Opinion Statement
Low grade serous carcinoma of the ovary has been delineated as a separate entity from its counterpart high grade serous carcinoma of the ovary. Molecular profiling has helped to further characterize this disease process and has led to new and exciting treatment options. Surgery has always been a cornerstone of management both in primary and recurrent disease settings. Chemotherapy has been a long-standing backbone of adjuvant treatment, but its efficacy continues to be questioned. Hormonal therapy for upfront and recurrent disease is an effective treatment option with a high response rate and minimal side effects. Newer therapies including MEK, CDK 4/6, and PI3KCA inhibitors have emerged as exciting options for recurrent disease. Ongoing clinical trials will hopefully lead to additional therapeutic opportunities based on novel biomarkers in this disease.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Low grade serous ovarian carcinoma (LGSOC) is uncommon, comprising only about 2% of epithelial ovarian cancers [1, 2]. While previously grouped with its high-grade serous counterpart, more contemporary data supports the distinction of LGSOC as a unique clinical entity. Molecular profiling of LGSOC has become instrumental for our understanding of disease biology and the development targeted therapeutics for a tumor type classically thought to be chemoresistant [3••].
The majority (60%) of LGSOC cases are associated with a serous borderline neoplasm, which is likely a precursor lesion. Still, a significant proportion of cases arise de novo and may be ovarian or primary peritoneal, the latter of which is associated with improved prognosis [4•]. When compared to patients with high grade serous ovarian carcinoma (HGSOC), those with LGSOC tend to be younger, have higher BMI, have lower CA-125 levels, and are less likely to have ascites [5]. Patients with LGSOC may have more indolent onset of symptoms, but still most are diagnosed at advanced stages (FIGO II-IV). While professional societies recommend germline genetic testing for all patients with epithelial ovarian cancer, the likelihood of LGSOC being associated with a genetic predisposition is low, < 5% [6,7,8]. Somatic testing of LGSOC also reveals low rates of genetic mutation associated with homologous recombination deficiency [9, 10]. Somatic MAPK pathway alteration has been associated with improved survival outcomes, in addition to older age, lower BMI, and lack of tobacco use [4•, 8, 11, 12].
Surgery is the mainstay of treatment for LGSOC. Primary surgical management is the same as that for ovarian cancer in general, where those patients with apparent early-stage disease undergo staging and those with advanced-stage disease undergo debulking [13]. Completeness of cytoreduction is an important prognostic factor. In an ancillary analysis of GOG 182, only residual disease at the time of surgery was significantly associated with survival on multivariate analysis (median PFS 33.2 vs 14.1 months for those with microscopic vs macroscopic residual disease, respectively), highlighting the importance of optimal tumor debulking if possible [5]. Adjuvant chemotherapy is often given following surgical resection despite relatively low response rates of LGSOC to standard cytotoxic chemotherapy [14]. Unlike its high-grade serous counterpart where response rates to platinum-based chemotherapy reach 90%, LGSOC has been associated with low overall response rates of 4–20% [15,16,17].
Most patients (> 70%) diagnosed with advanced-stage LGSOC will recur. Given the relative chemoresistance of LGSOC, treatment in the recurrent setting often focuses on a combination of secondary cytoreduction (when feasible), hormonal therapy, targeted therapy, and/or clinical trial [3••, 6]. The pathologic and molecular features of the tumor often drive these treatment decisions. Most are hormone-receptor positive (90% estrogen receptor [ER], 50% progesterone receptor [PR]), making progestins or aromatase inhibitors particularly enticing in this setting [18, 19]. Additionally, a significant proportion of LGSOC tumors have KRAS (40%) or BRAF (5%) molecular alterations, highlighting the dominant role of the MAPK pathway in tumor biology and unveiling an important therapeutic target [8, 20, 21]. Clinical trials currently enrolling patients with recurrent LGSOC focus on these and other molecular alterations, highlighting the importance of precision medicine in the LGSOC treatment paradigm. Based on results of these trials, targeted therapy may become more prominent in the frontline setting.
