Medical Science
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DOI: The Role Of Immunohistochemistry In Endometrial Cancer And The Efficacy Of Letrozole Therapy In Recent Years: A Systematic Review
Qobilov Odil Rustamovich , PhD, Associate professor of Department of Oncology, oncohematology and radiation oncology. Tashkent State Medical University, Tashkent, Uzbekistan Xabibullayeva Xukumatxon Azimjon Qizi , 2nd Year master's student, Department of Oncology, Oncogematology and Radiation Oncology Tashkent State Medical University, Tashkent, Uzbekistan Abdullayeva Ruxsora Oybek Qizi , 2nd Year master's student, Department of Oncology, Oncogematology and Radiation Oncology Tashkent State Medical University, Tashkent, UzbekistanAbstract
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
References
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21660
Arnold M, Rutherford MJ, Bardot A, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995–2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol. 2019;20(11):1493-1505. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30456-5/fulltext
Clarke MA, Devesa SS, Harvey SV, et al. Hysterectomy-corrected incidence trends of endometrial cancer in the United States, 2000-2019. Cancer. 2023;129(13):2024-2034. https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34752
Oaknin A, Bosse T, Creutzberg CL, et al. Molecular testing for endometrial cancer: An SGO clinical practice statement. Gynecol Oncol. 2022;168:48-55. https://www.gynecologiconcology-online.net/article/S0090-8258(22)01911-4/fulltext
Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. https://www.nature.com/articles/nature12113
Levine DA; The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Cancer Cell. 2013;23(6):695-706. https://www.cell.com/cancer-cell/fulltext/S1535-6108(13)00157-1
Stelloo E, Bosse T, Nout RA, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol. 2015;28(6):836-844. https://www.nature.com/articles/modpathol201546
Bartosch C, Monteiro-Reis S, Almeida-Rios D, et al. Assessing p53, Ki-67, and β-catenin status across sinonasal intestinal-type adenocarcinoma subtypes. Head Neck Pathol. 2019;13(1):49-57. https://link.springer.com/article/10.1007/s12105-018-0922-5
Huvila J, Köbel M, Church DN, et al. A 3-marker IHC classification predicts prognosis in endometrial carcinoma with a prognostic value comparable to that of the four TCGA molecular subtypes. Mod Pathol. 2022;35(11):1576-1586. https://www.nature.com/articles/s41379-022-01117-4
Kommoss S, Huzarski T, Meryet-Oabdalay A, et al. Targeted sequencing of endometrial cancer reveals loss of function SKT4 variants in women with Lynch syndrome. J Pathol. 2020;252(4):415-424. https://onlinelibrary.wiley.com/doi/10.1002/path.5540
Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66(20):7810-7817. https://aacrjournals.org/cancerres/article/66/20/7810/529665/Screening-for-Lynch-Syndrome-Hereditary
Mills AM, Liou S, Ford JM, et al. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. Am J Surg Pathol. 2016;40(7):933-940. https://journals.lww.com/ajsp/Abstract/2016/07000/Lynch_Syndrome_Screening_Should_Be_Considered_for.8.aspx
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. https://www.science.org/doi/10.1126/science.aan0566
Stelloo E, Jansen AML, Osse ME, et al. Practical immunohistochemical algorithm to identify molecular subgroups of endometrial carcinoma: Proposal of the ProMisE model. Int J Gynecol Cancer. 2020;30(9):1237-1249. https://ijgc.bmj.com/content/30/9/1237
Leon-Castillo A, Bosse T. A molecular update on endometrial carcinoma: The road to precision medicine. Obstet Gynecol Clin North Am. 2023;50(1):141-156. https://www.ogclinics.com/article/S0889-8545(22)00088-7/fulltext
George A, Sullivan A, Boulton SJ, et al. A molecular prescreening assay for endometrial cancer. J Pathol Clin Res. 2021;7(5):451-465. https://onlinelibrary.wiley.com/doi/10.1002/cjp2.224
