in their ability to capture the underlying biological diversity of EC. The TCGA classification system, by contrast, provides a more nuanced understanding of the molecular drivers of EC, allowing for more accurate predictions of disease behavior.

Next-generation sequencing (NGS) has been instrumental in the development of molecular classification systems for EC. NGS enables the identification of key genetic mutations, such as those in the POLE, PIK3CA, and PTEN genes, which play a critical role in the development and progression of EC [11, 12]. These mutations not only provide valuable diagnostic information but also serve as therapeutic targets, allowing for the development of personalized treatment strategies.

For example, patients with POLE ultramutated tumors generally have an excellent prognosis and may benefit from less aggressive treatment [8]. In contrast, patients with p53abn tumors, which are associated with poor outcomes, often require more intensive therapeutic interventions, such as HER2-targeted therapies or immune checkpoint inhibitors.

The therapeutic implications of molecular classification in EC are profound. By identifying specific molecular subtypes, clinicians can tailor treatment strategies to the individual characteristics of a patient's tumor. This approach is particularly important in the case of MMRd tumors, which respond well to immune checkpoint inhibitors like pembrolizumab and dostarlimab [15]. These therapies have revolutionized the treatment of MMRd tumors, offering new hope for patients with this aggressive subtype.

Similarly, the identification of HER2-positive serous carcinomas within the p53abn subtype has led to the use of trastuzumab, a HER2-targeted therapy, in combination with chemotherapy. This approach has been shown to improve survival outcomes in patients with HER2-positive tumors, highlighting the importance of molecular classification in guiding targeted therapies [6].

However, despite these advancements, challenges remain in the implementation of molecular classification in clinical practice. The high cost and complexity of NGS and other molecular testing methodologies present significant barriers, particularly in resource-limited settings [10]. Furthermore, the static nature of certain genetic markers, such as BRA mutations and homologous recombination deficiency (HRD), limits their utility in guiding dynamic treatment decisions [13].

Challenges in Molecular Testing

While molecular profiling has greatly improved the diagnosis and treatment of EC, several challenges remain. One of the primary challenges is the cost of molecular testing, particularly in resource-limited settings. Next-generation sequencing, while highly effective, is expensive and requires specialized equipment and expertise, limiting its accessibility in many healthcare settings [10].

Another challenge is the static nature of certain genetic markers. For example, while MSI and HRD status are useful for guiding initial treatment decisions, they remain unchanged over time, limiting their utility in guiding dynamic treatment adjustments [13]. This underscores the need for ongoing research to identify more dynamic biomarkers that can provide real-time information about a tumor's response to treatment.

Future Directions in Molecular Classification

The molecular classification of endometrial carcinoma is a rapidly evolving field, with significant potential for further advancements. One promising area of research is the development of dynamic biomarkers that can provide real-time information about a tumor's response to treatment. This would allow for more personalized and adaptive treatment strategies, improving outcomes for patients with aggressive or treatment-resistant tumors.

Another area of interest is the integration of molecular classification with emerging technologies, such as liquid biopsy techniques. These non-invasive methods offer a practical tool for early detection and monitoring of treatment response, providing valuable information without the need for invasive procedures [5]. As these technologies continue to advance, they have the potential to revolutionize the way EC is diagnosed and treated.

Addressing Disparities in Access to Molecular Testing

While molecular classification has the potential to significantly improve outcomes for patients with EC, there are concerns about accessibility. The high cost of molecular testing and the need for specialized equipment and expertise limit its availability in many parts of the world, particularly in low- and middle-income countries. Addressing these disparities will require concerted efforts to reduce the cost of testing and increase access to the necessary technology and expertise.

Future research should also focus on ensuring that molecular classification systems are applicable to diverse populations. Disparities in treatment outcomes across different racial and ethnic groups highlight the need for more inclusive research to ensure that the benefits of molecular profiling are available to all patients [13].
The molecular classification of endometrial carcinoma has led to significant improvements in both diagnostic accuracy and therapeutic outcomes. The identification of four distinct molecular subtypes—POLE ultramutated, MMRd, p53abn, and NSMP—has provided a more nuanced understanding of EC, allowing for more personalized treatment strategies.

Patients with POLE ultramutated tumors generally have an excellent prognosis and may benefit from less aggressive treatments. In contrast, patients with p53abn tumors often require more intensive therapies due to the aggressive nature of their disease. The use of immune checkpoint inhibitors in MMRd tumors has proven particularly effective, offering new hope for patients with this challenging subtype.

However, despite these advancements, challenges remain in the implementation of molecular testing. The high cost and complexity of next-generation sequencing, as well as disparities in access to care, continue to limit the widespread adoption of molecular classification systems.

The molecular classification of endometrial carcinoma, as defined by The Cancer Genome Atlas (TCGA), has revolutionized the diagnosis, prognosis, and treatment of this malignancy. By identifying four distinct molecular subtypes—POLE ultramutated, MMRd, p53abn, and NSMP—clinicians now have a more nuanced understanding of the biological diversity of EC. This has enabled the development of more tailored treatment strategies that align with the unique characteristics of each subtype.

While significant progress has been made, challenges remain in translating these advancements into clinical practice. The high cost and complexity of molecular testing, as well as disparities in access to care, highlight the need for ongoing efforts to make these technologies more accessible and cost-effective. Additionally, further research is needed to refine molecular classification systems and ensure that they are applicable to diverse populations.

In conclusion, the molecular classification of EC represents a significant step forward in the field of oncology. By continuing to refine these systems and address the challenges of cost and accessibility, the field can move closer to achieving personalized care for all patients with endometrial carcinoma.

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