HORMONAL THERAPY IN HIGH-GRADE SEROUS OVARIAN CARCINOMA: A REVIEW OF CURRENT EVIDENCE
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5387Keywords:
High-Grade Serous Ovarian Carcinoma, Hormonal Therapy, Oestrogen Receptor, Aromatase Inhibitors, Tamoxifen, MATAO Trial, CDK4/6 Inhibitors, LetrazoleAbstract
Ovarian cancer remains one of the leading causes of cancer-related mortality among women worldwide. The most common histological subtype is high-grade serous ovarian carcinoma (HGSOC), which accounts for approximately 70-80% of epithelial cases and is characterized by profound genomic instability, nearly universal TP53 mutations, and a high propensity for recurrence. While the standard of care - comprising maximal cytoreductive surgery, platinum-based chemotherapy, and maintenance with poly (ADP-ribose) polymerase PARP inhibitors or anti-angiogenic agents- has improved outcomes, long-term prognosis for advanced disease remains poor. Hormonal therapy (HT) has emerged as a clinically relevant treatment option for selected patients with recurrent ovarian cancer, particularly in oestrogen receptor (ER)- positive tumours. Agents such as Tamoxifen and aromatase inhibitors (AIs), including Letrozole, Anastrozole, and Exemestane, demonstrate reproducible clinical benefit rates of 25-45%, primarily through disease stabilisation. Recent real-world cohort data (2025) and ongoing prospective trials- notably the phase III ENGOT-ov54/Swiss-GO-2/MATAO trial (NCT04111978) - represent critical steps towards establishing evidence-based endocrine therapy in HGSOC. This review evaluates the biological rationale for targeting the ER and progesterone receptor (PR) pathways, critically appraises current and emerging clinical evidence, discusses combination strategies with CDK4/6 inhibitors, PI3K/mTOR inhibitors, and PARP inhibitors, and highlights the unmet need for biomarker-driven patient selection.
References
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660
Doubeni, C. A., Doubeni, A. R., & Myers, A. E. (2016). Diagnosis and management of ovarian cancer. American Family Physician, 93(11), 937–944.
Kurman, R. J., & Shih, I.-M. (2016). The dualistic model of ovarian carcinogenesis revisited, revised, and expanded. The American Journal of Pathology, 186(4), 733–747. https://doi.org/10.1016/j.ajpath.2015.11.011
Cancer Genome Atlas Research Network. (2011). Integrated genomic analyses of ovarian carcinoma. Nature, 474(7353), 609–615. https://doi.org/10.1038/nature10166
Colombo, N., Sessa, C., du Bois, A., Ledermann, J., McCluggage, W. G., McNeish, I., Morice, P., Pignata, S., Ray-Coquard, I., Vergote, I., Baert, T., Belaroussi, I., Dashora, A., Olbrecht, S., Planchamp, F., & Querleu, D. (2019). ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Annals of Oncology, 30(5), 672–705. https://doi.org/10.1093/annonc/mdz062
Armstrong, D. K., Alvarez, R. D., Bakkum-Gamez, J. N., Barber, E. L., Chen, L. M., Eisenhauer, E., Ozols, R. F., & Rubin, S. C. (2019). NCCN Guidelines Insights: Ovarian cancer, version 1.2019. Journal of the National Comprehensive Cancer Network, 17(8), 896–909. https://doi.org/10.6004/jnccn.2019.0039
