Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Heterogeneity and treatment landscape of ovarian carcinoma

Nature Reviews Clinical Oncology volume 20, pages 820–842 (2023)Cite this article

Subjects

Abstract

Ovarian carcinoma is characterized by heterogeneity at the molecular, cellular and anatomical levels, both spatially and temporally. This heterogeneity affects response to surgery and/or systemic therapy, and also facilitates inherent and acquired drug resistance. As a consequence, this tumour type is often aggressive and frequently lethal. Ovarian carcinoma is not a single disease entity and comprises various subtypes, each with distinct complex molecular landscapes that change during progression and therapy. The interactions of cancer and stromal cells within the tumour microenvironment further affects disease evolution and response to therapy. In past decades, researchers have characterized the cellular, molecular, microenvironmental and immunological heterogeneity of ovarian carcinoma. Traditional treatment approaches have considered ovarian carcinoma as a single entity. This landscape is slowly changing with the increasing appreciation of heterogeneity and the recognition that delivering ineffective therapies can delay the development of effective personalized approaches as well as potentially change the molecular and cellular characteristics of the tumour, which might lead to additional resistance to subsequent therapy. In this Review we discuss the heterogeneity of ovarian carcinoma, outline the current treatment landscape for this malignancy and highlight potentially effective therapeutic strategies in development.

Key points

  • Ovarian carcinoma is characterized by a high degree of interpatient, intrapatient and intratumour heterogeneity, which poses therapeutic challenges because this disease cannot be considered as a single entity.

  • A better understanding of the extra-ovarian origins of precursor lesions can help with early detection and prevention of ovarian carcinoma.

  • Primary debulking surgery helps to reduce tumour burden and control tumours that are resistant to chemotherapy.

  • Maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitors after a response to platinum-based chemotherapy in both first-line and second-line settings has prolonged the interval between response and disease relapse.

  • The integration of assessments of patient-reported outcomes in routine cancer treatment improves management.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Diverse aspects of ovarian carcinoma heterogeneity.
Fig. 2: Evolutionary roadmap of ovarian carcinoma from precursor lesions.
Fig. 3: Leveraging the TME for targeted therapy in ovarian carcinoma.

Similar content being viewed by others

References

  1. Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).

    Article  PubMed  Google Scholar 

  2. SEER*Explorer Application. All cancer sites combined. Recent trends in SEER age-adjusted incidence rates, 2000–2020. https://seer.cancer.gov/statistics-network/explorer/application.html?site=1&data_type=1&graph_type=2&compareBy=sex&chk_sex_3=3&chk_sex_2=2&rate_type=2&race=1&age_range=1&hdn_stage=101&advopt_precision=1&advopt_show_ci=on&hdn_view=0&advopt_show_apc=on&advopt_display=2#resultsRegion0 (2020).

  3. Slomovitz, B., de Haydu, C., Taub, M., Coleman, R. L. & Monk, B. J. Asbestos and ovarian cancer: examining the historical evidence. Int. J. Gynecol. Cancer 31, 122–128 (2021).

    Article  PubMed  Google Scholar 

  4. Vachon, C. M. et al. Association of parity and ovarian cancer risk by family history of breast or ovarian cancer in a population-based study of postmenopausal women. Epidemiol. Camb. Mass. 13, 66–71 (2002).

    Article  Google Scholar 

  5. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use. N. Engl. J. Med. 316, 650–655 (1987).

    Article  Google Scholar 

  6. Liu, Y. L. et al. Risk-reducing bilateral salpingo-oophorectomy for ovarian cancer: a review and clinical guide for hereditary predisposition genes. JCO Oncol. Pract. 18, 201–209 (2022).

    Article  PubMed  Google Scholar 

  7. Permuth-Wey, J. & Sellers, T. A. Epidemiology of ovarian cancer. Cancer Epidemiol. 472, 413–437 (2009).

    Article  Google Scholar 

  8. Ngoi, N. Y. L. & Tan, D. S. P. The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it? ESMO Open. 6, 100144 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bell, D. et al. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

    Article  CAS  Google Scholar 

  10. Vázquez-García, I. et al. Ovarian cancer mutational processes drive site-specific immune evasion. Nature 612, 778–786 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brutovský, B. Scales of cancer evolution: selfish genome or cooperating cells? Cancers 14, 3253 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hu, Z. et al. The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells. Cancer Cell 37, 226–242.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Ishak, C. A., Lheureux, S. & De Carvalho, D. D. DNA methylation as a robust classifier of epithelial ovarian cancer. Clin. Cancer Res. 25, 5729–5731 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Bodelon, C. et al. Molecular classification of epithelial ovarian cancer based on methylation profiling: evidence for survival heterogeneity. Clin. Cancer Res. 25, 5937–5946 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Höhn, A. K. et al. WHO classification of female genital tumors. Geburtshilfe Frauenheilkd. 81, 1145–1153 (2021). 2020.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Prat, J., D’Angelo, E. & Espinosa, I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum. Pathol. 80, 11–27 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Peres, L. C. et al. Invasive epithelial ovarian cancer survival by histotype and disease stage. J. Natl Cancer Inst. 111, 60–68 (2019).

    Article  PubMed  Google Scholar 

  18. Meinhold-Heerlein, I. et al. Statement by the kommission ovar of the AGO: the new FIGO and WHO classifications of ovarian, fallopian tube and primary peritoneal cancer. Geburtshilfe Frauenheilkd. 75, 1021–1027 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hanley, G. E. et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Netw. Open. 5, e2147343 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chen, S. et al. A review of the clinical characteristics and novel molecular subtypes of endometrioid ovarian cancer. Front. Oncol. 11, 668151 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhu, C. et al. Clinical characteristics and prognosis of ovarian clear cell carcinoma: a 10-year retrospective study. BMC Cancer 21, 322 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Montag, A. G. et al. Ovarian clear cell carcinoma. A clinicopathologic analysis of 44 cases. Int. J. Gynecol. Pathol. 8, 85–96 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Bolton, K. L. et al. Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes. Clin. Cancer Res. 28, 4947–4956 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lheureux, S. Multi-omics uncovering different faces of clear cell ovarian cancer. Clin. Cancer Res. 28, 4838–4839 (2022).

