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Low-Grade Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions

  • Rachel N. Grisham
  • Gopa Iyer
Gynecologic Cancers (LA Cantrell, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Gynecologic Cancers

Opinion statement

Low-grade serous ovarian cancer (LGSOC) is a rare subtype of ovarian cancer, accounting for approximately 10% of cases of serous ovarian cancer. Patients typically present at a younger age have a protracted clinical course with survival for those with recurrent disease nearing 10 years, and have a high prevalence of somatic (tumor-specific) mutations affecting the mitogen-activated protein kinase (MAPK) pathway. Initial treatment of patients with stage IC–IV disease is similar to that of high-grade serous ovarian cancer with surgery and platinum/taxane-based chemotherapy. Selected patients may benefit from hormonal maintenance therapy following chemotherapy, in particular those with evidence of residual disease at completion of therapy. In the recurrent setting, the highest response rates to chemotherapy have been noted in those patients receiving chemotherapy in combination with bevacizumab. While hormonal therapies may offer disease stabilization with relatively low toxicity, objective response rates remain low. The use of targeted therapies such as MEK inhibitors remains an active area of investigation and those patients with MAPK pathway alterations may derive the greatest benefit from these agents.

Keywords

Low-grade serous ovarian cancer Ovarian cancer Gynecologic cancer, rare tumors KRAS BRAF MAPK Targeted therapy MEK Hormonal therapy Bevacizumab 