Petousis, S., Kahramanoglu, I., Appenzeller-Herzog, C., Setiawan, A., Sharma, A., Petrillo, M., Papadia, A., Kimmig, R., Gasimli, K., Czogalla, B., Mahner, S., Cibula, D., Fotopoulou, C., Sölétormos, G., Alcázar, J. L., Heinzelmann-Schwarz, V., & Zwimpfer, T. A. (2025). PARP inhibitor maintenance after first-line chemotherapy in advanced-stage epithelial ovarian cancer: A systematic review and meta-analysis. JAMA Network Open, 8(11), Article e2541648. https://doi.org/10.1001/jamanetworkopen.2025.41648
Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., ... Ramus, S. J. (2013). Hormone-receptor expression and ovarian cancer survival: An Ovarian Tumor Tissue Analysis Consortium study. The Lancet Oncology, 14(9), 853–862. https://doi.org/10.1016/S1470-2045(13)70253-5
Langdon, S. P., Gourley, C., Gabra, H., & Stanley, B. (2017). Endocrine therapies in epithelial ovarian cancer. Expert Review of Anticancer Therapy, 17(2), 109–117. https://doi.org/10.1080/14737140.2017.1272414
Vetter, M., Stadlmann, S., Bischof, E., Georgescu Margarint, E. L., Schötzau, A., Singer, G., Heinzelmann-Schwarz, V., & Montavon, C. (2022). Hormone receptor expression in primary and recurrent high-grade serous ovarian cancer and its implications in early maintenance treatment. International Journal of Molecular Sciences, 23(22), Article 14242. https://doi.org/10.3390/ijms232214242
George, A., Atkinson, M. J., Bhatt, M., Jones, R., Mahon, M., Boulton, C., & Kaye, S. B. (2017). The role of hormonal therapy in patients with relapsed high-grade ovarian carcinoma: A retrospective series of tamoxifen and letrozole. BMC Cancer, 17(1), Article 456. https://doi.org/10.1186/s12885-017-3440-0
Aubert, M., Mathiot, L., Vegas, H., Ouldamer, L., Linassier, C., Augereau, P., Bocquet, F., Frenel, J.-S., & Cancel, M. (2024). Endocrine therapy in advanced high-grade ovarian cancer: Real-life data from a multicenter study and a review of the literature. The Oncologist, 29(7), e910–e917. https://doi.org/10.1093/oncolo/oyae093
Geissler, F., Graf, F., Zwimpfer, T. A., Heinzelmann-Schwarz, V. A., Heinzmann, N., Perren, T., & Gasparri, M. L. (2025). Endocrine maintenance therapy in high-grade serous ovarian cancer: A retrospective off-label real-world cohort study. Cancers, 17(8), 1301. https://doi.org/10.3390/cancers17081301
Salvati, A., Gigantino, V., Nassa, G., Giurato, G., Alexandrova, E., Rizzo, F., Tarallo, R., & Weisz, A. (2019). The histone methyltransferase DOT1L is a functional component of estrogen receptor alpha signaling in ovarian cancer cells. Cancers, 11(11), Article 1720. https://doi.org/10.3390/cancers11111720
Choi, K. C., Kang, S. K., Tai, C. J., Auersperg, N., & Leung, P. C. (2001). Estradiol up-regulates antiapoptotic Bcl-2 messenger ribonucleic acid and protein in tumorigenic ovarian surface epithelium cells. Endocrinology, 142(6), 2351–2360. https://doi.org/10.1210/endo.142.6.8144
Matsumura, S., Ohta, T., Yamanouchi, K., Liu, Z., Kanno, Y., Tashiro, H., Sato, F., Kitajima, M., & Hamasaki, T. (2017). Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells. Cancer Biology & Therapy, 18(9), 730–739. https://doi.org/10.1080/15384047.2016.1235656