    Article  PubMed  Google Scholar 

  25. Manning-Geist, B. et al. MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma. Clin. Cancer Res. 28, 4456–4465 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Veneziani, A. C. & Oza, A. M. Taking the road less traveled: following molecular trail markers. Clin. Cancer Res. 28, 4357–4359 (2022).

    Article  PubMed  Google Scholar 

  27. Morice, P., Gouy, S. & Leary, A. Mucinous ovarian carcinoma. N. Engl. J. Med. 380, 1256–1266 (2019).

    Article  CAS  PubMed  Google Scholar 

  28. Babaier, A. & Ghatage, P. Mucinous cancer of the ovary: overview and current status. Diagnostics 10, 52 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tischkowitz, M. et al. Small-cell carcinoma of the ovary, hypercalcemic type-genetics, new treatment targets, and current management guidelines. Clin. Cancer Res. 26, 3908–3917 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McCluggage, W. G., Witkowski, L., Clarke, B. A. & Foulkes, W. D. Clinical, morphological and immunohistochemical evidence that small-cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) may be a primitive germ-cell neoplasm. Histopathology 70, 1147–1154 (2017).

    Article  PubMed  Google Scholar 

  31. Bieging, K. T., Mello, S. S. & Attardi, L. D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 14, 359–370 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ahmed, A. A. et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J. Pathol. 221, 49–56 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li, X. & Heyer, W.-D. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. 18, 99–113 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Bowtell, D. D. et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat. Rev. Cancer 15, 668–679 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kroeger, P. T. & Drapkin, R. Pathogenesis and heterogeneity of ovarian cancer. Curr. Opin. Obstet. Gynecol. 29, 26–34 (2017).

    Article  PubMed  Google Scholar 

  36. Etemadmoghadam, D. et al. Amplicon-dependent CCNE1 expression is critical for clonogenic survival after cisplatin treatment and is correlated with 20q11 gain in ovarian cancer. PLoS ONE 5, e15498 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lheureux, S., Braunstein, M. & Oza, A. M. Epithelial ovarian cancer: evolution of management in the era of precision medicine. Ca. Cancer J. Clin. 69, 280–304 (2019).

    Article  PubMed  Google Scholar 

  38. Veneziani, A. C., Scott, C., Wakefield, M. J., Tinker, A. V. & Lheureux, S. Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer. Ther. Adv. Med. Oncol. 15, 17588359231157644 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Matulonis, U. A. et al. Ovarian cancer. Nat. Rev. Dis. Prim. 2, 16061 (2016).

    Article  PubMed  Google Scholar 

  40. Macintyre, G. et al. Copy-number signatures and mutational processes in ovarian carcinoma. Nat. Genet. 50, 1262–1270 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Iida, Y., Okamoto, A., Hollis, R. L., Gourley, C. & Herrington, C. S. Clear cell carcinoma of the ovary: a clinical and molecular perspective. Int. J. Gynecol. Cancer 31, 605–616 (2021).

    Article  PubMed  Google Scholar 

  42. Mullen, J., Kato, S., Sicklick, J. K. & Kurzrock, R. Targeting ARID1A mutations in cancer. Cancer Treat. Rev. 100, 102287 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Tsuchiya, A. et al. Expression profiling in ovarian clear cell carcinoma. Am. J. Pathol. 163, 2503–2512 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gadducci, A. & Cosio, S. Therapeutic approach to low-grade serous ovarian carcinoma: state of art and perspectives of clinical research. Cancers 12, 1336 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ryland, G. L. et al. Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. Genome Med. 7, 87 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Anglesio, M. S. et al. Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. J. Pathol. 229, 111–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Schoutrop, E. et al. Molecular, cellular and systemic aspects of epithelial ovarian cancer and its tumor microenvironment. Semin. Cancer Biol. 86, 207–223 (2022).

    Article  CAS  PubMed  Google Scholar 

  48. Horst, E. N. et al. Personalized models of heterogenous 3d epithelial tumor microenvironments: ovarian cancer as a model. Acta Biomater. 132, 401–420 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fucikova, J. et al. Immunological configuration of ovarian carcinoma: features and impact on disease outcome. J. Immunother. Cancer 9, e002873 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Sato, E. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538–18543 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339–1346 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Mastelic-Gavillet, B. et al. Quantitative and qualitative impairments in dendritic cell subsets of patients with ovarian or prostate cancer. Eur. J. Cancer 135, 173–182 (2020).

    Article  CAS  PubMed  Google Scholar 

  54. Chen, Y. et al. Tumor-associated macrophages: an accomplice in solid tumor progression. J. Biomed. Sci. 26, 78 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zheng, X. et al. Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget 8, 48436–48452 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Schweer, D. et al. Tumor-associated macrophages and ovarian cancer: implications for therapy. Cancers 14, 2220 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kandalaft, L. E., Dangaj Laniti, D. & Coukos, G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat. Rev. Cancer 22, 640–656 (2022).

    Article  CAS  PubMed  Google Scholar 

  58. Zhang, A. W. et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell 173, 1755–1769.e22 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Burdett, N. L. et al. Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer. Nat. Genet. 55, 437–450 (2023).

    Article  CAS  PubMed  Google Scholar 

  60. Pickup, M. W., Mouw, J. K. & Weaver, V. M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15, 1243–1253 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. McPherson, A. et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat. Genet. 48, 758–767 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Garsed, D. W. et al. The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer. Nat. Genet. 54, 1853–1864 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sioulas, V. D. et al. Optimal primary management of bulky stage IIIC ovarian, fallopian tube and peritoneal carcinoma: are the only options complete gross resection at primary debulking surgery or neoadjuvant chemotherapy? Gynecol. Oncol. 145, 15–20 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wright, A. A. et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of gynecologic oncology and American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 34, 3460–3473 (2016).

