Distinct and different

Low-grade serous ovarian cancer

Low-grade serous ovarian cancer (LGSOC) is a rare ovarian cancer that is insidious, persistent, and ultimately fatal.1-5 It is molecularly and histopathologically distinct from high-grade serous ovarian cancer (HGSOC). Clinically, it required different treatment.1,6,7 There are currently no FDA-approved treatments specifically for LGSOC,8 creating significant unmet need for patients and the healthcare providers (HCPs) who care for them.

On this page:
Key Distinctions
Key Stats
LGSOC vs HGSOC
Pathogenesis of LGSOC
Need for Better Treatments

About LGSOC

Key distinctions

LGSOC is RAS/MAPK driven: ~70% of LGSOC patients have RAS/MAPK (rat sarcoma virus/mitogen-activated protein kinase) pathway-associated mutations.9-12

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend both germline mutation testing and somatic tumor testing for all patients with ovarian cancer, including LGSOC, at both diagnosis and recurrence.13

LGSOC is highly recurrent

Over 80% of patients with LGSOC experience recurrence.3,4 Unfortunately, LGSOC often responds poorly to chemotherapy compared with high-grade serous ovarian cancer (HGSOC)—making treatment more challenging.14

LGSOC affects a younger patient population

LGSOC has a bimodal age distribution with peaks at ages 20-30 years and 50-60 years.6,9

Key stats

~90%

of patients are diagnosed with LGSOC at an advanced stage3,15

Over 80%

of patients will experience a recurrence3,4

98%

of patients with stage II-IV LGSOC relapsed within 5 years of diagnosis following primary treatment4

Less than 5%

of all serous ovarian cancers are LGSOC16,17

~2,000

new cases are diagnosed in the US each year18

LGSOC treated with contemporary primary therapy has been shown to reach a median overall survival of

~11 years4

Molecularly, histopathologically, and clinically distinct

LGSOC vs HGSOC—how they differ

While once thought to be on a continuum with high-grade serous ovarian cancer (HGSOC), LGSOC is now recognized as a distinct ovarian cancer, with different characteristics from HGSOC.19 LGSOC behaves differently than HGSOC in both clinical course and overall prognosis.19 Although LGSOC is associated with prolonged survival compared to HGSOC, quality of life is an important issue, and patients may undergo years of ineffective treatments.17,20

High-grade serous ovarian cancer cells
HGSOC
Low-grade serous ovarian cancer cells
LGSOC

Move the slider from right to left to view histological features of HGSOC vs LGSOC.

High-grade serous ovarian cancer is characterized by marked nuclear pleomorphism and abundant mitotic features. Low-grade serous ovarian cancer shows less predominant nuclear atypia.17,21

Graphical representation of development of low-grade serous ovarian carcinoma

A closer look

The pathogenesis of LGSOC

Apart from estrogen-related signaling, the rat sarcoma virus/mitogen-activated protein kinase (RAS/MAPK) pathway plays a prominent role in the pathogenesis of LGSOC, present in ~70% of patients.9-12,22 LGSOC may arise from serous borderline tumors (SBT) or as a de novo malignancy from the ovary or peritoneum.23 Alterations affecting the MAPK pathway are most commonly somatic KRAS (33%), NRAS (11%), and BRAF (11%).9-12,22

Learn about LGSOC diagnosis

Younger patient population, advanced disease, few options

Unmet need in LGSOC

With no FDA-approved drugs or treatments specifically for LGSOC, there is a high unmet need for patients diagnosed with this rare form of ovarian cancer.8 These characteristics of LGSOC highlight the urgency of the unmet need:

Advanced stage at diagnosis

Because signs and symptoms are nonspecific to LGSOC, patients may be misdiagnosed, and accurate diagnosis of LGSOC can be significantly delayed.20,24 In fact, ~90% patients are diagnosed with LGSOC at an advanced stage.3,15

LGSOC affects a younger patient population

LGSOC has a bimodal age distribution which peaks at ages 20-30 years and 50-60 years and disproportionately impacts health, fertility, and long-term quality of life.9 Quality of life is an important issue, and patients may undergo prolonged ineffective treatments.14,17,25

Current treatment regimens

The primary treatment method is surgery when possible in both newly diagnosed and recurrent low-grade serous ovarian cancer.26 Patients may be treated with chemotherapy alone or along with endocrine therapy.27 However, when comparing LGSOC vs HGSOC, LGSOC is less sensitive to chemotherapy than HGSOC, and endocrine therapy for LGSOC is not well studied.14,27 Recurrence rates with current regimens are high in LGSOC; in over 80% of patients, cancer will recur.3,4

Limited treatment options

Recurrent low-grade serous ovarian cancer has limited treatment options, including secondary cytoreduction, clinical trials, chemotherapy, endocrine therapy, or targeted therapies.9,13,26 No standard sequence of therapy exists in LGSOC.13,17

Hear from experts

Considerations when treating younger women with LGSOC

Gynecologic oncologists Shannon M. Westin, M.D. and Premal Thaker, M.D., M.S. discuss treatment and fertility issues when treating younger patients with LGSOC.