Li, X., Zhang, Y., Wang, J., Chen, H., Liu, M., & Zhao, R. (2023). Estrogen promotes epithelial ovarian cancer cells proliferation via down-regulating expression and activating phosphorylation of PTEN. Archives of Biochemistry and Biophysics, 743, Article 109662. https://doi.org/10.1016/j.abb.2023.109662
Heinzelmann-Schwarz, V., Knipprath Mészaros, A., Stadlmann, S., Jacob, F., Schoetzau, A., Russell, K., Friedlander, M., Singer, G., & Vetter, M. (2018). Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients. Gynecologic Oncology, 148(1), 79–85. https://doi.org/10.1016/j.ygyno.2017.10.036
Andersen, C. L., Sikora, M. J., Boisen, M. M., Ma, T., Christie, A., Tseng, G., Park, Y., Lutber, S., Oesterreich, S., & Edwards, R. P. (2017). Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens. Clinical Cancer Research, 23(14), 3802–3812. https://doi.org/10.1158/1078-0432.CCR-16-1501
Bossard, C., Busson, M., Vindrieux, D., Gaudin, F., Machelon, V., Brigitte, M., Gompel, A., Barillot, E., Guénel, P., & Lazennec, G. (2012). Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer. PLoS ONE, 7(9), Article e44787. https://doi.org/10.1371/journal.pone.0044787
Langdon, S. P., Herrington, C. S., & Stanley, B. (2020). Estrogen signaling and its potential as a target for therapy in ovarian cancer. Cancers, 12(6), Article 1647. https://doi.org/10.3390/cancers12061647
Tan, J., Song, C., Wang, D., Hu, Y., Liu, D., Ma, D., & Gao, Q. (2021). Expression of hormone receptors predicts survival and platinum sensitivity of high-grade serous ovarian cancer. Bioscience Reports, 41(5), Article BSR20210478. https://doi.org/10.1042/BSR20210478
Choi, J. H., Wong, A. S., Huang, H. F., & Leung, P. C. (2007). Gonadotropins and ovarian cancer. Endocrine Reviews, 28(4), 440–461. https://doi.org/10.1210/er.2006-0036
Marolt, N., Kos, Š., Šturm, L., Brišnik, M., Plavec, J., & Lanišnik Rižner, T. (2025). Local androgen and 11-oxyandrogen metabolism and signaling emerges as a novel prognostic and therapeutic axis in high-grade serous ovarian cancer. Frontiers in Oncology, 15, Article 1459832. https://doi.org/10.3389/fonc.2025.1459832
Ahmed, A., Thompson, P., Weldon, R., Yeo, K. H., Tan, K. S., & Kristeleit, R. (2020). A case report of androgen receptor inhibitor therapy in recurrent high-grade serous ovarian cancer. Oncotarget, 11(44), 3993–4001. https://doi.org/10.18632/oncotarget.27790
Jordan, V. C. (2003). Tamoxifen: A most unlikely pioneering medicine. Nature Reviews Drug Discovery, 2(3), 205–213. https://doi.org/10.1038/nrd1031
Langdon, S. P., Lawrie, S. S., Hay, F. G., Hawkes, M. M., McDonald, A., Hayward, I. P., Schol, D. J., Hilgers, J., Leonard, R. C. F., & Smyth, J. F. (1988). Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Research, 48(21), 6166–6172.
Wu, J., Yan, J., Fang, P., Chen, Y., Li, J., Zhu, Y., & Zhang, H. (2020). Three-dimensional oxabicycloheptene sulfonate targets the homologous recombination and repair programmes through estrogen receptor α antagonism. Cancer Letters, 469, 78–88. https://doi.org/10.1016/j.canlet.2019.10.019
Food and Drug Administration. (2025). Letrozole [Prescribing information]. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fd92634-c9c5-457e-808c-a4614e8db7db