    Article  PubMed  Google Scholar 

  65. Straubhar, A., Chi, D. S. & Long Roche, K. Update on the role of surgery in the management of advanced epithelial ovarian cancer. Clin. Adv. Hematol. Oncol. 18, 723–731 (2020).

    PubMed  Google Scholar 

  66. Chi, D. S. et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol. Oncol. 103, 559–564 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Aletti, G. D. et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet. Gynecol. 107, 77–85 (2006).

    Article  PubMed  Google Scholar 

  68. Winter, W. E. et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J. Clin. Oncol. 25, 3621–3627 (2007).

    Article  PubMed  Google Scholar 

  69. Colombo, P.-E. et al. Aggressive surgical strategies in advanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients. Eur. J. Surg. Oncol. 35, 135–143 (2009).

    Article  PubMed  Google Scholar 

  70. Ray-Coquard, I. et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N. Engl. J. Med. 381, 2416–2428 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. Fagotti, A. et al. A laparoscopy-based score to predict surgical outcome in patients with advanced ovarian carcinoma: a pilot study. Ann. Surg. Oncol. 13, 1156–1161 (2006).

    Article  PubMed  Google Scholar 

  72. Suidan, R. S. et al. A multicenter assessment of the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease at primary debulking for advanced epithelial ovarian cancer. Gynecol. Oncol. 145, 27–31 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Reuss, A. et al. TRUST: trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33/AGO‐OVAR OP7). Int. J. Gynecol. Cancer 29, 1327–1331 (2019).

    Article  PubMed  Google Scholar 

  74. Lv, X., Cui, S., Zhang, X. & Ren, C. Efficacy and safety of neoadjuvant chemotherapy versus primary debulking surgery in patients with ovarian cancer: a meta-analysis. J. Gynecol. Oncol. 31, e12 (2020).

    Article  PubMed  Google Scholar 

  75. Mueller, J. J. et al. Neoadjuvant chemotherapy and primary debulking surgery utilization for advanced-stage ovarian cancer at a comprehensive cancer center. Gynecol. Oncol. 140, 436–442 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gu, S. et al. Computational modeling of ovarian cancer dynamics suggests optimal strategies for therapy and screening. Proc. Natl Acad. Sci. USA 118, e2026663118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Aletti, G. D. et al. Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment. Gynecol. Oncol. 120, 23–28 (2011).

    Article  PubMed  Google Scholar 

  78. Handley, K. F. et al. Frailty repels the knife: the impact of frailty index on surgical intervention and outcomes. Gynecol. Oncol. 166, 50–56 (2022).

    Article  PubMed  Google Scholar 

  79. Nelson, G. et al. Guidelines for perioperative care in gynecologic/oncology: enhanced Recovery After Surgery (ERAS) Society recommendations—2019 update. Int. J. Gynecol. Cancer 29, 651–668 (2019).

    Article  PubMed  Google Scholar 

  80. Miralpeix, E. et al. Impact of prehabilitation during neoadjuvant chemotherapy and interval cytoreductive surgery on ovarian cancer patients: a pilot study. World J. Surg. Oncol. 20, 46 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Axtell, A. E. et al. Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J. Clin. Oncol. 25, 384–389 (2007).

    Article  PubMed  Google Scholar 

  82. Salani, R., Axtell, A., Gerardi, M., Holschneider, C. & Bristow, R. E. Limited utility of conventional criteria for predicting unresectable disease in patients with advanced stage epithelial ovarian cancer. Gynecol. Oncol. 108, 271–275 (2008).

    Article  PubMed  Google Scholar 

  83. Qayyum, A. et al. Role of CT and MR imaging in predicting optimal cytoreduction of newly diagnosed primary epithelial ovarian cancer. Gynecol. Oncol. 96, 301–306 (2005).

    Article  PubMed  Google Scholar 

  84. Risum, S. et al. Prediction of suboptimal primary cytoreduction in primary ovarian cancer with combined positron emission tomography/computed tomography–a prospective study. Gynecol. Oncol. 108, 265–270 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Suidan, R. S. et al. A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer. Gynecol. Oncol. 134, 455–461 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Riester, M. et al. Risk prediction for late-stage ovarian cancer by meta-analysis of 1525 patient samples. J. Natl Cancer Inst. 106, dju048 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Penick, E. R. et al. Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues. Clin. Proteom. 19, 35 (2022).

    Article  CAS  Google Scholar 

  88. Piedimonte, S. et al. Using a machine learning algorithm to predict outcome of primary cytoreductive surgery in advanced ovarian cancer. J. Surg. Oncol. 127, 465–472 (2023).

    Article  CAS  PubMed  Google Scholar 

  89. Kawakami, E. et al. Application of artificial intelligence for preoperative diagnostic and prognostic prediction in epithelial ovarian cancer based on blood biomarkers. Clin. Cancer Res. 25, 3006–3015 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Piedimonte, S. et al. Evaluating the use of machine learning use in ovarian cancer: a systematic review. J. Clin. Oncol. 40, e17570–e17570 (2022).

    Article  Google Scholar 

  91. Griffiths, C. T. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst. Monogr. 42, 101–104 (1975).

    CAS  PubMed  Google Scholar 

  92. du Bois, A. et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 115, 1234–1244 (2009).

    Article  PubMed  Google Scholar 

  93. Long Roche, K. & Gardner, G. J. State of the science: evolving role of surgery for the treatment of ovarian cancer. Gynecol. Oncol. 155, 3–7 (2019).