Treatment
Surgery
Surgery is the preferred primary treatment strategy for LGSOC [6, 7]. Surgical staging for patients with early-stage disease includes hysterectomy, bilateral salpingo-oophorectomy, omentectomy, pelvic and para-aortic lymphadenectomy, peritoneal washings and biopsies [22]. Fertility-sparing surgery may be an option for patients with stage IA-IC1 LGSOC [3••, 23]. For those with advanced-stage disease, complete gross resection is associated with improved survival [5, 11, 16]. In an ancillary analysis of GOG 182, Fader et al. reported that residual disease was the only factor independently associated with PFS (HR 2.28) and OS (HR 2.12) [5]. Grabowski et al. reported on an exploratory analysis of 4 AGO-OVAR phase 3 trials including patients with advanced epithelial ovarian cancer who underwent upfront surgical management followed by 6 cycles of platinum-based chemotherapy. Of 145 patients with LGSOC, those who underwent complete cytoreduction had significantly improved OS (HR 0.14) compared to those with suboptimal cytoreduction [16]. Expert consensus favors attempting cytoreduction even if the probability of complete gross resection is low [3••, 7]. Neoadjuvant platinum-based chemotherapy is not the favored approach for LGSOC given its relative chemoresistance and association with worse PFS [16, 17, 24,25,26]. However, a recently presented abstract from a phase 2 pilot study of neoadjuvant fulvestrant plus abemaciclib in patients with LGSOC demonstrated 47% ORR, indicating that neoadjuvant hormonal/targeted therapy combinations may be beneficial for patients when primary cytoreduction is not feasible [27•].
Secondary cytoreduction at time of recurrence should be strongly considered, especially if complete gross resection is achievable. In a retrospective review of 41 recurrent LGSOC patients by Crane et al., median PFS following secondary cytoreduction was significantly improved for patients with no gross residual disease compared to those with residual disease (60.3 vs 10.7 months; p = 0.008), and OS was also significantly improved (93.6 vs 45.8 months; p = 0.04) [28]. A meta-analysis of patients with LGSOC reported that survival was superior for patients whose initial treatment at time of recurrence was surgery as compared to chemotherapy [29]. However, patient selection for secondary cytoreduction in the setting of recurrent LGSOC is not well defined, as most patient selection criteria are based on studies of patients with HGSOC. In general, the gynecologic oncologist is encouraged to consider the disease-free interval and number of recurrence sites when determining eligibility for secondary cytoreduction [30]. Expert consensus recommends a lower threshold for surgical management of recurrent LGSOC given the indolent nature of disease and likely survival benefit even if complete gross resection is not achieved [3••].
Chemotherapy
Patients with LGSOC were included in historical Gynecologic Oncology Group (GOG) trials that defined platinum-based chemotherapy as the standard of care for ovarian cancer patients following surgical cytoreduction [31,32,33]. As a result, carboplatin and paclitaxel have become the recommended cytotoxic regimen in the upfront setting. Recommended dosing of carboplatin is an area under the curve of 5–6, and paclitaxel 175 mg/m2 on day 1 of every 21 day cycle, as administered in the control arm of GOG 218 [32]. Dose reductions or discontinuation of therapy may occur for performance status and/or treatment-related toxicities. Myelosuppression is the dose-limiting toxicity associated with carboplatin, with up to 20% of patients experiencing grade 3–4 thrombocytopenia [32,33,34,35]. Neurotoxicity is another dose-limiting toxicity associated with paclitaxel, where peripheral neuropathy may be permanent [36].
Based upon clinical practice and ancillary analyses of early ovarian cancer trials, it has become more apparent that those patients with HGSOC drive the response seen to platinum-based chemotherapy. An exploratory case–control study of the AGO-meta-database looked at 4 randomized phase 3 clinical trials where ovarian cancer patients were treated with first-line platinum-based chemotherapy. Of 145 patients with LGSOC, 39 had a suboptimal debulking and response that was able to be evaluated. An overall response rate (ORR) of only 23% was noted, compared to an ORR of 90% in a control cohort of high-grade serous ovarian cancer (p < 0.001) [16]. Other studies have reported even lower response rates (ORR 4%) of LGSOC to cytotoxic chemotherapy [15, 17].
Other non-platinum-based cytotoxic chemotherapies have also been studied in LGSOC prospectively as the standard of care control arms in GOG 281 and MILO/ENGOT-ov11. Physicians choice chemotherapy included either weekly paclitaxel (80 mg/m2 IV on days 1, 8, 15 of every 28 day cycle), liposomal doxorubicin (40–50 mg/m2 IV on day 1 of every 28 day cycle), or topotecan (either 4 mg/m2 on days 1, 8, 15 of every 28 day cycle, or 1.25 mg/m2 on days 1–5 of every 21 day cycle). Response rates to each of these regimens were low, ranging from 0–15% [37••, 38•]. The most common toxicities related to these regimens included abdominal pain (17%), nausea/vomiting (11%), anemia (10%), and palmar plantar erythrodysesthesia (5%). Given the toxicity risk associated with cytotoxic chemotherapy and lack of substantial response in the setting of LGSOC, alternative treatments have emerged including anti-angiogenesis, hormonal therapy, and targeted therapies.
