Endometrial cancer is the most common gynecologic malignancy in the United States. Traditionally, management decisions relied heavily on the tumor’s microscopic appearance, known as histology, and its grade. This approach has proven insufficient for accurately predicting disease behavior and tailoring treatment. Diagnosis is now rapidly shifting to incorporate the tumor’s molecular characteristics, which provides a more precise roadmap for guiding treatment and predicting outcomes.
Understanding Molecular Classification
The current standard for classifying endometrial cancer is based on The Cancer Genome Atlas (TCGA) system, which categorizes tumors into four distinct molecular subgroups. These classifications are based on specific genetic features and provide prognostic information beyond traditional pathology. The four molecular groups are the POLE ultratmutated, the Microsatellite Instability (MSI) high, the p53 abnormal (also called Copy Number High), and the p53 wild-type, also referred to as the No Specific Molecular Profile (NSMP) group.
The p53 wild-type status signifies that the TP53 gene, which normally acts as a tumor suppressor, is functioning correctly. In contrast, a p53 abnormal or mutated status is associated with an aggressive tumor profile and poor prognosis. P53 status is often determined through immunohistochemistry (IHC), which detects the protein expression pattern. A normal, or wild-type, pattern is characterized by a mix of negative cells and those with weak p53 protein signals.
The p53 wild-type group, or NSMP, represents the largest subgroup of endometrial cancers, encompassing approximately 40% to 50% of all cases. This subtype is defined by the absence of the molecular features found in the other three groups, lacking POLE mutations and mismatch repair defects. Tumors in this category are typically low-grade endometrioid adenocarcinomas and often show high expression of estrogen and progesterone receptors. This molecular typing helps refine risk assessment, especially for tumors that might appear clinically similar but behave differently.
Prognosis and Disease Behavior
Molecular classification is used for risk stratification, particularly for patients with p53 wild-type disease. This group is generally associated with an intermediate prognosis, distinct from the favorable POLE ultratmutated group and the high-risk p53 abnormal group. The p53 wild-type classification helps determine which patients require more or less aggressive treatment post-surgery.
Tumors classified as p53 wild-type typically exhibit lower rates of recurrence and better disease-specific survival compared to p53 abnormal tumors. For instance, studies show that the two-year disease-free survival rate for p53 wild-type tumors can be around 94.3%, compared to 83.5% reported for p53 mutant varieties. This distinction is important because the p53 abnormal status is strongly associated with more aggressive tumor behavior and poor outcomes, leading to its incorporation into updated staging guidelines.
The presence of a p53 wild-type profile, often correlating with lower-grade endometrioid histology, places patients into a lower to intermediate-risk category based on molecular criteria. However, the NSMP group is heterogeneous, and some patients may still have traditional high-risk factors like deep myometrial invasion or lymphovascular space invasion. This molecular information allows clinicians to de-escalate treatment for low-risk patients or selectively intensify care for those who harbor other poor prognostic features.
Current Treatment Approaches
Management strategies for patients with p53 wild-type endometrial cancer are tailored based on the intermediate-risk nature of this molecular subtype. The standard initial treatment is surgical, involving a hysterectomy and often removal of the fallopian tubes and ovaries. Lymph node assessment, frequently via sentinel lymph node biopsy, is performed to accurately stage the disease.
The decision regarding post-operative, or adjuvant, therapy is where the molecular status is most influential. For patients considered low-risk based on both molecular and traditional pathology factors, observation alone after surgery may be sufficient. Since the p53 wild-type group has a favorable prognosis, the goal is to avoid overtreatment and associated side effects.
For intermediate-risk p53 wild-type patients, adjuvant treatment may be necessary to reduce the risk of local recurrence. This often involves vaginal brachytherapy, which delivers targeted radiation to the top of the vagina. External beam radiation therapy may be considered for those with higher risk features, such as deeper myometrial invasion or involvement of the cervix. The molecular profile guides the intensity of postoperative care, ensuring that only those at risk of recurrence receive additional therapy.
In cases of advanced or recurrent p53 wild-type disease, systemic therapy is often required. Platinum-based chemotherapy regimens have been the standard treatment. However, new targeted maintenance therapies are emerging. For example, the use of selinexor as maintenance therapy has shown a substantial increase in progression-free survival in patients with advanced or recurrent p53 wild-type disease. This demonstrates how molecular classification is driving the development of personalized and effective treatment options.