Argenta, P. A., Um, I., Kay, C., Harrison, D., Faratian, D., Suh, D. H., Bartlett, J. M., & Langdon, S. P. (2013). Predicting response to the anti-estrogen fulvestrant in recurrent ovarian cancer. Gynecologic Oncology, 131(2), 368–373. https://doi.org/10.1016/j.ygyno.2013.07.099
Fedotcheva, T. A., Fedotcheva, N. I., & Shimanovsky, N. L. (2021). Progestins as anticancer drugs and chemosensitizers, new targets and applications. Pharmaceutics, 13(10), 1616. https://doi.org/10.3390/pharmaceutics13101616
Wuntakal, R., Seshadri, S., Montes, A., & Lane, G. (2016). Luteinising hormone releasing hormone (LHRH) agonists for the treatment of relapsed epithelial ovarian cancer. Cochrane Database of Systematic Reviews, 2016(6), Article CD011322. https://doi.org/10.1002/14651858.CD011322.pub2
Hatch, K. D., Beecham, J. B., Blessing, J. A., & Creasman, W. T. (1991). Responsiveness of patients with advanced ovarian carcinoma to tamoxifen: A Gynecologic Oncology Group study of second-line therapy in 105 patients. Cancer, 68(2), 269–271. https://doi.org/10.1002/1097-0142(19910715)68:2%3C269::aid-cncr2820680209%3E3.0.co;2-o
Stanley, B., Hollis, R. L., Nunes, H., Gilks, C. B., Kommoss, S., & Gourley, C. (2019). Endocrine treatment of high grade serous ovarian carcinoma; quantification of efficacy and identification of response predictors. Gynecologic Oncology, 152(2), 278–285. https://doi.org/10.1016/j.ygyno.2018.11.030
Papadimitriou, C. A., Markaki, S., Siapkaras, J., Vlachos, G., Efstathiou, E., Grimani, I., Pantazopoulos, D., & Dimopoulos, M. A. (2004). Hormonal therapy with letrozole for relapsed epithelial ovarian cancer: Long-term results of a phase II study. Oncology, 66(2), 112–117. https://doi.org/10.1159/000077436
McLaughlin, P. M. J., Klar, M., Zwimpfer, T. A., Dutilh, G., Vetter, M., Marth, C., du Bois, A., Schade-Brittinger, C., Reuss, A., Bommer, C., Kurzeder, C., & Heinzelmann-Schwarz, V. (2022). Maintenance therapy with aromatase inhibitor in epithelial ovarian cancer (MATAO): Study protocol of a randomized double-blinded placebo-controlled multi-center phase III trial. BMC Cancer, 22(1), Article 508. https://doi.org/10.1186/s12885-022-09555-8
Bonaventura, A., O'Connell, R. L., Mapagu, C., Meniawy, T., Munro, A., Basser, R., Friedlander, M., Harnett, P., Goh, J., Bowtell, D., DeFazio, A., & Obermair, A. (2017). Paragon (ANZGOG-0903): Phase 2 study of anastrozole in women with estrogen or progesterone receptor-positive platinum-resistant or -refractory recurrent ovarian cancer. International Journal of Gynecological Cancer, 27(5), 900–906. https://doi.org/10.1097/IGC.0000000000000978
del Carmen, M. G., Fuller, A. F., Matulonis, U., Horick, N. K., Goodman, A., Duska, L. R., Penson, R., Campos, S., Roche, M., & Seiden, M. V. (2003). Phase II trial of anastrozole in women with asymptomatic müllerian cancer. Gynecologic Oncology, 91(3), 596–602. https://doi.org/10.1016/j.ygyno.2003.08.021
Papadimitriou, C. A., Moulopoulos, L. A., Vlahos, G., & Dimopoulos, M. A. (2007). Activity of exemestane in recurrent epithelial ovarian cancer after failure on multiple lines of prior therapy: A phase II study. Anticancer Research, 27(5B), 3567–3571.