    Article  PubMed  Google Scholar 

  94. Chi, D. S. et al. The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas. Gynecol. Oncol. 119, 38–42 (2010).

    Article  PubMed  Google Scholar 

  95. Tseng, J. H. et al. Continuous improvement in primary debulking surgery for advanced ovarian cancer: do increased complete gross resection rates independently lead to increased progression-free and overall survival? Gynecol. Oncol. 151, 24–31 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Harter, P. et al. A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms. N. Engl. J. Med. 380, 822–832 (2019).

    Article  PubMed  Google Scholar 

  97. Voelker, R. Lighting the way for improved detection of ovarian cancer. JAMA 327, 27 (2022).

    PubMed  Google Scholar 

  98. Tanyi, J. L. et al. A phase III study of pafolacianine injection (OTL38) for intraoperative imaging of folate receptor-positive ovarian cancer (Study 006). J. Clin. Oncol. 41, 276–284 (2023).

    Article  CAS  PubMed  Google Scholar 

  99. Vergote, I. et al. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup. Lancet Oncol. 23, e374–e384 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Goldberg, R. M. et al. Secondary cytoreductive surgery for recurrent low-grade serous ovarian carcinoma: a systematic review and meta-analysis. Gynecol. Oncol. 164, 212–220 (2022).

    Article  PubMed  Google Scholar 

  101. Kurnit, K. C. & Frumovitz, M. Primary mucinous ovarian cancer: options for surgery and chemotherapy. Int. J. Gynecol. Cancer 32, 1455–1462 (2022).

    Article  Google Scholar 

  102. Berek, J. S., Hacker, N. F., Lagasse, L. D., Nieberg, R. K. & Elashoff, R. M. Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet. Gynecol. 61, 189–193 (1983).

    CAS  PubMed  Google Scholar 

  103. Al Rawahi, T. et al. Surgical cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst. Rev. 2013, CD008765 (2013).

    PubMed  PubMed Central  Google Scholar 

  104. Harter, P. et al. Surgery in recurrent ovarian cancer: the arbeitsgemeinschaft gynaekologische onkologie (AGO) desktop ovar trial. Ann. Surg. Oncol. 13, 1702–1710 (2006).

    Article  PubMed  Google Scholar 

  105. Harter, P. et al. Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the multicenter intergroup study DESKTOP II. A project of the AGO kommission OVAR, AGO study group, NOGGO, AGO-Austria, and MITO. Int. J. Gynecol. Cancer 21, 289–295 (2011).

    Article  PubMed  Google Scholar 

  106. Du Bois, A. et al. Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20. J. Clin. Oncol. 35, 5501 (2017).

    Article  Google Scholar 

  107. Harter, P. et al. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N. Engl. J. Med. 385, 2123–2131 (2021).

    Article  PubMed  Google Scholar 

  108. Coleman, R. L. et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N. Engl. J. Med. 381, 1929–1939 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Shi, T. et al. Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 22, 439–449 (2021).

    Article  CAS  PubMed  Google Scholar 

  110. Cowan, R. A. et al. A comparative analysis of prediction models for complete gross resection in secondary cytoreductive surgery for ovarian cancer. Gynecol. Oncol. 145, 230–235 (2017).

    Article  PubMed  Google Scholar 

  111. Janco, J. M. T., Kumar, A., Weaver, A. L., McGree, M. E. & Cliby, W. A. Performance of AGO score for secondary cytoreduction in a high-volume U.S. center. Gynecol. Oncol. 141, 140–147 (2016).

    Article  PubMed  Google Scholar 

  112. Lambert, H. E. & Berry, R. J. High dose cisplatin compared with high dose cyclophosphamide in the management of advanced epithelial ovarian cancer (FIGO stages III and IV): report from the North Thames Cooperative Group. Br. Med. J. 290, 889–893 (1985).

    Article  CAS  Google Scholar 

  113. Katsumata, N. et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet Lond. Engl. 374, 1331–1338 (2009).

    Article  CAS  Google Scholar 

  114. Katsumata, N. et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol. 14, 1020–1026 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Chan, J. K. et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N. Engl. J. Med. 374, 738–748 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pignata, S. et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 15, 396–405 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Clamp, A. R. et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. Lancet Lond. Engl. 394, 2084–2095 (2019).

    Article  CAS  Google Scholar 

  118. Clamp, A. R. et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 23, 919–930 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Marchetti, C., Muzii, L., Romito, A. & Benedetti Panici, P. First-line treatment of women with advanced ovarian cancer: focus on bevacizumab. Onco Targets Ther. 12, 1095–1103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Burger, R. A. et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 365, 2473–2483 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Perren, T. J. et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365, 2484–2496 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Tewari, K. S. et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J. Clin. Oncol. 37, 2317–2328 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Pfisterer, J. et al. Optimal treatment duration of bevacizumab as front-line therapy for advanced ovarian cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 open-label randomized phase III trial. J. Clin. Oncol. 41, 893–902 (2023).

    Article  CAS  PubMed  Google Scholar 

  124. Norquist, B. M. et al. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group Study. Clin. Cancer Res. 24, 777–783 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Maru, D., Venook, A. P. & Ellis, L. M. Predictive biomarkers for bevacizumab: are we there yet? Clin. Cancer Res. 19, 2824–2827 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Alberts, D. S. et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N. Engl. J. Med. 335, 1950–1955 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Markman, M. et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J. Clin. Oncol. 19, 1001–1007 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Tewari, D. et al. Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a gynecologic oncology group study. J. Clin. Oncol. 33, 1460–1466 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wenzel, L. B. et al. Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic Oncology Group Study. J. Clin. Oncol. 25, 437–443 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Walker, J. L. et al. Randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: an NRG Oncology/Gynecologic Oncology Group Study. J. Clin. Oncol. 37, 1380–1390 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Provencher, D. M. et al. OV21/PETROC: a randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer. Ann. Oncol. 29, 431–438 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Nagao, S. et al. Intraperitoneal carboplatin for ovarian cancer — a phase 2/3 trial. NEJM Evid. 2, EVIDoa2200225 (2023).

