Abstract
Purpose of Review
This review provides an overview of the current clinical standard in low-grade serous ovarian cancer (LGSOC). The available evidence for surgery and standard treatments is elaborated. In addition, we discuss recent findings and novel treatments for LGSOC.
Recent Findings
Two large multicenter trials studying MEK inhibitors in LGSOC have been presented in the last year. Binimetinib demonstrated an activity in LGSOC, especially in KRAS-mutated disease. Trametinib was associated with an improved progression-free survival in relapsed LGSOC. Based on the current results, MEK inhibitors could be an alternative treatment for LGSOC.
Summary
Surgery is an important step in the treatment of LGSOC. Hormonal therapy and bevacizumab can be beneficial, next to chemotherapy. Targeted treatments, such as the MEK-inhibitor trametinib, seem to be efficient and should be introduced into clinical practice.
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Introduction
Ovarian cancer is the fifth most frequent malignant tumor in women, affecting 1 in 52 women [1, 2]. Up to 90% of ovarian cancers are from epithelial origin [3]. Epithelial ovarian cancers are classified into different subtypes based on histological markers and immunohistochemistry. The most common subtypes are as follows: high-grade serous (70%), low-grade serous (< 5%), high-grade endometrioid, low-grade endometrioid, clear cell, and mucinous carcinomas of the ovary [4]. In 2004, Malpica et al. introduced a two-tier classification system to differentiate between high-grade and low-grade serous ovarian carcinomas (LGSOC) [5]. Based on differences in nuclear atypia and the mitotic rate, LGSOC was identified as a separate entity with specific genetic mutations and clinical behavior [5]. This two-tier classification system was validated retrospectively by the GOG [6]. Between 5 and 8% of ovarian carcinomas are classified as LGSOC [4, 7]. Patients diagnosed with LGSOC are typically younger with a median age at diagnosis of 46.9 years, compared with 63 years for epithelial ovarian cancer in general [8]. In addition, prognosis of LGSOC is favorable, with an estimated 10-year overall survival of 37.3% (95% CI 29.0–45.7) in advanced LGSOC compared with only 15.0% (95% CI 13.9–16.1) for high-grade serous ovarian carcinoma [9].
Diagnosis and Characteristics of LGSOC
Similar to other types of epithelial ovarian cancer, LGSOC can develop de novo and present with vague symptoms such as abdominal discomfort, bloating, dyspnea, dyspepsia, and changes in bowel movement pattern. Alternatively, LGSOC can arise as a malignant transformation of a borderline ovarian tumor [10]. Approximately one-third of patients with a presumed relapse of a borderline tumor turned out to have a malignant transformation [11]. Since 2014, borderline tumors with invasive implants are considered peritoneal LGSOC [12, 13]. In a retrospective cohort, malignant transformation of a borderline tumor accounted for approximately 60% of LGSOC cases [14]. Adequate sampling is crucial in this respect to reduce the number of patients with occult LGSOC classified as a borderline tumor with non-invasive implants [15]. Computer tomography (CT) is commonly used in the staging of LGSOC. Calcified implants are easily recognizable CT features, which are present in 90% of LGSOC [16].
LGSOC is characterized using immunohistochemistry as WT1 positive (95%), p53 wild-type (90%), ER positive (57%), and PR positive (78%) [17]. LGSOC typically present activating mutations in the RAS-RAF-MEK-ERK pathway. KRAS mutations have been described in 24% of LGSOC patients, ranging from 15.8 to 54.4%, BRAF mutations were less frequent with 7.8% (0–32%) of cases, and NRAS mutations were present in 8.3% of LGSOC (3.6–22%) [18•]. Additionally, mutations in PIK3CA, USP9X, EGFR, ESR1, and EIF1AX and low-level copy number alterations have been described [19,20,21]. Van Nieuwenhuysen et al. described loss of 1p36.33 as the most frequent genomic alteration in LGSOC, reflecting a reduction in tumor suppressor activity [18•]. These mutations could identify a specific focus for targeted therapy.