Without FDA-approved treatments for LGSOC,2 patients and HCPs may be unsure about the best next steps.

LEARN ABOUT DIAGNOSING LGSOC
  1. Babaier A, Mal H, Alselwi W, et al. Low-grade serous carcinoma of the ovary: the current status. Diagnostics (Basel). 2022;12(2):458.
  2. Ciucci A, Zannoni GF, Buttarelli M, et al. Ovarian low and high grade serous carcinomas: hidden divergent features in the tumor microenvironment. Oncotarget. 2016;7(42):68033-68043.
  3. Gershenson DM, Bodurka DC, Lu KH, 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):2675-2682.
  4. Gershenson DM, Cobb LP, Westin SN, et al. Contemporary primary treatment of women with stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC): determinants of relapse and disease-free survival. Gynecol Oncol. 2022;167(2):139-145.
  5. Monk BJ, Grisham RN, Banerjee S, 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. 2020;38(32):3753-3762.
  6. Gershenson DM. Low-grade serous carcinoma of the ovary or peritoneum. Ann Oncol. 2016;27(Suppl 1):i45-i49.
  7. Slomovitz B, Gourley C, Carey MS, et al. Low-grade serous ovarian cancer: state of the science. Gynecol Oncol. 2020;156(3):715-725.
  8. Banerjee SN, Ring KL, Nieuwenhuysen EV, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 2023;41(suppl 16):5515.
  9. Manning-Geist B, Gordhandas S, Liu YL, et al. MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma. Clin Cancer Res. 2022;28(20):4456-4465.
  10. Gershenson DM, Sun CC, Westin SN, et al. The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes. Gynecol Oncol. 2022;165(3):560-567.
  11. ElNaggar A, Robins D, Baca Y, et al. Genomic profiling in low grade serous ovarian cancer: identification of novel markers for disease diagnosis and therapy. Gynecol Oncol. 2022;167(2):306-313.
  12. Thomson JP, Hollis RL, van Baal J, et al. Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome. Gynecol Oncol. 2023;174:157-166.
  13. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed July 17, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org
  14. Grabowski JP, Harter P, Heitz F, et al. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. Gynecol Oncol. 2016;140(3):457-462.
  15. De Decker K, Wenzel HHB, Bart J, et al. Stage, treatment and survival of low-grade serous ovarian carcinoma in the Netherlands: a nationwide study. Acta Obstet Gynecol Scand. 2023;102(3):246-256.
  16. Matsuo K, Machida H, Grubbs BH, et al. Trends of low-grade serous ovarian carcinoma in the United States. J Gynecol Oncol. 2018;29(1):e15
  17. Grisham RN, Slomovitz BM, Andrews N, et al. Low-grade serous ovarian cancer: expert consensus report on the state of the science. Int J Gynecol Cancer. 2023;33(9):1331-1344.
  18. Cleveland Clinic. Epithelial Ovarian Cancer. Accessed July 9, 2024. https://my.clevelandclinic.org/health/diseases/22250-epithelial-ovarian-cancer 
  19. Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol. 2008;198(4):459.e1-8.
  20. Gockley A, Melamed A, Bregar AJ, et al. Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstet Gynecol. 2017;129(3):439-447.
  21. Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28(4):496-504.
  22. Nasioudis D, Latif NA, Ko EM, et al. Next generation sequencing reveals a high prevalence of pathogenic mutations in homologous recombination DNA damage repair genes among patients with uterine sarcoma. Gynecol Oncol. 2023;177:14-19.
  23. Shvartsman HS, Sun CC, Bodurka DC, et al. Comparison of the clinical behavior of newly diagnosed stages II-IV low-grade serous carcinoma of the ovary with that of serous ovarian tumors of low malignant potential that recur as low-grade serous carcinoma. Gynecol Oncol. 2007;105(3):625-629.
  24. Harvard Health. Certain symptoms may be early signs of ovarian cancer. Accessed July 9, 2024. https://www.health.harvard.edu/cancer/certain-symptoms-may-be-early-signs-of-ovarian-cancer 
  25. Schmeler KM, Sun CC, Bodurka DC, et al. Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2008;108(3):510-514.
  26. Crane EK, Sun CC, Ramirez PT, et al. The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer. Gynecol Oncol. 2015;136(1):25-29.
  27. Gershenson DM, Bodurka DC, Coleman RL, et al. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35(10):1103-1111.
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