    Article  Google Scholar 

  133. Schwameis, R., Chiva, L. & Harter, P. There is no role for hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. Int. J. Gynecol. Cancer 32, 578 (2022).

    Article  PubMed  Google Scholar 

  134. van Driel, W. J. et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N. Engl. J. Med. 378, 230–240 (2018).

    Article  PubMed  Google Scholar 

  135. Lim, P.-Q., Han, I.-H., Seow, K.-M. & Chen, K.-H. Hyperthermic Intraperitoneal Chemotherapy (HIPEC): an overview of the molecular and cellular mechanisms of actions and effects on epithelial ovarian cancers. Int. J. Mol. Sci. 23, 10078 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zivanovic, O. et al. Secondary cytoreduction and carboplatin hyperthermic intraperitoneal chemotherapy for platinum-sensitive recurrent ovarian cancer: an MSK Team Ovary Phase II Study. J. Clin. Oncol. 39, 2594–2604 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chiva, L. M. & Gonzalez-Martin, A. A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer. Gynecol. Oncol. 136, 130–135 (2015).

    Article  PubMed  Google Scholar 

  138. McMullen, M., Karakasis, K., Madariaga, A. & Oza, A. M. Overcoming platinum and PARP-inhibitor resistance in ovarian cancer. Cancers 12, 1607 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pennington, K. P. et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer Res. 20, 764–775 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. DiSilvestro, P. et al. Overall survival with maintenance olaparib at a 7-Year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J. Clin. Oncol. 41, 609–617 (2023).

    Article  CAS  PubMed  Google Scholar 

  141. González-Martín, A. et al. Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer. Eur. J. Cancer 189, 112908 (2023).

    Article  PubMed  Google Scholar 

  142. Monk, B. J. et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J. Clin. Oncol. 40, 3952–3964 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Coleman, R. L. et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Lond. Engl. 390, 1949–1961 (2017).

    Article  CAS  Google Scholar 

  144. Ray-Coquard, I. et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann. Oncol. 34, 681–692 (2023).

    Article  CAS  PubMed  Google Scholar 

  145. Loverix, L. et al. Predictive value of the Leuven HRD test compared with Myriad myChoice PLUS on 468 ovarian cancer samples from the PAOLA-1/ENGOT-ov25 trial (LBA 6). Gynecol. Oncol. 166, S51–S52 (2022).

    Article  Google Scholar 

  146. Watkins, J. A., Irshad, S., Grigoriadis, A. & Tutt, A. N. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res. 16, 211 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  147. González-Martín, A. et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 381, 2391–2402 (2019).

    Article  PubMed  Google Scholar 

  148. Hodgson, D. R. et al. Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Br. J. Cancer 119, 1401–1409 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Banerjee, S. et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 22, 1721–1731 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Tew, W. P. et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J. Clin. Oncol. 38, 3468–3493 (2020).

    Article  PubMed  Google Scholar 

  151. Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. Tattersall, A., Ryan, N., Wiggans, A. J., Rogozińska, E. & Morrison, J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst. Rev. 2, CD007929 (2022).

    PubMed  Google Scholar 

  153. Oza, A. M. et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 16, 87–97 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Yap, T. A. et al. Phase I trial of the PARP inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2- and non-BRCA1/2-mutant cancers. Cancer Discov. 10, 1528–1543 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Sun, C. et al. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci. Transl. Med. 9, eaal5148 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Westin, S. et al. SOLAR: phase Ib dose expansion of selumetinib (MEK inhibitor) and OLAparib (PARP inhibitor) combination in solid tumors with RAS pathway alterations and in PARP inhibitor-resistant ovarian cancer (LBA 9). Gynecol. Oncol. 176, S33 (2023).

    Article  Google Scholar 

  157. Yap, T. A. et al. Abstract CT030: genomic and pathologic determinants of response to RP-3500, an ataxia telangiectasia and Rad3-related inhibitor (ATRi), in patients (pts) with DNA damage repair (DDR) loss-of-function (LOF) mutant tumors in the phase 1/2 TRESR trial. Cancer Res. 82, CT030 (2022).

    Article  Google Scholar 

  158. Shima, N., Munroe, R. J. & Schimenti, J. C. The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm. Mol. Cell. Biol. 24, 10381–10389 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wyatt, D. W. et al. Essential roles for polymerase θ-mediated end joining in the repair of chromosome breaks. Mol. Cell 63, 662–673 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhou, J. et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zatreanu, D. et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun. 12, 3636 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rodriguez-Berriguete, G. et al. Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models. Clin. Cancer Res. 29, 1631–1642 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Hwang, W.-T., Adams, S. F., Tahirovic, E., Hagemann, I. S. & Coukos, G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol. Oncol. 124, 192–198 (2012).

    Article  PubMed  Google Scholar 

  164. Ni, Y. et al. The role of tumor-stroma interactions in drug resistance within tumor microenvironment. Front. Cell Dev. Biol. 9, 637675 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Matulonis, U. A. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 30, 1080–1087 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Pal, T., Permuth-Wey, J., Kumar, A. & Sellers, T. A. Systematic review and meta-analysis of ovarian cancers: estimation of microsatellite-high frequency and characterization of mismatch repair deficient tumor histology. Clin. Cancer Res. 14, 6847–6854 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Shakfa, N., Li, D., Nersesian, S., Wilson-Sanchez, J. & Koti, M. The STING pathway: therapeutic vulnerabilities in ovarian cancer. Br. J. Cancer 127, 603–611 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Shen, J. et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 79, 311–319 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. Higuchi, T. et al. CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol. Res. 3, 1257–1268 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Wang, Z. et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci. Rep. 9, 1853 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Appleton, K. M. et al. PD-1/PD-L1 checkpoint inhibitors in combination with olaparib display antitumor activity in ovarian cancer patient-derived three-dimensional spheroid cultures. Cancer Immunol. Immunother. 70, 843–856 (2021).