Surgical Management
Surgery is an essential step in the treatment of LGSOC [22]. In presumed early-stage LGSOC surgical staging, including peritoneal biopsies, omentectomy and systematic lymphadenectomy should be performed [23]. Systematic lymphadenectomy should not be omitted in these patients as approximately 20% of T1–2 LGSOC present occult lymph node metastasis [24]. In young patients with FIGO IA or IC1 LGSOC, fertility-preserving surgery can be offered [25, 26]. Assisted reproductive techniques with controlled ovarian stimulation are contraindicated in LGSOC, due to frequent estrogen and progesterone sensitivity [26].
In advanced ovarian cancer, patients should be offered primary debulking surgery. Complete cytoreduction at primary surgery was feasible in 51–65% of patients with LGSOC in retrospective series [27, 28]. The aim of surgery should be no residual disease [29], as a macroscopic complete resection at primary debulking surgery led to a better median overall survival (97 vs 35 months, p < 0.001). However, cytoreduction to residual disease 1–10 mm led to a risk reduction as well (HR 0.514, 95% CI 0.258–1.022) [27]. Patients with a malignant transformation of a borderline tumor should be offered surgery. In a retrospective analysis, complete resection after malignant transformation of a serous borderline tumor was also linked to improved survival [30]. Similar to other histological subtypes of epithelial ovarian cancer, neoadjuvant chemotherapy can be an option in patients with contraindications for primary surgery. If preoperative poor performance status or evidence of unresectable disease is available, the diagnosis should be confirmed histologically and patients are treated with neoadjuvant chemotherapy and considered for interval debulking surgery [31].
The option of secondary surgery should be considered in patients with late relapse (treatment-free interval for platinum-based chemotherapy > 6 months) of LGSOC. Secondary cytoreductive surgery (SCS) in patients with low-grade tumors improved overall survival after first relapse (93.6 after complete resection vs 45.8 months in case of residual disease) if complete resection was achieved (p = 0.04) [32]. A recent retrospective analysis showed a complete resection rate at SCS of 38.1% in low-grade tumors, which was slightly lower than in high-grade tumors (48.3% complete resection) [33]. The lower complete resection rate might be explained by the infiltrative nature of the disease, desmoplastic reaction, and calcifications [32]. However, if SCS seems feasible in relapsed low-grade serous ovarian carcinoma, this option should be discussed with the patient. In patients with third, fourth, or fifth relapse, surgery can be considered on an individual basis. Retrospective series suggest that repeat surgery is feasible and possibly beneficial [34].
Chemotherapy
Adjuvant chemotherapy can be safely omitted in completely staged FIGO IA LGSOC. In completely staged patients with FIGO IB/C LGSOC, the indication for adjuvant chemotherapy should be discussed with the patients. Based on the available evidence from ICON/ACTION, adjuvant chemotherapy can improve survival. In general, adjuvant chemotherapy in early-stage ovarian cancer can improve 5-year overall survival from approximately 74 to 82% (HR 0.67, 95% CI 0.50–0.80, p = 0.008). Subanalysis of well-differentiated carcinomas was also in benefit of adjuvant chemotherapy [35]. From FIGO IIA upwards, adjuvant chemotherapy is recommended [23]. Patients with advanced LGSOC (FIGO III–IV) should be treated with combination chemotherapy: carboplatin-paclitaxel [36]. LGSOC is considered less sensitive to chemotherapy as high-grade serous tumors [37,38,39]. The objective response rate of LGSOC to carboplatin-paclitaxel in first-line setting is reported to be between 23 and 25% [27, 39]. In retrospective series on recurrent LGSOC, objective response rates of 4.9% for platinum-based chemotherapy and 2.1% for platinum-free regimens were reported. Regardless of the objective response rate, more than half of patients achieved stable disease and median time-to-progression was 34.7 and 26.4 weeks respectively [38]. Pegylated liposomal doxorubicin showed promising results with two patients reported to have obtained a complete remission in a retrospective series. In addition, nine patients had a stable disease for a median duration of 9 months [40].