Notes

Compliance With Ethical Standards

Conflict of Interest

Rachel N. Grisham has received compensation from Clovis Oncology for service as a consultant. Gopa Iyer declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    •• Malpica A, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28(4):496–504. Pivotal change in classification of serous ovarain cancers from a three-tiered system to a binary high/low-grade system.CrossRefGoogle Scholar
  2. 2.
    Seidman JD, Horkayne-Szakaly I, Haiba M, Boice CR, Kurman RJ, Ronnett BM. The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol. 2004;23(1):41–4.CrossRefGoogle Scholar
  3. 3.
    Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol. 2008;198(4):459.e1–8. discussion 459 e8–9CrossRefGoogle Scholar
  4. 4.
    Integrated genomic analyses of ovarian carcinoma. Nature, 2011. 474(7353): p. 609–15.Google Scholar
  5. 5.
    Kaern J, Trope CG, Abeler VM. A retrospective study of 370 borderline tumors of the ovary treated at the Norwegian Radium Hospital from 1970 to 1982. A review of clinicopathologic features and treatment modalities. Cancer. 1993;71(5):1810–20.CrossRefGoogle Scholar
  6. 6.
    Kaldawy A, Segev Y, Lavie O, Auslender R, Sopik V, Narod SA. Low-grade serous ovarian cancer: a review. Gynecol Oncol. 2016;143(2):433–8.CrossRefGoogle Scholar
  7. 7.
    Nougaret S, Lakhman Y, Molinari N, Feier D, Scelzo C, Vargas HA, et al. CT features of ovarian tumors: defining key differences between serous borderline tumors and low-grade serous carcinomas. AJR Am J Roentgenol. 2018;210(4):918–26.CrossRefGoogle Scholar
  8. 8.
    Gershenson DM, Bodurka DC, Lu KH, Nathan LC, Milojevic L, Wong KK, et al. Impact of age and primary disease site on outcome in women with low-grade serous carcinoma of the ovary or peritoneum: results of a large single-institution registry of a rare tumor. J Clin Oncol. 2015;33(24):2675–82.CrossRefGoogle Scholar
  9. 9.
    Gershenson DM, Sun CC, Bodurka D, Coleman RL, Lu KH, Sood AK, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114(1):48–52.CrossRefGoogle Scholar
  10. 10.
    Gershenson DM, Sun CC, Lu KH, Coleman RL, Sood AK, Malpica A, et al. Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary. Obstet Gynecol. 2006;108(2):361–8.CrossRefGoogle Scholar
  11. 11.
    Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.CrossRefGoogle Scholar
  12. 12.
    FDA approves Genentech’s avastin (bevacizumab) plus chemotherapy as a treatment for women with advanced ovarian cancer following initial Surgery. Genentech. https://www.gene.com/media/press-releases/14729/2018-06-13/fda-approves-genentechs-avastin-bevacizu
  13. 13.
    •• Gershenson DM, et al. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35(10):1103–11. Large study showing significant improvement in progression-free survival with the use of hormonal maintenance therapy following initial therapy of LGSOC.CrossRefGoogle Scholar
  14. 14.
    Malpica A, Wong KK. The molecular pathology of ovarian serous borderline tumors. Ann Oncol. 2016;27(Suppl 1):i16–9.CrossRefGoogle Scholar
  15. 15.
    Grisham, R.N., et al., BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. Cancer, 2013;119(3):548–554CrossRefGoogle Scholar
  16. 16.
    Turashvili G, Grisham RN, Chiang S, DeLair DF, Park KJ, Soslow RA, et al. BRAF(V)(600E) mutations and immunohistochemical expression of VE1 protein in low-grade serous neoplasms of the ovary. Histopathology. 2018;73:438–43.CrossRefGoogle Scholar
  17. 17.
    Grisham RN. Low-grade serous carcinoma of the ovary. Oncology. 2016;30(7):650–2.PubMedGoogle Scholar
  18. 18.
    Bodurka, D.C., et al., Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study. Cancer, 2011.Google Scholar
  19. 19.
    Gershenson DM, Sun CC, Iyer RB, Malpica AL, Kavanagh JJ, Bodurka DC, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125(3):661–6.CrossRefGoogle Scholar
  20. 20.
    Grisham RN, Sylvester BE, Won H, McDermott G, DeLair D, Ramirez R, et al. Extreme outlier analysis identifies occult mitogen-activated protein kinase pathway mutations in patients with low-grade serous ovarian cancer. J Clin Oncol. 2015;33(34):4099–105.CrossRefGoogle Scholar
  21. 21.
    Singer G, Oldt R, Cohen Y, Wang BG, Sidransky D, Kurman RJ, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst. 2003;95(6):484–6.CrossRefGoogle Scholar
  22. 22.
    Wong KK, Tsang YTM, Deavers MT, Mok SC, Zu Z, Sun C, et al. BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol. 2010;177(4):1611–7.CrossRefGoogle Scholar
  23. 23.
    Vereczkey I, Serester O, Dobos J, Gallai M, Szakács O, Szentirmay Z, et al. Molecular characterization of 103 ovarian serous and mucinous tumors. Pathol Oncol Res. 2011;17(3):551–9.CrossRefGoogle Scholar
  24. 24.
    •• Grisham RN, et al. BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. Cancer. 2013;119(3):548–54. Initial study indicating that BRAF mutation is associated with improved prognosis in LGSOC.CrossRefGoogle Scholar
  25. 25.
    Mayr D, Hirschmann A, Löhrs U, Diebold J. KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol. 2006;103(3):883–7.CrossRefGoogle Scholar
  26. 26.
    Xu Y, Bi R, Xiao Y, Tu X, Li M, Li A, et al. Low frequency of BRAF and KRAS mutations in Chinese patients with low-grade serous carcinoma of the ovary. Diagn Pathol. 2017;12(1):87.Google Scholar
  27. 27.
    •• Farley J, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134–40. The first phase II prospective study of systemic MEK inhibitor therapy performed in LGSOC.CrossRefGoogle Scholar
  28. 28.
    Takekuma M, Wong KK, Coleman RL. A long-term surviving patient with recurrent low-grade serous ovarian carcinoma treated with the MEK1/2 inhibitor, selumetinib. Gynecol Oncol Res Pract. 2016;3:5.CrossRefGoogle Scholar
  29. 29.
    Grisham, R., Moore K.N., Gordon M.S., Harb W., Cody G.R., Halpenny D.F., Makker V., Aghajanian C., Phase Ib study of binimetinib with paclitaxel in patients with platinum-resistant ovarian cancer: final results, potential biomarkers, and extreme responders. Clin Cancer Res, 2018, clincanres.0494.2018.Google Scholar
  30. 30.
    Grisham RN, Iyer G, Sala E, Zhou Q, Iasonos A, DeLair D, et al. Bevacizumab shows activity in patients with low-grade serous ovarian and primary peritoneal cancer. Int J Gynecol Cancer. 2014;24(6):1010–4.CrossRefGoogle Scholar
  31. 31.
    Dalton HJ, Fleming ND, Sun CC, Bhosale P, Schmeler KM, Gershenson DM. Activity of bevacizumab-containing regimens in recurrent low-grade serous ovarian or peritoneal cancer: a single institution experience. Gynecol Oncol. 2017;145(1):37–40.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Weill Cornell Medical CollegeNew YorkUSA

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