    Article  CAS  PubMed  Google Scholar 

  174. Lampert, E. J. et al. Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase 2 study. Clin. Cancer Res. 26, 4268–4279 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kroon, P. et al. Radiotherapy and cisplatin increase immunotherapy efficacy by enabling local and systemic intratumoral T-cell activity. Cancer Immunol. Res. 7, 670–682 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Zhang, Z., Yu, X., Wang, Z., Wu, P. & Huang, J. Anthracyclines potentiate anti-tumor immunity: a new opportunity for chemoimmunotherapy. Cancer Lett. 369, 331–335 (2015).

    Article  CAS  PubMed  Google Scholar 

  177. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

    Article  CAS  PubMed  Google Scholar 

  178. Färkkilä, A. et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat. Commun. 11, 1459 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Pujade-Lauraine, E., Fujiwara, K., Dychter, S. S., Devgan, G. & Monk, B. J. Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 phase III study design. Future Oncol. Lond. Engl. 14, 2103–2113 (2018).

    Article  CAS  Google Scholar 

  180. Moore, K. N. et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J. Clin. Oncol. 39, 1842–1855 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).

    Article  CAS  PubMed  Google Scholar 

  182. Weir, G. M. et al. Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response. Oncoimmunology 3, e953407 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Santillan, A. et al. Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma. Int. J. Gynecol. Cancer 17, 601–606 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Schmeler, K. M. et al. Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. Gynecol. Oncol. 108, 510–514 (2008).

    Article  CAS  PubMed  Google Scholar 

  185. Nickles Fader, A., Gien, L. T., Miller, A., Covens, A. & Gershenson, D. M. A randomized phase III, two-arm trial of paclitaxel, carboplatin, and maintenance letrozole versus letrozole monotherapy in patients with stage II-IV, primary low-grade serous carcinoma of the ovary or peritoneum. J. Clin. Oncol. 39, TPS5601 (2021).

    Article  Google Scholar 

  186. Dalton, H. J. et al. Activity of bevacizumab-containing regimens in recurrent low-grade serous ovarian or peritoneal cancer: a single institution experience. Gynecol. Oncol. 145, 37–40 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Monk, B. J. et al. MILO/ENGOT-ov11: binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. J. Clin. Oncol. 38, 3753–3762 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Gershenson, D. M. et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet Lond. Engl. 399, 541–553 (2022).

    Article  CAS  Google Scholar 

  189. Shrestha, R. et al. Multiomics characterization of low-grade serous ovarian carcinoma identifies potential biomarkers of MEK inhibitor sensitivity and therapeutic vulnerability. Cancer Res. 81, 1681–1694 (2021).

    Article  CAS  PubMed  Google Scholar 

  190. Banerjee, S. N. et al. ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of VS-6766 (RAF/MEK clamp) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC). J. Clin. Oncol. 40, TPS5615 (2022).

    Article  Google Scholar 

  191. Business Wire. Verastem Oncology announces design for confirmatory trial of avutometinib and defactinib in recurrent low-grade serous ovarian cancer. https://www.businesswire.com/news/home/20230705791373/en/Verastem-Oncology-Announces-Design-for-Confirmatory-Trial-of-Avutometinib-and-Defactinib-in-Recurrent-Low-Grade-Serous-Ovarian-Cancer (2023).

  192. Seki, T. et al. Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: a multicenter, retrospective analysis. J. Clin. Oncol. 40, 5502–5502 (2022).

    Article  Google Scholar 

  193. Hogen, L. et al. The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma. Gynecol. Oncol. 143, 258–263 (2016).

    Article  PubMed  Google Scholar 

  194. Pautier, P. et al. Results of a prospective dose-intensive regimen in 27 patients with small cell carcinoma of the ovary of the hypercalcemic type. Ann. Oncol. 18, 1985–1989 (2007).

    Article  CAS  PubMed  Google Scholar 

  195. Blanc, F. et al. Effect of high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR) on outcome in ovarian small-cell carcinoma, hypercalcemic type (SCCOHT): prospective series from the French Rare Gynecologic Malignant Tumors Network (TMRG). J. Clin. Oncol. 38, 6023 (2020).

    Article  Google Scholar 

  196. Wang, Y. et al. The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 242, 371–383 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Xue, Y. et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat. Commun. 10, 558 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Zhu, X. et al. Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss. Nat. Commun. 14, 2894 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Hardy-Bessard, A.-C. et al. ENGOT-OV44/FIRST study: a randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC). J. Clin. Oncol. 37, TPS5600 (2019).

    Article  Google Scholar 

  200. Ledermann, J. A. et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 24, vi24–vi32 (2013).

    Article  PubMed  Google Scholar 

  201. Tomao, F., D’Incalci, M., Biagioli, E., Peccatori, F. A. & Colombo, N. Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum-free interval: myth or reality? Cancer 123, 3450–3459 (2017).

    Article  CAS  PubMed  Google Scholar 

  202. Stuart, G. C. E. et al. Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the fourth ovarian cancer consensus conference. Int. J. Gynecol. Cancer 21, 750–755 (2011).

    Article  PubMed  Google Scholar 

  203. Parmar, M. K. B. et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet Lond. Engl. 361, 2099–2106 (2003).

    Article  CAS  Google Scholar 

  204. Pfisterer, J. et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J. Clin. Oncol. 24, 4699–4707 (2016).

    Article  Google Scholar 

  205. Wagner, U. et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br. J. Cancer 107, 588–591 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Pujade-Lauraine, E. et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J. Clin. Oncol. 28, 3323–3329 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Aghajanian, C. et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J. Clin. Oncol. 30, 2039–2045 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Coleman, R. L. et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 18, 779–791 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Pignata, S. et al. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol. 22, 267–276 (2021).

    Article  CAS  PubMed  Google Scholar 

  210. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. Ledermann, J. et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366, 1382–1392 (2012).