Hormonal Treatment
Based on the known strong hormone receptor positivity and the results of retrospective trials, patients with LGSOC often receive anti-hormonal treatment [41]. Patients with LGSOC can be offered maintenance therapy in accordance with the retrospective series of Gershenson et al. who observed a significant lower risk of relapse in patients who received hormonal treatment (HR 0.44, 95% CI 0.31–0.64, p < 0.001). A trend towards a longer overall survival was longer in patients who were treated with hormonal maintenance therapy (p = 0.056) [42••]. Fader et al. investigated the possibility of a hormonal treatment with tamoxifen, letrozole, or anastrozole in patients who did not receive chemotherapy after debulking surgery. In this study, 22.2% have relapsed after a median follow-up of 41 months. The authors reported a 3-year progression-free survival (PFS) of 79.0%. Median PFS and OS were not reached at the time of publication [43]. In recurrent LGSOC, a retrospective analysis on hormonal treatment (letrozole, anastrozole, tamoxifen, leuprolide, etc.) showed an objective response rate of 9%. In this population, 61.8% of patients achieved stable disease [44]. Paragon was a prospective randomized phase II trial to study the role of anastrozole as a hormonal treatment in hormone receptor–positive (ER and/or PR) recurrent or metastatic LGSOC. An objective response rate of 14% was achieved after 6 months. At this time point, the clinical benefit rate was 61% [45]. These results confirm the activity of aromatase inhibition in relapsed LGSOC.
Anti-angiogenic Treatment
The synergistic effect of bevacizumab in combination with chemotherapy does not seem to be restricted to high-grade tumors. There are no appropriately designed/powered trials to evaluate the use of bevacizumab in first-line setting. In accordance with the current guidelines, LGSOC are treated in parallel to other epithelial ovarian cancer subtypes. The indication for anti-angiogenic treatment is identical [23]. In ICON7, 80 patients with advanced LGSOC were included; the results favored the addition of bevacizumab (HR 0.78, 95% CI 0.31–1.97, p = 0.07) [46]. In relapsed LGSOC, the combination of standard chemotherapy and bevacizumab is a possibly beneficial combination with 5 out of 13 patients achieving a partial remission in a trial by Schmeler et al. [47]. These findings were confirmed in a larger series in which the addition of bevacizumab led to an objective response rate of 47.5% [48]. Case reports have even suggested the activity of bevacizumab as a monotherapy in LGSOC [49, 50].
Targeted Treatment
Oncogenic mutations, such as those in the RAS-RAF-MEK-ERK pathway, can be suitable targets for therapy. Several case reports have demonstrated a potential role for MEK inhibitors in LGSOC [51, 52]. A phase II trial on selumetinib in LGSOC showed stable disease in 65% of patients with an objective response rate of 15% [53]. In addition, a phase Ib study with binimetinib in combination with paclitaxel weekly demonstrated an overall response rate of 14% [54]. The phase III trial on binimetinib (MILO/ENGOT-ov11) showed an objective response rate of 24% with a median PFS of 11.2 months. In this study, patients with a mutation in the RAS-RAF-MEK-ERK pathway had a higher response rate and a longer PFS (17.7 months) [55]. Recently, a randomized phase II/III trial was presented at ESMO 2019 meeting, studying the efficacy of trametinib, a MEK inhibitor, in comparison with standard of care (letrozole, pegliposomal doxorubicin, weekly paclitaxel, tamoxifen, or topotecan) in patients with recurrent LGSOC. In this study, patients treated with trametinib had a median progression-free survival of 13.0 months in comparison with 7.2 months in the control arm (HR 0.48, 95% CI 0.36–0.64, p < 0.0001) [56••]. An association between KRAS mutations and response to MEK inhibitor treatment has been observed; in addition, EGFR activity might lead to resistance to MEK inhibitors. Patients with known KRAS mutations would be good candidates for MEK inhibitor treatment, while patients with a EGFR mutation might not benefit from this therapy approach [57].
