A 48-year-old woman with a 10-year history of unopposed estrogen exposure (due to anovulation) presents with abnormal uterine bleeding. Endometrial biopsy confirms grade 2 endometrial adenocarcinoma. She is counselled about risk factors and treatment options. Which of the following molecular alterations is MOST commonly associated with this type of endometrial cancer and has implications for prognosis and targeted therapy?

Explanation

## Molecular Classification of Endometrial Cancer Endometrial cancers are increasingly classified using molecular profiling (TCGA, ProMisE) rather than histology alone. This patient has **type I (endometrioid) endometrial cancer** arising from unopposed estrogen exposure. ### Key Molecular Features of Type I Endometrial Cancer: **PTEN loss and PIK3CA mutations** are hallmark alterations in estrogen-driven endometrial adenocarcinomas: - **PTEN** (phosphatase and tensin homolog) is lost in ~60% of type I endometrial cancers - **PIK3CA** mutations occur in ~30–40% of cases - These drive **PI3K/AKT/mTOR pathway hyperactivation** → unopposed proliferation - **Microsatellite instability (MSI-high)** is present in ~30% of type I cancers (due to MLH1 promoter methylation, not germline mutations) ### Clinical Significance: - **Prognosis**: MSI-high tumors have *better* prognosis despite advanced stage - **Targeted therapy**: mTOR inhibitors (e.g., everolimus) and PI3K inhibitors are under investigation - **Immunotherapy**: MSI-high tumors respond to checkpoint inhibitors (pembrolizumab, nivolumab) ### Why This Matters: The combination of PTEN/PIK3CA alterations + MSI-high status defines a molecularly distinct endometrial cancer subtype with specific therapeutic vulnerabilities, making this the most clinically relevant answer. **High-Yield:** Type I endometrial cancer = estrogen-driven, PTEN/PIK3CA mutations, MSI-high → better prognosis, immunotherapy responsive.