Anti-angiogenics
Bevacizumab is a monoclonal antibody that binds and prevents the activity of vascular endothelial growth factor (VEGF). Its use in LGSOC may be considered in the primary setting in combination with platinum-based chemotherapy and continued as maintenance, or in the recurrent setting either as combination or monotherapy treatment.
Several large clinical trials have demonstrated a progression-free survival (PFS) benefit with the addition of bevacizumab for frontline treatment of advanced-stage ovarian cancer, although again most patients included in these trials had HGSOC. In the phase III trial GOG 218, Burger et al. demonstrated the addition of bevacizumab to platinum-based chemotherapy, followed by maintenance bevacizumab, provided a 4-month PFS benefit [32]. Oza et al. reported a 2-month PFS improvement when bevacizumab was added to platinum-based chemotherapy in the frontline setting in a phase III randomized trial, ICON 7 (median PFS 24.1 vs 22.4 months for chemotherapy alone, p = 0.04). Only 80 patients in this trial had LGSOC and in this small subgroup, there was not a demonstrated survival benefit [39]. Additionally, the OCTAVIA trial was a single-arm, open-label, international study that demonstrated 12-month PFS 85.6% with the addition of bevacizumab to platinum-based chemotherapy and continued as maintenance for patients with newly diagnosed ovarian cancer. Only 22 (12%) of the study population had LGSOC or endometrioid histology, and these were not separately analyzed [40].
In the recurrent setting, the addition of bevacizumab to chemotherapy has demonstrated improvement in PFS when compared to chemotherapy alone in large phase III clinical trials [41, 42]. In one of these trials (OCEANS), histologic grade was not reported, and in the other (AURELIA), low-grade histology only comprised 5% of the patient population and was not separately evaluated. Retrospective studies have looked at bevacizumab specifically in LGSOC patients. A review of 17 patients with recurrent LGSOC or serous borderline tumors reported an ORR of 55% for those patients with LGSOC who received bevacizumab alone (n = 2) or in combination (n = 15) [43]. Rose et al. reported a low ORR (8.3%) in 12 LGSOC patients treated with bevacizumab, however clinical benefit was significant with most patients achieving long duration of stable disease, and median PFS was 48 months [44]. Dalton et al. reviewed 40 patients with LGSOC undergoing 45 different treatment regimens with the addition of bevacizumab and found an ORR of 47.5%, median PFS 10.2 months, and median overall survival (OS) 34.6 months [45]. Based on these reports, expert consensus and guidelines recommend consideration of the addition of bevacizumab in the treatment of LGSOC [3••, 6, 7].
Bevacizumab is administered intravenously at 10 mg per kilogram (mg/kg) of body weight every two weeks or 7.5–15 mg/kg every three weeks. Contraindications include the presence of a fistula, patients at high risk of bleeding, or those within four weeks of major surgery. Common side effects include hypertension, proteinuria, arthralgias, rhinorrhea, and epistaxis. Less common, but significant side effects include gastrointestinal perforation, fistula, bleeding, and venous thromboembolism [40,41,42, 46]. Bevacizumab costs $184 to $239 per milliliter of medication [47]. Bevacizumab can interact with various medications. Notably, it enhances the effects of myelosuppressive agents, such as cytotoxic chemotherapy. Additionally, it can worsen the cardiotoxic effect of anthracyclines and should not be administered in combination [47].
Hormonal Therapy
Hormonal therapy may be utilized in the primary treatment, primary maintenance, and recurrent treatment settings for patients with LGSOC.