    Article  CAS  PubMed  Google Scholar 

  212. Pujade-Lauraine, E. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1274–1284 (2017).

    Article  CAS  PubMed  Google Scholar 

  213. Poveda, A. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 22, 620–631 (2021).

    Article  CAS  PubMed  Google Scholar 

  214. Pujade-Lauraine, E. et al. LBA33. Maintenance olaparib rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated with a PARP inhibitor (PARPi): phase IIIb OReO/ENGOT Ov-38 trial. Ann. Oncol. 32, S1308–S1309 (2021).

    Article  Google Scholar 

  215. Lheureux, S. et al. EVOLVE: a multicenter open-label single-arm clinical and translational phase II trial of cediranib plus olaparib for ovarian cancer after PARP inhibition progression. Clin. Cancer Res. 26, 4206–4215 (2020).

    Article  CAS  PubMed  Google Scholar 

  216. Colombo, N. et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†. Ann. Oncol. 30, 672–705 (2019).

    Article  CAS  PubMed  Google Scholar 

  217. Pujade-Lauraine, E. et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J. Clin. Oncol. 32, 1302–1308 (2014).

    Article  CAS  PubMed  Google Scholar 

  218. Coelho, R. et al. Overlapping gene dependencies for PARP inhibitors and carboplatin response identified by functional CRISPR-Cas9 screening in ovarian cancer. Cell Death Dis. 13, 909 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Paracchini, L. et al. Targeted mutational analysis of circulating tumor DNA to decipher temporal heterogeneity of high-grade serous ovarian cancer. Cancers 14, 3697 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Martin, L. P. et al. Characterization of folate receptor alpha (FRα) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: a phase I expansion study of the FRα-targeting antibody-drug conjugate mirvetuximab soravtansine. Gynecol. Oncol. 147, 402–407 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Kalli, K. R. et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol. Oncol. 108, 619–626 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Ab, O. et al. IMGN853, a folate receptor-α (FRα)-targeting antibody-drug conjugate, exhibits potent targeted antitumor activity against frα-expressing tumors. Mol. Cancer Ther. 14, 1605–1613 (2015).

    Article  CAS  PubMed  Google Scholar 

  223. Matulonis, U. A. et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J. Clin. Oncol. 41, 2436–2445 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Moore, K. N. et al. Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann. Oncol. 32, 757–765 (2021).

    Article  CAS  PubMed  Google Scholar 

  225. Moore, K. N. et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. J. Clin. Oncol. 41 (Suppl. 17), LBA5507 (2023).

    Article  Google Scholar 

  226. Konstantinopoulos, P. A. et al. TOPACIO/Keynote-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort. J. Clin. Oncol. 36, 106 (2018).

    Article  Google Scholar 

  227. Banerjee, S. et al. 529MO. Phase II study of olaparib plus durvalumab with or without bevacizumab (MEDIOLA): final analysis of overall survival in patients with non-germline BRCA-mutated platinum-sensitive relapsed ovarian cancer. Ann. Oncol. 33, S788–S789 (2022).

    Article  Google Scholar 

  228. Dorigo, O. et al. Maveropepimut-S, a DPX-based immune-educating therapy, shows promising and durable clinical benefit in patients with recurrent ovarian cancer, a phase II trial. Clin. Cancer Res. 29, 2808–2815 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Veneziani, A. et al. Pembrolizumab, maveropepimut-S, and low-dose cyclophosphamide in advanced epithelial ovarian cancer: results from phase 1 and expansion cohort of PESCO trial. J. Clin. Oncol. 40, 5505 (2022).

    Article  Google Scholar 

  230. Moore, K. N. et al. First-in-human phase 1/2 study of ubamatamab, a MUC16xCD3 bispecific antibody, administered alone or in combination with cemiplimab in patients with recurrent ovarian cancer. J. Clin. Oncol. 41, TPS5624 (2023).

    Article  Google Scholar 

  231. Lheureux, S. et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397, 281–292 (2021).

    Article  CAS  PubMed  Google Scholar 

  232. McGee, J. et al. Fifth ovarian cancer consensus conference: individualized therapy and patient factors. Ann. Oncol. 28, 702–710 (2017).

    Article  CAS  PubMed  Google Scholar 

  233. Madariaga, A. et al. Patient self-reporting of tolerability using PRO-CTCAE in a randomized double-blind, placebo-controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in patients with platinum resistant or refractory epithelial ovarian carcinoma. Gynecol. Oncol. 167, 226–233 (2022).

    Article  CAS  PubMed  Google Scholar 

  234. Wenzel, L. et al. Quality of life and adverse events: prognostic relationships in long-term ovarian cancer survival. J. Natl Cancer Inst. 113, 1369–1378 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Madariaga, A., Bowering, V., Ahrari, S., Oza, A. M. & Lheureux, S. Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events. Int. J. Gynecol. Cancer 30, 903–915 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Friedlander, M. et al. Patient-centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation receiving maintenance olaparib or placebo (SOLO1): a randomised, phase 3 trial. Lancet Oncol. 22, 632–642 (2021).

    Article  CAS  PubMed  Google Scholar 

  237. Friedlander, M. et al. Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial. Lancet Oncol. 19, 1126–1134 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Lee, Y. C. et al. Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study. Int. J. Gynecol. Cancer 32, 761–768 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Basch, E. et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 318, 197–198 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Donovan, H. S. et al. Effects of the WRITE Symptoms Interventions on symptoms and quality of life among patients with recurrent ovarian cancers: an NRG Oncology/GOG Study (GOG-0259). J. Clin. Oncol. 40, 1464–1473 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Herzog, T. J. et al. ARTISTRY-7: a phase 3, multicenter study of nemvaleukin alfa in combination with pembrolizumab versus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (GOG-3063; ENGOT-OV68). J. Clin. Oncol. 41, TPS5612 (2023).

    Article  Google Scholar 

  242. Tobalina, L., Armenia, J., Irving, E., O’Connor, M. J. & Forment, J. V. A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann. Oncol. 32, 103–112 (2021).