Chia, S., Gradishar, W., Mauriac, L., Bines, J., Amant, F., Federico, M., Fein, L., Romieu, G., Buzdar, A., Robertson, J. F. R., Brufsky, A., Possinger, K., Renber, M., Sapunar, F., & Osborne, C. K. (2008). Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor–positive, advanced breast cancer: Results from EFECT. Journal of Clinical Oncology, 26(10), 1664–1670. https://doi.org/10.1200/JCO.2007.13.5822
Silverstein, J., Moore, K., Birrer, M. J., Hamilton, E. P., Lee, J. M., Alvarez, E. A., et al. (2025). Phase 2 study of abemaciclib plus hormonal therapy in patients with recurrent low- or high-grade serous ovarian cancer or endometrioid endometrial cancer [Abstract]. Gynecologic Oncology, 176(Suppl. 1), S3. https://doi.org/10.1016/j.ygyno.2025.01.009
Slomovitz, B. M., Weroha, S. J., Deng, W., Killion, J., Gershenson, D. M., Westin, S. N., Broaddus, R. R., Brady, W. E., Lankes, H. A., Godwin, A. K., Cohn, D. E., Duska, L. R., & Aghajanian, C. (2025). Phase II trial of ribociclib plus letrozole in women with recurrent low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum: A GOG Partners trial (GOG 3026). Journal of Clinical Oncology. Advance online publication. https://doi.org/10.1200/JCO-25-01348
Ribeiro, J. R., & Freiman, R. N. (2014). Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer. The Journal of Steroid Biochemistry and Molecular Biology, 143, 160–173. https://doi.org/10.1016/j.jsbmb.2014.02.010
Klein, M., Wittkopf, V., Bloss, C., Hilpert, F., Mahner, S., Müller, V., Jänicke, F., & Czogalla, B. (2025). Promising new drugs and therapeutic approaches for treatment of ovarian cancer—targeting the hallmarks of cancer. BMC Medicine, 23(1), Article 12. https://doi.org/10.1186/s12916-024-03825-5
Blagojevic, I., Vujovic, A., Markovic, I. S., Ristovic, A., Jocic, M., & Miletic, T. (2025). Efficacy and safety of combination therapy with PARP inhibitors and anti-angiogenic agents in ovarian cancer: A systematic review and meta-analysis. Journal of Clinical Medicine, 14(5), Article 1776. https://doi.org/10.3390/jcm14051776
Burstein, H. J., Lacchetti, C., Anderson, H., Buchholz, T. A., Davidson, N. E., Gelmon, K. E., Giordano, S. H., Hudis, C. A., Solky, A. J., Stearns, V., Winer, E. P., & Griggs, J. J. (2019). Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: ASCO clinical practice guideline focused update. Journal of Clinical Oncology, 37(5), 423–438. https://doi.org/10.1200/JCO.18.01160
Coates, A. S., Winer, E. P., Goldhirsch, A., Gelber, R. D., Gnant, M., Piccart-Gebhart, M., Thürlimann, B., & Senn, H.-J. (2015). Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Annals of Oncology, 26(8), 1533–1546. https://doi.org/10.1093/annonc/mdv221
National Comprehensive Cancer Network. (2026). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (Version 2.2026). https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1453
Svoronos, N., Perales-Puchalt, A., Allegrezza, M. J., Rutkowski, M. R., Payne, K. K., Tesone, A. J., Nguyen, J. M., Curiel, T. J., Cadungog, M. G., Singhal, S., & Conejo-Garcia, J. R. (2017). Tumor cell–independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discovery, 7(1), 72–85. https://doi.org/10.1158/2159-8290.CD-16-0502
Bidard, F.-C., Kaklamani, V. G., Neven, P., Streich, G., Montero, A. J., Forget, F., Mouret-Reynier, M.-A., Sohn, J. H., Taylor, D., Harnden, K. K., Khong, H., & Bardia, A. (2022). Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: Results from the randomized phase III EMERALD trial. Journal of Clinical Oncology, 40(28), 3246–3256. https://doi.org/10.1200/JCO.22.00338
Basu, G. D., Innis, P. E., Deem, A. K., Fellman, B. M., Jazaeri, A. A., & Yap, T. A. (2024). Characterization of ESR1 mutations in endometrial and ovarian cancers [Conference abstract]. Journal of Clinical Oncology, 42(Suppl. 16), Abstract 5598. https://doi.org/10.1200/JCO.2024.42.16_suppl.5598
Gaillard, S. L., Andreano, K. J., Gay, L. M., Steiner, M., Jure-Kunkel, M. N., Greshock, J., Abrouk, N., Harding, T. C., Doman, S. E., Frampton, G. M., & Tung, N. M. (2019). Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies. Gynecologic Oncology, 154(1), 199–206. https://doi.org/10.1016/j.ygyno.2019.04.010
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Agnieszka Zaręba, Dawid Juszkiewicz, Krzysztof Kiełczewski, Barbara Fetner, Magdalena Dłużewska, Zuzanna Gebert, Ivanna Ilkiv, Agata Kucharska, Konrad Adler, Patrycja Stanowska

This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.