Conclusion
LGSOC is a relatively rare subtype of ovarian cancer, which is only partially sensitive to standard chemotherapy. Surgery plays an important role in the treatment of LGSOC, but systemic treatments are becoming increasingly important. Through extensive studies on the biology of LGSOC novel targets are discovered. The results of trametinib in recurrent LGSOC are very encouraging. We hope that in the future, studies will define novel treatment strategies for LGSOC.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Ferlay J, Steliarova-foucher E, Lortet-tieulent J, Rosso S. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374–403.
Cancer Research UK [Internet]. [cited 2018 Feb 1]. Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ovarian-cancer#heading-Zero
Ries LAG, Young JL, Keel GE, Eisner ME, Lin YD, Horner MJD. Cancer survival among adults: US SEER program, 1988-2001. SEER Surviv Monogr. 2007;07:1988–2001.
Prat J, D’Angelo E, Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular. Hum Pathol. 2018;80:11–27.
Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28(4):496–504.
Bodurka DC, Deavers MT, Tian C, Sun CC, Malpica A, Coleman RL, et al. Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group study. Cancer. 2012;118(12):3087–94.
Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol. 2008;198:459.e1–9.
Gershenson DM, Sun CC, Wong KK. Impact of mutational status on survival in low-grade serous carcinoma of the ovary or peritoneum. Br J Cancer. 2015;113(9):1254–8.
Peres LC, Cushing-haugen KL, Ko M, Harris HR, Berchuck A, Rossing MA, et al. Invasive epithelial ovarian cancer survival by histotype and disease stage. JNCI J Natl Cancer Inst. 2019;111(May 2018):1–9.
Kurman RJ, Shih IM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34(3):433–43.
du Bois A, Ewald-riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, et al. Borderline tumours of the ovary: a cohort study of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group. Eur J Cancer. 2013;49:1905–14.
Hauptmann S, Friedrich K, Redline R, Avril S. Ovarian borderline tumors in the 2014 WHO classification: evolving concepts and diagnostic criteria. Virchows Arch. 2017;470(2):125–42.
Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumours of female reproductive organs. IACR Publications; 2014.
Wong KK, Gershenson D. The continuum of serous ovarian tumors of low malignant potential and low-grade serous carcinoma of the ovary. Dis Markers. 2007;23(2007):377–87.
Seidman JD, Savage J, Krishnan J, Vang R, Kurman RJ. Intratumoral heterogeneity accounts for apparent progression of noninvasive serous tumors to invasive low-grade serous carcinoma: a study of 30 low-grade serous tumors of the ovary in 18 patients with peritoneal carcinomatosis. Int J Gynecol Pathol. 2018;00:1–12.
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. Am J Radiol. 2018;210(April):918–26.
Leskela S, Romero I, Cristobal E, Pérez-mies B, Rosa-rosa JM, Gutierrez-pecharroman A, et al. The frequency and prognostic significance of the histologic type in early-stage ovarian carcinoma: a reclassification study by the Spanish Group For Ovarian. Am J Surg Pathol. 2019;00(00):1–13.
Van Nieuwenhuysen E, Busschaert P. Loss of 1p36.33 frequent in low-grade serous ovarian cancer. Neoplasia. 2019;21(6):582–90 Paper describing the identification of 1p36.33 loss as the most commmon mutation in low-grade serous ovarian cancer, thus reduction of tumor suppressor activity pointing to a possible focus of targeted therapies.
Jones S, Wang T, Kurman RJ, Nakayama K, Velculescu VE, Vogelstein B, et al. Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol. 2012;226:413–20.
Hunter SM, Anglesio MS, Ryland GL, Sharma R, Chiew Y, Rowley SM, et al. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget. 2015;6(35):37663–77.
