Medical Science
| Open Access |
DOI: The Role Of Immunohistochemistry In Endometrial Cancer And The Efficacy Of Letrozole Therapy In Recent Years: A Systematic Review
Abstract
Endometrial cancer (EC) stands as the most common gynecologic malignancy in developed countries, with global incidence rates surpassing 417,000 new cases annually and a rising trend driven by obesity, metabolic syndromes, and demographic shifts toward aging populations. Immunohistochemistry (IHC) has become integral to EC management, serving as a surrogate for molecular profiling to classify tumors into The Cancer Genome Atlas (TCGA) subgroups: POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), p53-abnormal (p53abn), and no specific molecular profile (NSMP). This classification refines diagnosis, prognosticates outcomes—with POLEmut offering excellent survival (5-year recurrence-free survival [RFS] >95%) and p53abn indicating poor prognosis (5-year overall survival [OS] <50%)—and guides theragnostic decisions, such as identifying MMRd tumors (20-30% prevalence) for immunotherapy due to high PD-L1 expression (up to 100%). Emerging IHC markers like L1CAM, CTNNB1, and AKR1B1/AKR1B10 further stratify NSMP tumors, enhancing precision in risk assessment and adjuvant therapy selection. In parallel, letrozole, a non-steroidal aromatase inhibitor, has evolved as a key endocrine therapy for estrogen receptor-positive (ER+) EC, particularly in advanced or recurrent settings where 70-80% of tumors express ER/PR. Monotherapy yields modest objective response rates (ORRs) of 8-14% and progression-free survival (PFS) of 3-4 months, but recent trials (2020-2025) combining letrozole with mTOR inhibitors (e.g., everolimus), CDK4/6 inhibitors (e.g., abemaciclib, palbociclib), or metformin have markedly improved efficacy, achieving ORRs of 25-32%, clinical benefit rates (CBRs) of 40-75%, and PFS up to 9.1 months in ER+ endometrioid subtypes. Biomarkers such as CTNNB1 mutations and ER/PR IHC positivity predict enhanced responses, while safety profiles show predominantly low-grade toxicities (e.g., fatigue, anemia, neutropenia). This expanded systematic review synthesizes data from over 70 high-impact studies, adhering to PRISMA guidelines, to underscore IHC's diagnostic/prognostic/theragnostic utility and letrozole's advancing role in precision endocrine therapy. It highlights the need for integrated biomarker-driven strategies to address EC heterogeneity, reduce recurrence (up to 30% in advanced cases), and improve OS in underserved populations, including ethnic minorities with distinct molecular profiles. Future avenues include phase III trials validating combinations and multi-omic integration for personalized regimens, potentially transforming EC from a hormone-driven malignancy into a manageable chronic condition.
Keywords
immunohistochemistry, Endometrial Cancer, Mismatch Repair Deficiency, p53 Abnormal
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