Retrospective data supports the use of hormonal therapy as a maintenance strategy for LGSOC. In a large retrospective review of 203 patients with surgical stage II-IV LGSOC, Gershenson et al. reported outcomes of patients who underwent surveillance (n = 133) versus hormonal maintenance (n = 70) following adjuvant platinum-based chemotherapy. Hormonal therapy included a variety of medication regimens: 57% aromatase inhibitor (54% letrozole, 3% anastrazole), 29% tamoxifen, 7% leuprolide, 3% leuprolide and letrozole, 3% leuprolide and tamoxifen, and 1% depo-provera. Median PFS was 64.9 months in those who received hormonal therapy and 26.4 months in those who had undergone surveillance, an almost 40-month difference (p < 0.001). Notably, there was no difference in OS (102.7 vs. 115.7 months) [48]. In another retrospective study by Fader et al., 27 patients with stage II-IV LGSOC received hormonal monotherapy after cytoreductive surgery. Most tumors (96%) had positive ER expression on immunohistochemistry, and 32% had positive PR expression. Hormonal treatment options included letrozole (55%), anastrozole (37%), and tamoxifen (7.4%). Over a median follow-up of 41 months, only 22% of patients recurred, and 3-year PFS and OS were 79% and 93%, respectively [49]. Based on results of these two retrospective studies, a phase III trial, NRG-GY019 (NCT04095364) was developed to evaluate the noninferiority of hormonal monotherapy (letrozole) compared to standard platinum-based chemotherapy followed by letrozole maintenance in the frontline treatment of patients with stage II-IV LGSOC. This trial is currently ongoing and has the potential to change the standard of care for LGSOC treatment in the upfront setting.
The use of hormonal therapy in the recurrent setting is supported by clinical benefit demonstrated in one prospective trial and several retrospective studies. The PARAGON study is a prospective, single-arm phase II trial that evaluated the aromatase inhibitor anastrazole in the setting of recurrent/metastatic ER/PR positive LGSOC and serous borderline ovarian tumors. Most patients (34 of 36) enrolled had LGSOC. Treatment was anastrazole 1 mg daily. While ORR was relatively low at 14%, clinical benefit was observed in 61% of patients, with median duration of benefit 9.5 months, and the regimen was well-tolerated [50]. Additionally, in a single-institution retrospective review by Gershenson et al., 64 patients with LGSOC were reported to have received 89 different regimens of hormonal therapy (aromatase inhibitor, selective estrogen receptor modulator, GnRH agonist, progestin, or a combination of these). ORR was again low at 9%, however 62% had stable disease resulting in a clinical benefit rate of 71%. This was most pronounced for those patients with platinum-sensitive recurrence (disease recurrence 6 months or more following last platinum-based chemotherapy), with clinical benefit rate of 83% as compared to 54% for those with platinum-resistant disease. Additionally, time to progression was longer in patients with ER/PR positive tumors, indicating this may be a predictive marker for treatment [19]. As this has not been further validated in prospective studies, clinical consensus recommends against using ER/PR status as a driving factor in decision to treat LGSOC with hormonal therapy [3••].
The optimal hormonal therapy regimen remains unknown for both primary and recurrent disease. However, in GOG 281, patients in the standard of care treatment arm were eligible to receive hormonal therapy in the form of letrozole (2.5 mg daily) or tamoxifen (20 mg twice daily). Those who received letrozole demonstrated a superior response rate of 14% as compared to 0% with tamoxifen use [37••]. Common hormonal therapy regimens utilized in the treatment of LGSOC including class, dosing, cost, common side effects, and medication interactions are included in Table 1.
MEK Inhibitors
LGSOC tumors are characterized by frequent MAPK pathway alterations, including mutations of KRAS (27%), BRAF (13%), and NRAS (9%) [18, 58,59,60,61,62]. This has prompted investigation of mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors, which target a downstream protein kinase of the MAPK pathway, as a potential therapeutic target. Several recent clinical trials have demonstrated improved survival of patients with recurrent LGSOC treated with a MEK inhibitor when compared to standard of care chemotherapy or hormonal therapy. Based on sub-analyses of these studies, whether the presence of a MAPK pathway alteration improves response to MEK inhibitor remains unclear, supporting MEK inhibitor use regardless of mutational status [3••, 37••, 38•, 56, 63•].
In GOG 281/LOGS, a randomized, multicenter, phase II/III clinical trial, Gershenson et al. compared the MEK inhibitor trametinib to standard-of-care chemotherapy or hormonal therapy in patients with recurrent LGSOC. In the standard of care arm, physician’s treatment choice included either paclitaxel, doxorubicin, topotecan, letrozole, or tamoxifen. Those who were randomized to trametinib received 2 mg orally daily until unacceptable toxicity or disease progression. Patients enrolled (n = 260) were divided evenly among treatment arms. Over a median follow-up of 31 months, trametinib was associated with a significant improvement in PFS when compared to standard of care treatment (median PFS 13 vs 7.2 months; HR 0.48; p < 0.001). The benefit of trametinib remained when compared against each treatment type in the standard of care arm separately. Trametinib was associated with an ORR of 26%, and clinical benefit rate of 85%. Notably, only 22% of patients had a KRAS, BRAF, or NRAS mutation in each arm. While patients with a RAS or RAF mutation compared to wild type had a greater ORR to trametinib (ORR 50% versus 8%), this was not statistically significant (p = 0.11), and the study was not powered to detect this difference. Additionally, mutation status was not found to be predictive for PFS (p for interaction 0.72). Together, results of this trial support the benefit of trametinib regardless of MAPK pathway mutational status. Trametinib was relatively well-tolerated when compared to standard of care therapy. The most common grade 3 to 4 adverse events in the trametinib group were rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%), and fatigue (8%) [37••].