Stover E, Feltmate C, Berkowitz RS, Lindeman NI, Matulonis UA, Konstantinopoulos PA. Targeted next-generation sequencing reveals clinically actionable BRAF and ESR1 mutations in low-grade serous ovarian carcinoma. JCO Precis Oncol. 2018;2:1–8.
Ricciardi E, Ataseven B, Heitz F, Prader S, Bommert M, Schneider S, et al. Low-grade serous ovarian carcinoma Low-grade seröse Ovarialkarzinome: a key role for primary cytoreductive surgery in LGSOC. Geburtshilfe Frauenheilkd. 2018;78:972–6.
Colombo N, Sessa C, du Bois A, Ledermann JA, Mccluggage WG, Mcneish IA, et al. ESMO – ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, special article. Ann Oncol. 2019;30(May):672–705.
Heitz F, Harter P, Ataseven B, Heikaus S, Schneider S, Prader S, et al. Stage- and histologic subtype-dependent frequency of lymph node metastases in patients with epithelial ovarian cancer undergoing systematic pelvic and paraaortic lymphadenectomy. Ann Surg Oncol. 2018;25(7):2053–9.
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.
Adda-herzog E, Rousset-jablonski C, Selleret L, Pomel C, Daraı E, Chabbert-buffet N, et al. Fertility preservation , contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers. Eur J Cancer. 2019;116:35–44.
Grabowski JP, Harter P, Heitz F, Pujade-Lauraine E, Reuss A, Kristensen G, 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.
Bogani G, Leone U, Maggiore R, Paolini B, Diito A, Martinelli F, et al. The detrimental effect of adopting interval debulking surgery in advanced stage low-grade serous ovarian cancer. J Gynecol Oncol. 2019;30(1):1–9.
du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials. Cancer. 2009;115(6):1234–44.
Crispens MA, Bodurka D, Deavers M, Lu K, Silva EG, Gershenson DM. Response and survival in patients with progressive or recurrent serous ovarian tumors of low malignant potential. Obstet Gynecol. 2002;99(1):3–10.
du Bois A, Baert T, Vergote IB. Role of neoadjuvant chemotherapy in advanced epithelial ovarian cancer. J Clin Oncol. 2019;37(27):2398–405.
Crane EK, Sun CC, Ramirez PT, Schmeler KM, Malpica A, Gershenson DM. The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer. Gynecol Oncol. 2015;136(1):25–9.
Canaz E, Grabowski JP, Richter R, Braicu EI, Chekerov R, Sehouli J. Gynecologic oncology survival and prognostic factors in patients with recurrent low-grade epithelial ovarian cancer: an analysis of five prospective phase II/III trials of NOGGO metadata base. Gynecol Oncol. 2019;154(xxxx):539–46.
Falcone F, Scambia G, Benedetti Panici P, Signorelli M, Cormio G, Giorda G, et al. Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer: a multicentre MITO retrospective study. Gynecol Oncol. 2017;147(1):66–72.
Colombo N, Guthrie D, Chiari S, Parmar M, Qian W, Swart AM, et al. International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm Trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst. 2003;95(2):125–32.
Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(SUPPL.6).
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.
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.
Schmeler KM, Sun CC, Bodurka DC, T. Deavers M, Malpica A, Coleman RL, et al. Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2008;108:510–4.
Rose PG, Radeva M, Michener CM, Link N, Adbul-Karim F. Efficacy of pegylated liposomal doxorubicin in low-grade serous ovarian carcinoma. Int J Gynecol Cancer. 2017;27(5):907–11.
Escobar J, Klimowicz AC, Dean M, Chu P, Nation JG, Nelson GS, et al. Quantification of ER/PR expression in ovarian low-grade serous carcinoma. Gynecol Oncol. 2013;128(2):371–6.
Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35(10):1103–11 Retrospective single-center analysis demonstrating that hormonal maintenance therapy (HMT) in women with low-grade serous ovarian cancer after debulking surgery and standard chemotherapy has an PFS benefit.