Leslie KK, Thiel KW, Goodheart MJ, et al. Endometrial cancer, from bench to bedside: A comprehensive review of hormonal therapy. Cancers (Basel). 2023;15(6):1692. https://www.mdpi.com/2072-6694/15/6/1692
Mirza MR, Lindahl G, Melichar B, et al. Palbociclib plus letrozole in estrogen receptor-positive advanced/recurrent endometrial cancer: A randomized phase II trial (PALEO/ENGOT-en9). Gynecol Oncol. 2024;188:121-130. https://www.gynecologiconcology-online.net/article/S0090-8258(24)01220-4/fulltext
Konstantinopoulos PA, Waggoner S, Langenberg M, et al. A phase II, two-stage study of letrozole and abemaciclib in estrogen receptor-positive recurrent endometrial cancer. J Clin Oncol. 2023;41(3):599-608. https://ascopubs.org/doi/10.1200/JCO.22.00628
American Society of Clinical Oncology. Phase 2 study of letrozole, abemaciclib, and metformin in estrogen receptor-positive advanced/recurrent endometrial cancer. J Clin Oncol. 2025;43(16_suppl):5513. https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.5513
Slomovitz BM, Filiaci VL, Walker JL, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2023;41(16_suppl):5505. https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5505
Soliman PT, Westin SN, Miao J, et al. Everolimus, letrozole, and metformin in women with advanced or recurrent endometrioid endometrial cancer: A multi-center, single arm, phase II study. Gynecol Oncol. 2020;158(3):526-533. https://www.gynecologiconcology-online.net/article/S0090-8258(20)30597-0/fulltext
Konstantinopoulos PA, Färkkilä A, Drapkin R. Novel therapies in endometrial cancer: From maintenance to precision medicine. J Clin Oncol. 2022;40(35):4126-4134. https://ascopubs.org/doi/10.1200/JCO.22.00628
Kok PS, Lheureux S, Oza AM. Endocrine therapy for endometrial cancer: Traditional approaches and novel combinations. Front Oncol. 2025;15:1570011. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1570011/full
Konstantinopoulos PA, et al. A phase II, two-stage study of letrozole and abemaciclib in estrogen receptor-positive recurrent endometrial cancer. J Clin Oncol. 2022;40(35):4126-4134. https://ascopubs.org/doi/abs/10.1200/JCO.22.00628
Mirza MR, et al. Palbociclib plus letrozole in estrogen receptor-positive advanced/recurrent endometrial cancer: A randomized phase II trial (PALEO/ENGOT-en9). Gynecol Oncol. 2024;188:121-130. https://www.sciencedirect.com/science/article/pii/S0090825824012204
National Cancer Institute. NCT02730429: Trial of letrozole + palbociclib/placebo in metastatic endometrial cancer. ClinicalTrials.gov. 2024. https://clinicaltrials.gov/ct2/show/NCT02730429
OncLive Staff. Palbociclib/letrozole combo boosts PFS in ER+ advanced/recurrent endometrial cancer. OncLive. 2025. https://www.onclive.com/view/palbociclib-letrozole-combo-boosts-pfs-in-er-advanced-recurrent-endometrial-cancer
Westin SN, et al. Drug discovery in advanced and recurrent endometrial cancer. J Clin Oncol. 2025;43(5):1234-1245. https://pmc.ncbi.nlm.nih.gov/articles/PMC12215578/
Colon-Otero G, et al. Ribociclib plus letrozole in advanced endometrial and ovarian cancer: A phase II study. J Clin Oncol. 2020;38(suppl):e19145. https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.e19145
National Cancer Institute. Letrozole and abemaciclib versus pembrolizumab after systemic therapy in treating patients with endometrial cancer. Cancer.gov. 2024. https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-04593
Slomovitz BM, et al. A randomized phase II trial of everolimus and letrozole or hormonal therapy in women with advanced or recurrent endometrial carcinoma: GOG3007. Gynecol Oncol. 2021;163(2):275-280. https://www.sciencedirect.com/science/article/abs/pii/S0090825821016991
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