Two other clinical trials have evaluated MEK inhibitors in recurrent LGSOC. GOG 239 was a phase II single-arm trial that evaluated selumetinib in patients with recurrent LGSOC with measurable disease. Fifty-two patients received 100 mg twice daily until disease progression or unacceptable toxicity. Selumetinib demonstrated activity with ORR 15.4% and clinical benefit rate 81%. While the treatment regimen was reported to be well-tolerated, 25% of patients discontinued study treatment due to toxicity and grade 3–4 adverse events included cardiac (1), pain (1), pulmonary (1), gastrointestinal (13), dermatologic (9), and metabolic (7). Tumor tissue was available for testing for 34 patients, and BRAF (6%), KRAS (41%), other RAS (21%) mutations were observed. Mutational status was not associated with a significant difference in ORR [56]. MILO/ENGOT-ov11 was a phase III trial where patients with persistent/recurrent LGSOC with measurable disease were randomized 2:1 to binimetinib 45 mg twice daily or physician’s choice chemotherapy (paclitaxel, topotecan, or pegylated liposomal doxorubicin). Three-hundred and three patients were enrolled. At the time of interim analysis, median PFS did not significantly differ between treatment arms (9.1 months binimetinib versus 10.6 months control), resulting in early study closure according to the prespecified futility boundary. Tumor testing was available for analysis for 215 patients, of which 33% had a KRAS mutation, distributed evenly between treatment arms. Interestingly, the presence of a KRAS mutation was associated with improved median PFS when patients were treated with binimetinib (17.7 months vs 10.8 months, p = 0.006), as well as improved ORR (OR 3.4, 95% CI 1.53–7.66), indicating that KRAS mutation may be predictive of response to binimetinib. KRAS mutation in the control arm was not associated with a significant difference in survival [38•]. MEK inhibitor regimens utilized in the treatment of LGSOC including class, dosing, cost, common side effects, and medication interactions are included in Table 1.
Additional research regarding MEK inhibitors in LGSOC is ongoing. RAMP 201 is a phase II randomized trial evaluating the efficacy and safety profile of the MEK inhibitor avutometinib alone or in combination with defactinib, a small molecule inhibitor of focal adhesion kinase (FAK) in patients with recurrent LGSOC. Preliminary data demonstrated a high disease control rate (90% for 8 weeks or longer) for both monotherapy and combination therapy, with both arms having a tolerable safety profile [63•].
Cyclin-dependent Kinase (CDK) 4/6 and PI3KCA Inhibitors
In addition to MAPK pathway alterations, there is data to support involvement of cyclin-dependent kinase (CDK) inhibitor deletion and PIK3CA alterations in the pathogenesis of LGSOC, highlighting another potential therapeutic target [10, 64]. Recent data presented from a pilot phase II trial demonstrated activity of the CDK 4/6 inhibitor abemaciclib in combination with fulvestrant in the neoadjuvant setting for patients with unresectable stage III-IV LGSOC. Patients subsequently underwent interval cytoreductive surgery and received four additional cycles of abemaciclib and fulvestrant, followed by letrozole as maintenance therapy. Cobb et al. enrolled a total of 15 patients: 7 (47%) had a partial response and 5 (33%) had stable disease. Although only a pilot study, this treatment regimen is promising especially in the setting of advanced-stage unresectable disease, in particular given known poor response rate of LGSOC to standard platinum-based neoadjuvant chemotherapy [24, 25, 27•].
Ongoing trials evaluating CDK inhibitors in recurrent LGSOC include GOG 3026 and PARAGON II. GOG 3026 is a phase II trial investigating the CDK 4/6 inhibitor ribociclib in combination with letrozole. Preliminary results reported in March 2023 demonstrated activity of the regimen, with an ORR of 23% and clinical benefit rate of 79%. Overall, the combination was well-tolerated with the most common grade 3 events being neutropenia (44%) and leukopenia (8%) [65]. PARAGON II is a phase II, non-randomized, open-label study that is currently enrolling patients with advanced/recurrent hormone receptor positive gynecologic malignancy. Treatment arms include letrozole with either a CDK4/6 inhibitor (ribociclib) or a PIK3CA inhibitor (alpelisib), and patients are allocated based on PIK3CA mutational status [66].
In the above phase II trial conducted by Cobb et al., abemaciclib was administered at a dose of 150 mg orally twice daily, a dose that has been established as efficacious in hormone-receptor-positive breast cancer [27•, 67]. In both GOG 3026 and PARAGON II, ribociclib is given at 600 mg daily on days 1–21 of a 28 day cycle [68]. Alpelisib is given as an oral tablet 300 mg daily continuously. Side effects of CDK 4/6 inhibitors include but are not limited to fatigue, myelosuppression, nausea, gastrointestinal disturbances, and alopecia. In a large study of hormone-receptor-positive breast cancer with over 3,000 patients, grade three to four adverse events included neutropenia, increased liver transaminases, and QT prolongation [68]. CDK 4/6 inhibitors are a substrate of CYP3A4-mediated metabolism and therefore can interact with all drugs metabolized through this pathway [69, 70]. For abemaciclib, the cost of one 150 mg tablet is $311.44 and for ribociclib the cost is $311.91 to $374.29 for one 200 mg tablet. For alpelisib, the cost of one 150 mg tablet is $437.29. This would amount to $8,720.32 to $47,160.54 for one month of a CDK4/6 inhibitor without consideration of insurance coverage [71].
Emerging Therapies
There are several ongoing phase II/III clinical trials that are studying the efficacy of hormonal therapy, immunotherapy, CDK4/6 inhibitors, MEK inhibitors, and other targeted therapies for patients with LGSOC, both in the first-line and recurrent settings (Table 2). Results of these trials are highly anticipated and have the potential to change the standard of care for LGSOC treatment by replacing cytotoxic chemotherapy with more targeted therapeutic options, particularly in the frontline setting.
Data Availability
No datasets were generated or analysed during the current study.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Matsuo K, Machida H, Grubbs BH, Sood AK, Gershenson DM. Trends of low-grade serous ovarian carcinoma in the United States. J Gynecol Oncol. 2018;29(1):e15.
Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Ame J Obstet Gynecol. 2008;198(4):459.e1-8.
•• 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):1331–44. This reference is of outstanding importance because it provides a very comprehensive report on the pathology, epidemiology, and recommended management of low-grade serous carcinoma based on high-quality evidence and leading expert consensus in the field of gynecologic oncology. Additionally, it provides one of the most thorough descriptions of patient perspectives with regard to the disease and treatment toxicity to date.
• Slomovitz B, Gourley C, Carey M, et al. Low-grade serous ovarian cancer: state of the science. Gynecol Oncol. 2020;156(3):715–25. This reference is of importance because it provides a detailed overview of low-grade serous carcinoma of the ovary, including epidemiology and risk factors, pathology, translational research correlates, and clinical trial information.
Fader AN, Java J, Ueda S, et al. Survival in women with grade 1 serous ovarian carcinoma. Obstet Gynecol. 2013;22(2 Pt 1):225–32.
National Comprehensive Cancer Network. 2023. NCCN clinical practice guidelines in oncology (NCCN Guidelines®) for Guideline Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V.2.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed 1 Oct 2023.
Colombo N, Sessa C, du Bois A, 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. 2019;30(5):672–705.
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):4456–65.
Norquist BM, Brady MF, Harrell MI, 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. 2018;24(4):777–83.
Musacchio L, Califano D, Bartoletti M, et al. Clinical characteristics and molecular aspects of low-grade serous ovarian and peritoneal cancer: a multicenter, observational, retrospective analysis of MITO Group (MITO 22). Br J Cancer. 2022;127(8):1479–86.
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):2675–82.
Schlumbrecht MP, Sun CC, Wong KN, et al. Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma. Cancer. 2011;117(16):3741–9.
Gershenson DM. The life and times of low-grade serous carcinoma of the ovary. Am Soc Clin Oncol Educ Book. 2013;33:e195-199.
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):439–47.
Schmeler KM, Gershenson DM. Low-grade serous ovarian cancer: a unique disease. Curr Oncol Rep. 2008;10(6):519–23.
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):457–62.
Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114(1):48–52.
Cheasley D, Nigam A, Zethoven M, et al. Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities. J Pathol. 2021;253(1):41–54.
Gershenson DM, Sun CC, Iyer RB, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125(3):661–6.
Jones S, Wang TL, Kurman RJ, et al. Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol. 2012;226(3):413–20.
Hunter SM, Anglesio MS, Ryland GL, et al. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget. 2015;6(35):37663–77.
Benedet JL, Bender H, Jones H 3rd, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2000;70(2):209–62.
Chelariu-Raicu A, Cobb LP, Gershenson DM. Fertility preservation in rare ovarian tumors. Int J Gynecol Cancer. 2021;31(3):432–41.
Cobb LP, Sun CC, Iyer R, et al. The role of neoadjuvant chemotherapy in the management of low-grade serous carcinoma of the ovary and peritoneum: Further evidence of relative chemoresistance. Gynecol Oncol. 2020;158(3):653–8.
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):510–4.
Scott SA, Llaurado Fernandez M, Kim H, et al. Low-grade serous carcinoma (LGSC): A Canadian multicenter review of practice patterns and patient outcomes. Gynecol Oncol. 2020;157(1):36–45.
• Cobb LP, Davis J, Hull S, et al. A pilot phase II study of neoadjuvant fulvestrant plus abemaciclib in women with advanced low-grade serous carcinoma. Gynecol Oncol. 2022;158(3):653–8. This reference is of importance because it is a phase II pilot trial that has demonstrated exciting response to neoadjuvant CDK4/6 inhibitor in combination with fulvestrant for patients with advanced low-grade serous carcinoma. While small in number as a pilot study, this provides excitement regarding a neoadjuvant option for patients with advanced/unresectable disease given the classic chemoresistance of low-grade serous ovarian cancer.
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):25–9.
Goldberg RM, Kim SR, Fazelzad R, et al. Secondary cytoreductive surgery for recurrent low-grade serous ovarian carcinoma: A systematic review and meta-analysis. Gynecol Oncol. 2022;164(1):212–20.
Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer. 2006;106(9):1933–9.
Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000;92(9):699–708.
Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.
Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17):3194–200.
Wagstaff AJ, Ward A, Benfield P, et al. Carboplatin. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs. 1989;37(2):162–90.
Dunton CJ. Management of treatment-related toxicity in advanced ovarian cancer. Oncologist. 2002;7(Suppl 5):11–9.
Gordon AN, Stringer CA, Matthews CM, Willis DL, Nemunaitis J. Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: rapid development of neurotoxicity is dose-limiting. J Clin Oncol. 1997;15(5):1965–73.
•• Gershenson DM, Miller A, Brady WE, 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. 2022;399(10324):541–53. This reference is of outstanding importance because it is a phase III clinical trial that demonstrated improved outcomes with the MEK inhibitor trametinib as compared to standard of care cytotoxic chemotherapy or hormonal therapy for patients with recurrent low-grade serous carcinoma of the ovary, leading to significantly longer progression-free survival.
• 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):3753–62. This reference is of importance because it is a randomized clinical trial that compared the MEK inhibitor binimetinib to physicians’ choice chemotherapy for patients with recurrent low-grade serous carcinoma of the ovary. While survival outcomes at interim analysis were not significantly different and led to early trial closure, analysis of tumor tissue led to an understanding of KRAS mutation prevalence in a real-world population, and potential improved response rates to MEK inhibitor use in this setting.
Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928–36.
Gonzalez-Martin A, Gladieff L, Tholander B, et al. Efficacy and safety results from OCTAVIA, a single-arm phase II study evaluating front-line bevacizumab, carboplatin and weekly paclitaxel for ovarian cancer. Eur J Cancer. 2013;49(18):3831–8.
Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8.
Aghajanian C, Blank SV, Goff BA, 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. 2012;30(17):2039–45.
Grisham RN, Iyer G, Sala E, 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.
Rose PG, Mahdi H, Jernigan A, et al. Activity of Bevacizumab in Patients With Low-Grade Serous Ovarian Carcinoma. Int J Gynecol Cancer. 2016;26(6):1048–52.
Dalton HJ, Fleming ND, Sun CC, et al. 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.
Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33):5165–71.
Bevacizumab (including biosimilars): Drug information. In: UpToDate, Connor RF, editors. Wolters Kluwer. https://www.uptodate.com/contents/bevacizumab-including-biosimilars-drug-information?search=bevacizumab&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1. Accessed 1 Oct 2023.
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):1103–11.
Fader AN, Bergstrom J, Jernigan A, et al. Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival? Gynecol Oncol. 2017;147(1):85–91.
Tang M, O’Connell RL, Amant F, et al. PARAGON: A Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors. Gynecol Oncol. 2019;154(3):531–8.
Dowsett M, Cuzick J, Howell A, Jackson I, ATAC Trialists’ Group. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the “Arimidex and tamoxifen alone or in combination” (ATAC) trial. Br J Cancer. 2001;85(3):317–24.
Dowsett M, Tobias JS, Howell A, et al. The effect of anastrozole on the pharmacokinetics of tamoxifen in post-menopausal women with early breast cancer. Br J Cancer. 1999;79(2):311–5.
Tamoxifen: Drug information. In: UpToDate, Connor RF, editors. Wolters Kluwer.
Anastrazole: Drug information. In: UpToDate, Connor RF, editors. Wolters Kluwer.
Binkhorst L, van Gelder T, Loos WJ, et al. Effects of CYP induction by rifampicin on tamoxifen exposure. Clin Pharmacol Ther. 2012;92(1):62–7.
Farley J, Brady WE, Vathipadiekal V, 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.
Dymond AW, So K, Martin P, et al. Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials. Eur J Clin Pharmacol. 2017;73(2):175–84.
Anglesio MS, Arnold JM, George J, et al. Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors. Mol Cancer Res. 2008;6(11):1678–90.
Ho CL, Kurman RJ, Dehari R, et al. Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res. 2004;64(19):6915–8.
Mayr D, Hirschmann A, Löhrs U, et al. 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.
Sieben NL, Macropoulos P, Roemen GM, et al. In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol. 2004;202(3):336–40.
Singer G, Oldt R 3rd, Cohen Y, 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.
• 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. This reference is of importance because it is a phase II trial studying the safety and efficacy of a MEK inhibitor in combination with a FAK inhibitor, and preliminary data has reported excitingly high disease control rate (90% for 8 weeks or longer.
Kuo KT, Guan B, Feng Y, et al. Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas. Cancer Res. 2009;69(9):4036–42.
The Gynecologic Oncology Group (GOG) (2023, March 25). GOG 3026 Press Release. Retrieved October 1, 2023, from: https://www.gog.org/news/gog-3026-press-release/.
NHMRC Clinical Trials Centre at the University of Sydney (2022, May 31). Advanced Gynaecological Cancers: PARAGON-II. Retrieved October 1, 2023, from https://ctc.usyd.edu.au/our-research/research-areas/cancer/cancer-divisions/gynaecological-cancers/open-trials/paragon-ii/.
Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38(34):3987–98.
De Laurentiis M, Borstnar S, Campone M, et al. Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population. Breast Cancer Res Treat. 2021;189(3):689–99.
Abemaciclib: Drug information. In: UpToDate, Connor RF, editors. Wolters Kluwer. https://www.uptodate.com/contents/abemaciclib-drug-information?search=abemaciclib&source=panel_search_result&selectedTitle=1~32&usage_type=panel&kp_tab=drug_general&display_rank=1. Accessed 1 Oct 2023.
Ribociclib: Drug information. In: UpToDate, Connor RF, editors. Wolters Kluwer. https://www.uptodate.com/contents/ribociclib-drug-information?search=ribociclib%20&source=panel_search_result&selectedTitle=1~28&usage_type=panel&kp_tab=drug_general&display_rank=1. Accessed 1 Oct 2023.
Alpelisib: Drug information. In: UpToDate, Connor RF, editors. Wolters Kluwer. https://www.uptodate.com/contents/alpelisib-drug-information?search=alpelisib&source=panel_search_result&selectedTitle=1~16&usage_type=panel&kp_tab=drug_general&display_rank=1. Accessed 1 Oct 2023.
A study evaluating the efficacy and safety of biomarker-driven therapies in patients with persistent or recurrent rare epithelial ovarian tumors (BOUQUET), NCT04931342, ClinicalTrials.gov; 2021. https://classic.clinicaltrials.gov/ct2/show/NCT04931342. Accessed 1 Oct 2023.
Ethics declarations
Conflict of Interest
The authors declare no competing interests.
Human and Animal Rights
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Anna Gonzalez and Christa I. Nagel contributed equally to the publication.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Gonzalez, A., Nagel, C.I. & Haight, P.J. Targeted Therapies in Low-Grade Serous Ovarian Cancers. Curr. Treat. Options in Oncol. 25, 854–868 (2024). https://doi.org/10.1007/s11864-024-01205-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11864-024-01205-4