Fader AN, Bergstrom J, Jernigan A, Tanner EJ, Roche KL, Stone RL, 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.
Gershenson D, Sun C, Lyer R, Wong K, Kavanagh J, Malpica A, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125(s3):s35.
Tang M, Connell RLO, Amant F, Beale P, Mcnally O, Sjoquist KM, 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.
Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, 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.
Schmeler K, Tao X, Sun C, Malpica A, Deavers M, Sood A, et al. Encouraging responses with bevacizumab in recurrent low-grade serous ovarian cancer. J Clin Oncol. 2010;28(15):Suppl S.
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.
Rose PG, Mahdi H, Jernigan A, Yang B. Activity of bevacizumab in patients with low-grade serous ovarian carcinoma. Int J Gynecol Cancer. 2016;26(6):1048–52.
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.
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.
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(1):1–5.
Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, 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.
Grisham RN, Moore KN, Gordon MS, Harb W, Cody G, Halpenny DF, et al. 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;24(22):5525–33.
Grisham RN, Monk BJ, Banerjee S, Coleman RL, Oza A. MILO/ENGOT-ov11: phase-3 study of binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. In: IGCS. 2019.
Gershenson DM, Miller A, Brady W, Paul J, Carty K, Rodgers W, et al. A randomized phase II / III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer. Ann Oncol. 2019;30(Suppl_5):mdz394.058 Randomized phase II/III trial that showed that the MEK-inbitor trametinib has a significant OS and PFS benefit in women with recurrent low-grade serous ovarian cancer when compared with standard of therapy.
Fernandez ML, Dawson A, Hoenisch J, Kim H, Bamford S, Salamanca C, et al. Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target. Cancer Cell Int. 2019;19(10):1–17.
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Nina Pauly declares that she has no conflict of interest.
Sarah Ehmann has received non-financial research support from Tesaro.
Enzo Ricciardi declares that he has no conflict of interest.
Beyhan Ataseven has received non-financial research support from Roche, Tesaro, and PharmaMar, and has received compensation from Roche, Amgen, AstraZeneca, Tesaro, Clovis Oncology, and Celgene for service as a consultant.
Mareike Bommert declares that she has no conflict of interest.
Florian Heitz has received non-financial research support from Tesaro and AstraZeneca, and has received compensation from Roche, Tesaro, PharmaMar, and AstraZeneca for service as a consultant.
Sonia Prader declares that she has no conflict of interest.
Stephanie Schneider has received non-financial research support from Tesaro and PharmaMar, and has received compensation from Roche, Tesaro, Clovis Oncology, and AstraZeneca for service as a consultant.
Andreas du Bois has received compensation from Roche, AstraZeneca, BIOCAD, Genmab, Clovis Oncology, Tesaro, PharmaMar, and Pfizer for service as a consultant.
Philipp Harter has received research funding from Tesaro, GlaxoSmithKline, Boehringer Ingelheim, Medac Pharma, Genmab, AstraZeneca, Roche, the American Society of Clinical Oncology, Deutsche Krebshilfe, and Deutsche Forschungsgemeinschaft; and has received compensation from Sotio, Tesaro, Stryker, Zai Lab, MSD, Clovis Oncology, ImmunoGen, AstraZeneca, Roche, the American Society of Clinical Oncology, Deutsche Krebshilfe, and Deutsche Forschungsgemeinschaft for service as a consultant.
Thaïs Baert has received research funding from Amgen, has received non-financial research support from Roche and Amgen, and has received compensation from Tesaro for service as a consultant.
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Pauly, N., Ehmann, S., Ricciardi, E. et al. Low-grade Serous Tumors: Are We Making Progress?. Curr Oncol Rep 22, 8 (2020). https://doi.org/10.1007/s11912-020-0872-5
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DOI: https://doi.org/10.1007/s11912-020-0872-5