    Article  CAS  PubMed  Google Scholar 

  243. Fu, S. et al. 562TiP. A phase Ib dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer. Ann. Oncol. 32, S618 (2021).

    Article  Google Scholar 

  244. Konstantinopoulos, P. A. et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 21, 957–968 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Ngoi, N. Y. L., Leo, E., O’Connor, M. J. & Yap, T. A. Development of next-generation poly(ADP-ribose) polymerase 1-selective inhibitors. Cancer J. Sudbury Mass. 27, 521–528 (2021).

    Article  CAS  Google Scholar 

  246. Hou, J. Y. et al. Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer. Gynecol. Oncol. 167, 334–341 (2022).

    Article  CAS  PubMed  Google Scholar 

  247. Ovarian, fallopian tube, and peritoneal cancer - statistics. Cancer.Net https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/statistics (2012).

  248. Momenimovahed, Z., Tiznobaik, A., Taheri, S. & Salehiniya, H. Ovarian cancer in the world: epidemiology and risk factors. Int. J. Women’s Health 11, 287 (2019).

    Article  Google Scholar 

  249. Walsh, T. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl Acad. Sci. USA 108, 18032–18037 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Brundage, M. et al. Health-related quality of life in recurrent platinum-sensitive ovarian cancer—results from the CALYPSO trial. Ann. Oncol. 23, 2020–2027 (2012).

    Article  CAS  PubMed  Google Scholar 

  251. Gordon, A. N. et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J. Clin. Oncol. 19, 3312–3322 (2001).

    Article  CAS  PubMed  Google Scholar 

  252. Monk, B. J. et al. Patient reported outcomes of a randomized, placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: a Gynecologic Oncology Group. Study. Gynecol. Oncol. 128, 573–578 (2013).

    Article  CAS  PubMed  Google Scholar 

  253. Stark, D. et al. Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial. Lancet Oncol. 14, 236–243 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  254. Stockler, M. R. et al. Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J. Clin. Oncol. 32, 1309–1316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Barretina-Ginesta, M.-P. et al. Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial. Ther. Adv. Med. Oncol. 14, 17588359221126148 (2022).

    Article  Google Scholar 

  256. Vergote, I. et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N. Engl. J. Med. 363, 943–953 (2010).

    Article  CAS  PubMed  Google Scholar 

  257. Joly, F. et al. Time without symptoms or toxicity (TWiST) in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib or placebo plus bevacizumab: analysis of PAOLA-1/ENGOT-ov25 phase III trial. J. Clin. Oncol. 40, 5562 (2022).

    Article  Google Scholar 

  258. Aoki, D. & Chiyoda, T. PARP inhibitors and quality of life in ovarian cancer. Lancet Oncol. 19, 1012–1014 (2018).

    Article  PubMed  Google Scholar 

  259. Matulonis, U. A. et al. Niraparib maintenance treatment improves time without symptoms or toxicity (TWiST) versus routine surveillance in recurrent ovarian cancer: a TWiST analysis of the ENGOT-OV16/NOVA trial. J. Clin. Oncol. 37, 3183–3191 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Oza, A. M. et al. Patient-centered outcomes in ARIEL3, a phase III, randomized, placebo-controlled trial of rucaparib maintenance treatment in patients with recurrent ovarian carcinoma. J. Clin. Oncol. 38, 3494–3505 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Madariaga, A., Rustin, G. J. S., Buckanovich, R. J., Trent, J. C. & Oza, A. M. Wanna get away? maintenance treatments and chemotherapy holidays in gynecologic cancers. Am. Soc. Clin. Oncol. 39, e152–e166 (2019).

    Google Scholar 

  262. Ortiz, M., Wabel, E., Mitchell, K. & Horibata, S. Mechanisms of chemotherapy resistance in ovarian cancer. Cancer Drug Resist. 5, 306–316 (2022).

    Google Scholar 

  263. Alatise, K. L., Gardner, S. & Alexander-Bryant, A. Mechanisms of drug resistance in ovarian cancer and associated gene targets. Cancers 14, 6246 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Szymczyk, J. et al. FGF/FGFR-dependent molecular mechanisms underlying anti-cancer drug resistance. Cancers 13, 5796 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank W. Xu and D. Sharma (University of Toronto) for their invaluable contributions to the development of the Circos plots.

Author information

Authors and Affiliations

  1. Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Ana C. Veneziani, Eduardo Gonzalez-Ochoa, Husam Alqaisi, Gita Bhat, Suku Sneha & Amit M. Oza

  2. Medical Oncology Department, 12 De Octubre University Hospital, Madrid, Spain

    Ainhoa Madariaga

  3. Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, Toronto, Ontario, Canada

    Marjan Rouzbahman

  4. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Amit M. Oza

Authors
  1. Ana C. Veneziani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eduardo Gonzalez-Ochoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Husam Alqaisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ainhoa Madariaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gita Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marjan Rouzbahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Suku Sneha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amit M. Oza
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, drafted the manuscript and reviewed the manuscript before submission. A.M.O conceptualized the manuscript, figures and made substantial revision to the original manuscript.

Corresponding author

Correspondence to Amit M. Oza.

Ethics declarations

Competing interests

A.M. has received honoraria from AstraZeneca, Clovis, GSK and PharmaMar. A.M.O. is a principal investigator and participates in steering committees of trials sponsored by AstraZeneca, Clovis (without compensation) and GSK, and is the CEO of Ozmosis Research (without compensation). The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks R. Arend and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Clinical trials: https://www.clinicaltrials.gov/

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Veneziani, A.C., Gonzalez-Ochoa, E., Alqaisi, H. et al. Heterogeneity and treatment landscape of ovarian carcinoma. Nat Rev Clin Oncol 20, 820–842 (2023). https://doi.org/10.1038/s41571-023-00819-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-023-00819-1

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer