Article Text
Abstract
Low-grade serous ovarian cancer is a rare subtype of epithelial ovarian cancer clinically characterized by younger age at diagnosis, relative chemoresistance, and prolonged survival compared with its high-grade serous counterpart. It is molecularly characterized by estrogen and progesterone receptor positivity, aberrations in the MAPK (mitogen-activated protein kinase) pathway, and wild-type TP53 expression pattern. As research into low-grade serous ovarian cancer as a distinct entity has been able to accelerate independently, we have learned more about its unique pathogenesis, oncogenic drivers, and opportunities for novel therapeutics. In the primary setting, cytoreductive surgery in combination with platinum-based chemotherapy remain the standard of care. However, low-grade serous ovarian cancer has demonstrated relative chemoresistance in the primary and recurrent settings. Endocrine therapy is also commonly utilized in the maintenance and recurrent settings and is being evaluated in the adjuvant setting. Given the many similarities of low-grade serous ovarian cancer to luminal breast cancer, many recent studies have utilized similar therapeutic strategies including endocrine therapy combinations with CDK (cyclin-dependent kinase) 4/6 inhibitors. Additionally, recent trials have investigated combination therapies targeting the MAPK pathway, including MEK (mitogen-activated protein kinase kinase), BRAF (v-raf murine sarcoma viral oncogene homolog B1), FAK (focal adhesion kinase), and PI3K (phosphatidylinositol 3-kinase) inhibition. In this review, we will outline these novel therapeutic strategies for low-grade serous ovarian cancer.
- Ovarian Cancer
- Gynecology
- Cystadenocarcinoma, Serous
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Introduction
Low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum is a rare histologic subtype of epithelial carcinoma and is a histologically, molecularly, and clinically distinct entity from its high-grade serous counterpart. Low-grade serous carcinomas comprise approximately 2.05% of all epithelial ovarian carcinomas and 4.66% of serous ovarian cancers based on a recent study of trends in the Surveillance, Epidemiology, and End Results (SEER) database.1 This represents a decrease in the proportion of low-grade serous ovarian cancers over time, possibly due to the increase in diagnosis of borderline ovarian tumors that may have been previously considered carcinomas, stricter pathologic guidelines for diagnosing low-grade serous carcinomas, or the aging population with an increased proportion of high-grade serous diagnoses, thus leading to a relatively decreased incidence of low-grade cancers.
Generally low-grade serous cancers are characterized by younger age at diagnosis, relative chemo-resistance, and prolonged overall survival compared with high-grade serous cancer.2 As we now understand this disease as a separate entity, investigation and understanding of low-grade serous carcinoma of the ovary has been able to accelerate separately. In this article, we will review novel therapies as well as ongoing trials for the treatment of this disease.
Histology and Molecular Biology
Historically, serous ovarian cancer was classified as grade 1, 2, or 3.3 With the seemingly separate pathogenesis of low-grade from high-grade serous ovarian cancer, a simpler binary grading system was developed, with a new characterization of serous ovarian cancers as high- versus low-grade. This new grading system is based primarily on the assessment of nuclear atypia, with mitotic rate used as a secondary feature. Tumors with mild to moderate cytologic atypia are designated as low-grade, whereas tumors with marked cytologic atypia are designated as high-grade. Low-grade tumors tend to have a lower mitotic rate (usually up to 12 mitoses per 10 high-power fields (HPFs)). In contrast, high-grade tumors have conspicuous mitotic activity (>12 mitoses per 10 HPFs) and multinucleated cells. This system was subsequently validated, and inter- and intra-observer reproducibility was demonstrated.4 5
Multiple studies have highlighted the similarities between luminal breast cancer and low-grade serous ovarian cancers. The majority of low-grade serous ovarian cancers are positive for estrogen receptors (ER), and some are also positive for progesterone receptors (PR).6 Additionally, like luminal breast cancer, endocrine therapy seems to provide clinical benefit in the majority of recurrences,7 and worse outcomes are seen when diagnosed at a younger age.2 7
In addition to ER and PR positivity, many low-grade serous ovarian cancers have positive nuclear staining for PAX8 (paired-box gene 8) and WT1 (Wilms’ tumor gene 1). Unlike their high-grade serous counterparts, low-grade serous cancers usually demonstrate a wild-type p53 expression pattern.8 Additionally, the MAPK (mitogen-activated protein kinase) pathway is important in its pathogenesis. Specifically, KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations are seen in approximately 20–40%, and BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations are seen in 2–6% of low-grade serous ovarian cancers.9–12 While the National Comprehensive Cancer Network guidelines recommend germline testing for all patients diagnosed with epithelial ovarian cancer, low-grade serous carcinomas do not appear to be associated with hereditary breast and ovarian cancer syndrome,13 and demonstrate reduced germline mutation frequency in classically mutated genes in ovarian cancer such as BRCA1 and BRCA2.13 14
Clinical Management
Cytoreductive Surgery
As in all histologic subtypes of ovarian cancer, cytoreductive surgery is a mainstay of treatment followed by platinum/taxane chemotherapy, with increasing survival correlating with decreasing residual disease. This was demonstrated in an ancillary analysis of Gynecologic Oncology Group (GOG) protocol 182, a phase III randomized trial of paclitaxel and carboplatin versus triplet or sequential doublet combinations in patients with epithelial ovarian or primary peritoneal carcinoma. This trial included a subset of 189 patients with low-grade serous disease. For patients with low-grade serous cancer, only residual disease was significantly associated with survival (overall survival of 96.9 months, 44.5 months, and 42.0 months in patients with no gross residual disease, <1 cm residual disease, and >1 cm residual disease, respectively). This highlights the importance of maximal effort during cytoreductive surgery in women with low-grade serous ovarian cancer.15
In the recent consensus recommendations from the Gynecologic Cancer InterGroup (GCIG), it is recommended that for chemotherapy-resistant histologies such as low-grade serous ovarian cancer, primary cytoreductive surgery is preferred over neoadjuvant chemotherapy followed by interval cytoreductive surgery, even if a complete resection is questionable.16 The authors of this article agree with the importance of maximal cytoreductive effort for this disease; however, it is reasonable to attempt neoadjuvant therapy in patients with extensive tumor burden in an effort to reduce significant morbidity. A pilot trial exploring an alternative neoadjuvant therapy with CDK4/6 inhibition and endocrine therapy will be addressed later in this article.
In the recurrent setting, secondary cytoreduction should be considered as well. While the utility of secondary cytoreduction remains controversial for high-grade serous carcinomas, there is a survival benefit when complete gross resection or optimal resection is achieved. This was shown in a recent systematic review and meta-analysis performed by Goldberg and colleagues.17 In this analysis, nine studies were included in the systematic review and two were included in the meta-analysis for progression-free survival and overall survival. In patients with recurrent low-grade serous ovarian cancer, complete gross resection of disease significantly improved overall survival (HR 0.4, 95% CI 0.23 to 0.7).17
Relative Chemoresistance to Chemotherapy
Unfortunately, low-grade serous cancers have demonstrated relative chemo-resistance in multiple clinical settings: primary adjuvant therapy, neoadjuvant chemotherapy, and therapy for recurrent disease.
Response of low-grade serous ovarian cancer to adjuvant therapy was evaluated by Grabowski and colleagues in an exploratory case–control study of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) metadatabase of four randomized phase III trials with first-line platinum combination therapy.18 Patients with advanced International Federation of Gynecology and Obstetrics (FIGO) stage IIIB to IV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous ovarian cancer. Thirty-nine low-grade serous ovarian cancer patients in this database underwent suboptimal debulking with residual disease >1 cm, thus being eligible for response evaluation. The objective response rate for these patients was only 23.1%, which was significantly lower than that seen in the control cohort of high-grade serous ovarian cancer patients with a response rate of 90.1%.18
Chemoresistance in the neoadjuvant setting for low-grade serous ovarian cancer was first evaluated by Schmeler and colleagues with a retrospective review of 24 patients treated between 1989 and 2006.19 In this study, only one patient (4%) demonstrated complete response, 21 (88%) had stable disease, and two (8%) had disease progression following neoadjuvant chemotherapy.19 We have recently published our update to these data in a group of 36 patients with only five patients overlapping with Schmeler’s original study.20 We matched these patients to high-grade serous ovarian cancer patients undergoing neoadjuvant chemotherapy. The objective response rate was still quite low in this updated study with only four patients (11%) demonstrating partial response.20
The response rates of recurrent low-grade serous carcinoma to chemotherapy are perhaps the least promising of all. In a retrospective review of 58 patients who received 108 separate chemotherapy regimens in the recurrent setting, only one complete response and three partial responses were seen (overall response rate 3.7%). Notably, the response rate for the platinum-sensitive cohort was slightly better at 4.9% than for the platinum-resistant cohort (2.1%). Stable disease was observed in 65 (60.2%) and progressive disease was observed in 39 (36.1%) of 108 patient-regimens.21 These low responses to chemotherapy underscore the need for more effective therapies for the treatment of low-grade serous carcinoma.
Endocrine Therapy
While response rates to endocrine therapy alone in the recurrent setting are relatively low, it is quite tolerable with demonstrated clinical benefit. In a retrospective study by Gershenson et al of 64 patients with recurrent low-grade serous ovarian cancer, 89 different hormonal patient-regimens were described.22 In this study, the overall response rate was 9% (six responses to letrozole were observed, one to anastrazole, and one to tamoxifen). Additionally, progression-free survival duration was noted to be at least 6 months in 61% of the patient-regimens.22 In the PARAGON phase II study performed by Tang and colleagues, the clinical benefit rate of anastrazole was investigated in patients with estrogen and/or progesterone receptor-positive recurrent low-grade serous (n=34) and low-grade endometrioid (n=2) carcinomas.23 A partial response was seen in five patients (14%) and clinical benefit was observed in 23 patients (64%) at 3 months and 61% at 6 months.23 See Table 1 for a summary of clinical trials in low-grade serous ovarian cancer.
Given the similarities of low-grade serous ovarian carcinomas to luminal breast cancer, the utilization of hormonal maintenance strategies in hormone receptor-positive breast cancer, and the clinical benefit seen in the recurrent low-grade serous cancers, Gershenson and colleagues reported a retrospective study of patients with low-grade serous ovarian cancer who received hormonal maintenance therapy following primary platinum-based chemotherapy (n=70) compared with those who were observed following chemotherapy (n=133).7 While there are no data guiding the duration of hormonal maintenance therapy, in this study, median duration was 33.3 months (range 1–223.2 months). Median progression-free survival was significantly higher for patients receiving hormonal maintenance therapy (64.9 months) compared with patients undergoing observation (26.4 months).7 In light of these promising results, a phase III randomized trial evaluating maintenance hormonal therapy is currently enrolling (MAintenance Therapy With Aromatase Inhibitor in Epithelial Ovarian Cancer (MATAO) trial, NCT04111978). Despite a lack of evidence, the current consensus is for maintenance endocrine therapy to be continued indefinitely, until disease progression or unacceptable toxicity.24
Endocrine therapy alone has been evaluated in the adjuvant setting as well. Fader and colleagues performed a retrospective study of 27 patients with stages II to IV low-grade serous ovarian cancer who underwent primary or interval cytoreductive surgery followed by adjuvant hormonal therapy without chemotherapy.25 Optimal cytoreduction with complete gross resection was accomplished in 85.2% of the patients in this group. After a median follow-up of 41 months, only six patients (22%) had relapsed and median progression-free survival and overall survival had not been reached. Based on these promising data, a randomized phase III trial evaluating adjuvant paclitaxel/carboplatin followed by maintenance letrozole versus adjuvant letrozole monotherapy alone in stage II–IV low-grade serous carcinoma was initiated and is currently enrolling (NRG-GY019, NCT04095364).
Other endocrine agents are also actively being studied. A basket study of an oral progesterone antagonist, onapristone extended release, is being evaluated with or without anastrazole in progesterone receptor-positive recurrent granulosa cell tumor, low-grade serous ovarian cancer or endometrioid endometrial cancer (NCT03909152).
Endocrine Therapy Combinations
As previously discussed, low-grade serous carcinoma of the ovary, fallopian tube, and peritoneum has many similarities to luminal breast cancer. CDK 4/6 inhibitors play a key role in cell cycle progression and have been extensively studied in combination with endocrine therapy in hormone receptor-positive metastatic breast cancer.26–32 Estrogen receptor increases amplification of D-cyclins which then deregulate the CDK4/6 pathway, making this a rational target for this disease. Specifically, the CDK4/6 inhibitors ribociclib, abemaciclib, and palbociclib have been evaluated with fulvestrant and non-steroidal aromatase inhibitors in randomized phase III trials of hormone receptor-positive metastatic breast cancer and have demonstrated significant survival benefit.26–32 Given this significant benefit, a phase II study of ribociclib with letrozole is enrolling for recurrent low-grade serous ovarian cancer (GOG 3026, NCT03673124).
A similar combination is also being explored in the neoadjuvant setting. A phase II pilot study of neoadjuvant abemaciclib with fulvestrant for patients with unresectable stage III or IV low-grade serous ovarian, fallopian tube, or primary peritoneal cancer (NCT03531645) has completed enrollment, and results were presented at the American Society of Clinical Oncology annual meeting 2022. At the time of analysis, nine of 15 patients (60%) had achieved a complete or partial response to neoadjuvant therapy. Of the seven patients who had undergone debulking surgery, all achieved optimal cytoreduction and 5/7 (71%) had complete gross resection of disease. These results are unprecedented for low-grade serous ovarian cancer and are promising for the use of future similar combinations.
PARAGON II is a phase II basket study of an aromatase inhibitor plus PI3K (phosphatidylinositol 3-kinase) inhibitor or CDK4/6 inhibitor in women with hormone receptor-positive recurrent/metastatic gynecologic malignancies. This study is currently enrolling in Australia and New Zealand (ACTRN12621000639820). The trial builds on the aforementioned PARAGON study of single agent anastrazole and evaluates if the combination treatment of letrozole plus alpelisib (PI3K inhibitor), and letrozole plus ribociclib will lead to an increase in overall response as compared with historical controls from the PARAGON trial in hormone receptor-positive advanced gynecologic cancers that are either PIK3CA-mutated or PIK3CA non-mutated.
Endocrine therapy in combination with bevacizumab or MEK (mitogen-activated protein kinase kinase) inhibition will be covered later in this review.
Anti-angiogenic Inhibitors
Significant responses have been reported in patients with recurrent low-grade serous carcinoma treated with bevacizumab. In a retrospective study by Grishham and colleagues at Memorial Sloan Kettering between 2005 and 2012, 17 patients with recurrent low-grade serous ovarian or peritoneal cancer or recurrent serous borderline tumor were evaluated.33 Two received single-agent bevacizumab, and the remainder received bevacizumab in combination with chemotherapy. Fourteen of 17 patients had low-grade ovarian or peritoneal disease rather than borderline disease. The overall response rate was 40%, with a response rate of 55% among the subgroup of patients with low-grade serous cancer.33
Dalton and colleagues also demonstrated activity of bevacizumab in recurrent low-grade serous carcinoma in a retrospective study of 40 patients treated at MD Anderson from 2007 to 2016.34 These 40 patients received 45 separate ‘patient-regimens’. Most patients received bevacizumab in combination with chemotherapy. The overall response rate was 47.5% and an additional 30% achieved stable disease.34
Both studies demonstrate that bevacizumab, most often in combination with chemotherapy, has activity in recurrent low-grade ovarian cancer and should be considered a treatment option for these patients. While these retrospective studies did not compare bevacizumab with chemotherapy to chemotherapy alone, bevacizumab with chemotherapy seems to have significantly better outcomes than the response rates of 2–5% with chemotherapy alone.
Bevacizumab with endocrine therapy is an interesting concept that warrants exploration in low-grade serous ovarian cancer. In patients with hormone receptor-positive metastatic breast cancer, results are conflicting. The LEA (letrozole/fulvestrant and Avastin) study did not demonstrate improvement in progression-free survival or overall survival with the addition of bevacizumab in first-line treatment of patients with hormone receptor-positive metastatic breast cancer.35 However, a similar study of letrozole with or without bevacizumab in this breast cancer population did demonstrate improvement in progression-free survival with the combination.36 In an attempt to increase precision in the estimation of treatment effect, a pooled analysis was performed of these two randomized trials and demonstrated a progression-free survival benefit but not overall survival benefit with the combination.37 Not surprisingly, the combination did demonstrate more grade 3 and 4 toxicities related to bevacizumab than endocrine therapy alone.37
MEK Inhibitors
As previously mentioned, it has been well-established that low-grade serous carcinoma harbors several aberrations in genes that activate the MAPK pathway and likely represents a ‘driver’ event for low-grade tumors. Multiple pharmaceutical agents have been developed to target this pathway.
The first prospective trial of MEK inhibition performed exclusively in low-grade serous ovarian cancer was a phase II study of 52 women with recurrent low-grade serous ovarian or peritoneal carcinoma treated with the MEK inhibitor selumetinib (GOG-0239, NCT00551070).38 In this study, an objective response was seen in 8/52 patients (15.4%) with one complete response (2%) and seven partial responses (13%). Sixty-five percent of patients had stable disease with a clinical benefit rate of 80%. There were also no statistically significant differences in the proportion of patients with complete or partial responses for either BRAF or KRAS mutations. This study suggested that selumetinib was well tolerated and active in the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum, and perhaps inhibitors of the MAPK pathway warranted further investigation in these patients.38
The MEK Inhibitor in Low-Grade Serous Ovarian Cancer (MILO)/European Network for Gynecological Oncological Trial (ENGOT)-ov11 was an international randomized phase III trial of over 300 patients with measurable recurrent or persistent low-grade serous cancer, randomized to receive either binimetinib (MEK162) or physician’s choice chemotherapy of pegylated liposomal doxorubicin, paclitaxel, or topotecan.39 This study was closed early when planned interim analysis demonstrated the progression-free survival hazard ratio crossed the predefined futility boundary. Median progression-free survival was 9.1 months for binimetinib and 10.6 months for physician’s choice chemotherapy.39
Grisham and colleagues performed a post-hoc tumor tissue biomarker analysis utilizing Foundation Medicine on archival tissue collected prior to randomization on MILO/ENGOT-ov11.40 In patients harboring a mutation in the MAPK pathway (KRAS, NRAS, BRAFV600E, RAF1, and NF1) the response rate was higher than those without a MAPK mutation (41% vs 13%). Progression-free survival was also improved for patients with a MAPK mutation versus those without a MAPK mutation who received binimetinib (HR 0.5, 95% CI 0.31 to 0.79, p=0.003). These data were presented at the American Society of Clinical Oncology annual meeting in 2021. While these data are hypothesis generating at this point, it does suggest that biomarker analysis of low-grade serous ovarian cancer may be useful for decision analysis when using MAPK pathway targeting agents in the future.40
A similar phase II/III study, GOG 281, investigated the efficacy of a different MEK inhibitor, trametinib, compared with physician’s choice standard of care of letrozole, tamoxifen citrate, paclitaxel, pegylated liposomal doxorubicin, or topotecan in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer.41 Unlike MILO/ENGOT-ov11, GOG 0281 met its primary end point, with a median progression-free survival of 13.0 months for trametinib and 7.2 months for physician’s choice standard of care (HR 0.48, 95% CI 0.36 to 0.64, p<0.001). The objective response rate for trametinib was 26% and for physicians’ choice was 6.2%.41 It is unclear why the primary endpoint was met for GOG 0281 but was not for MILO/ENGOT-ov11. It is possible that the physicians’ choice chemotherapy arm in MILO/ENGOT-ov11 had a better than anticipated outcome (median progression-free survival of 10.6 months vs expected median progression-free survival of 7 months), resulting in failure to demonstrate a benefit. While we cannot directly compare the arms of these trials, the improved outcome in the control arm of MILO/ENGOT-ov11 could have been related in part to patients having received fewer prior chemotherapy regimens, and therefore possibly having an improved prognosis as compared with the physician’s choice standard of care arm of GOG 281. Only 28% of patients in MILO/ENGOT-ov11 received greater than or equal to three prior chemotherapy regimens, while 48% of patients in GOG 281 had at least three prior chemotherapy regimens. It is also possible that trametinib has greater efficacy than binimetinib. In a preclinical study of molecularly characterized low-grade serous ovarian cancer cell lines, trametinib had the greatest anti-proliferative effects and was most capable of inducing apoptosis relative to selumetinib, binimetinib, and refametinib.42
BRAF Inhibitors
As previously mentioned, a small percentage of low-grade serous ovarian cancers harbors mutations in BRAF. In a phase II basket study of vemurafenib (a BRAF inhibitor) in BRAF V600E mutation-positive non-melanoma cancers, one patient with a BRAF mutated low-grade serous ovarian cancer had a durable partial response for over 12 months.43 A case report describes a similar durable response,44 suggesting that this warrants further investigation in BRAF mutated low-grade serous malignancies.
MEK Inhibitor Combination Therapies
Combination therapy with inhibition of BRAF and MEK allows for targeting of two steps in the MAPK pathway and has become a standard of care option in BRAF V600E mutated metastatic melanomas.45 46 These combinations have been shown to be effective in several other cancers (including non-small cell lung cancer and thyroid cancer) but less effective in others (including BRAF-mutant colon cancer), suggesting that response is partially histology dependent. In the NCI-MATCH Trial Subprotocol H, 35 patients with solid tumors harboring BRAF V600E mutation were treated with the BRAF inhibitor, dabrafenib, 150 mg twice daily and the MEK inhibitor, trametinib, 2 mg per day.47 Five of the 29 patients on this trial had low-grade serous ovarian cancer. Of these five patients, four (80%) had a partial response and one had stable disease. All four patients had prolonged progression-free survival (24.4 months (still progression-free at time of data cut-off), 25.1 months, 13.8 months, and 10.7 months). Among all solid tumors included in the study, objective response rate was 38% and progression-free survival was 11.4 months.47
Based on these promising results, as well as findings from patients enrolled in other open label cohort trials including the BRF117019 (NCT02034110), NCI-MATCH (NCT02465060), and CTMT212×2101 (NCT02124772), and supported by results in COMBI-d, COMBI-v, and BRF113928 trials, the Food and Drug Administration approved dabrafenib and trametinib on June 22, 2022 for the treatment of unresectable or metastatic solid tumors with BRAF V600E mutations in patients who have progressed following prior treatment and have no satisfactory alternative treatment options. Even though only a small proportion of patients with low-grade serous ovarian cancer harbor this mutation, this combination should certainly be considered when a BRAF V600E mutation is present.
The combination of RAF with MEK inhibition is being explored with other compounds as well. A phase I trial evaluating the safety and pharmacokinetics of BGB-283 (lifirafenib, RAF inhibitor) and PD-0325901 (mirdametinib, MEK inhibitor) in patients with advanced or refractory solid tumors is underway (NCT03905148).
Even with vertical inhibition of different steps in the same pathway (MEK inhibitor+BRAF inhibitor), responses are still variable, and drug and resistance mechanisms still develop. One strategy to possibly overcome resistance is utilization of a focal adhesion kinase (FAK) inhibitor. When the RAS pathway is blocked, FAK can act as a compensatory mechanism to continue to support growth and proliferation. Blocking this pathway with a FAK inhibitor may more effectively block this proliferation. A phase I trial (FRAME trial, NCT03875820) of defactinib (FAK inhibitor) with VS-6766 (a dual RAF/MEK inhibitor) demonstrated anti-tumor activity in patients with recurrent low-grade serous ovarian cancer.48 Of 24 evaluable patients, 11 (46%) demonstrated an objective response.48 A phase II study (GOG 3052, RAMP 201, NCT04625270) evaluating VS-6766 alone and in combination with defactinib in recurrent low-grade serous ovarian cancer is actively enrolling. Patients in this trial are stratified by KRAS mutation status.
With parallel feedback mechanisms, common inputs, common downstream targets, and the interconnected signaling network between the MAPK and PI3K/AKT pathways, targeting both pathways simultaneously in a horizontal inhibition approach seemed promising. Additionally, the PI3K/AKT pathway seems to be upregulated after MEK inhibitor therapy, making this strategy even more attractive.49 While responses in various clinical trials across cancer types seemed promising, dose limiting toxicities with this combination have generally remained a challenge with this strategy.50 51
In a study performed by Spreafico and colleagues,52 55 patients with type 1 epithelial ovarian cancer (including low-grade, mucinous, and clear cell) underwent molecular profiling. Thirty-five of these patients harbored ≥1 somatic mutations (KRAS, NRAS, PIK3CA, PTEN, BRAF, AKT, TP53, and CTNNB1.) Fifteen of these patients were treated with genotype-matched therapy on phase I or phase II clinical trials. Twelve of the 15 patients evaluated had low-grade serous ovarian cancer (harboring KRAS mutation) and 11/12 were treated with MEK/PI3K inhibitor combination therapy. Notably, five (42%) had partial responses, and the remaining seven (58%) had stable disease with a clinical benefit of 100%.52 Unfortunately, less promising results were seen in a phase II randomized double-blind placebo-controlled trial of combination pimasertib (MEK inhibitor) with or without voxtalisib (SAR245409, dual inhibitor of PI3K and mTOR (mammalian target of rapamycin)) in patients with previously treated unresectable low-grade serous ovarian cancer. Objective tumor response was 9.4% in the combination and 12.1% in the pimasertib alone arm. Due to the high rate of discontinuation and low objective response rate, this trial closed for futility.53
The MAPK signaling pathway has also been linked to the development of endocrine resistance. In estrogen receptor-positive preclinical models, endocrine therapy appears to be synergistic with MEK inhibitors. In an ovarian cancer mouse model, tumor response was improved with MEK-inhibitor+fulvestrant compared with either alone.54
The efficacy and safety of fulvestrant with or without selumetinib (MEK inhibitor) was evaluated in advanced stage breast cancer after progression on an aromatase inhibitor, but the combination was poorly tolerated, and the disease control rate was worse than with fulvestrant alone (23% vs 50%).55 This was felt to be in part due to poor tolerance of the 75 mg twice daily dosing of selumetinib. After selumetinib dosing was reduced to 75 mg daily, the combination reached a disease control rate closer to placebo. The authors suspect that this dose reduction resulted in loss of biologic activity of selumetinib and therefore loss of the negative impact on the efficacy of fulvestrant. One hypothesis is that MAPK pathway inhibition could increase activity of other pathways, such as the PI3K pathway, that lead to endocrine therapy resistance.55
Further exploration may be warranted in ovarian cancer as these worse outcomes with dual therapy may be specific to cancer type. Bussies and Schlumbrecht reported a case of a patient with low-grade serous ovarian cancer who received trametinib with fulvestrant and had progression-free survival of 9 months.56 The authors suggested that while this progression-free survival is similar to that seen in GOG 239 and 281 with MEK inhibitor alone, this patient was heavily pre-treated and resistant to platinum chemotherapy and non-fulvestrant endocrine therapy, making this progression-free survival possibly more promising.56 A trial exploring regorafenib (a multikinase inhibitor targeting RAF1, CSF1R (colony stimulating factor 1 receptor), and angiogenesis) with fulvestrant for patients with recurrent low-grade serous ovarian cancer (NCT05113368) will start enrolling soon and may provide more insight to the utility of simultaneously targeting the MAPK pathway and giving endocrine therapy.
RAS mutant tumors are usually resistant to PARP (poly-ADP ribose polymerase) inhibitors, as well as other chemotherapy types. However, Sun and colleagues have demonstrated that inhibition of MEK or ERK (extracellular signal-regulated kinase) can reverse PARP inhibitor resistance in RAS mutant tumors.57 In a pre-clinical study, they demonstrated synergistic activity of PARP and MEK inhibition in vitro and in vivo in multiple RAS mutant tumor models, including an ovarian cancer xenograft using the OVCAR8 cell line.57
Given this promising pre-clinical data, a phase I/II study (NCT03162627) was initiated by Westin and colleagues evaluating olaparib and selumetinib in ovarian, endometrial, and other solid tumors harboring RAS pathway mutations as well as ovarian tumors with PARP resistance. Initial data were presented at the American Association for Cancer Research annual meeting in 2019, demonstrating tolerability of the combination. Evaluation of expansion cohorts is ongoing.
While bevacizumab (VEGF-A (vascular endothelial growth factor-A) inhibitor) has demonstrated efficacy in combination and as a single agent in multiple tumor types, a trial evaluating the combination of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor) with or without bevacizumab in patients with stage IV BRAF V600E/K mutant melanoma had slow accrual and limiting toxicity, and therefore was terminated (NCT01495988). In recurrent platinum resistant high-grade serous ovarian cancer, a phase II trial of cobimetinib, bevacizumab, and atezolizumab (PDL1 (programmed cell death ligand) inhibitor) is currently enrolling (BEACON trial, NCT03363867).
As we explore new combination therapies, unique clinical trial platforms will be critical to expedite our understanding of these treatment options. A platform trial for rare tumors recently initiated enrollment (BOUQUET, GOG 3051, NCT04931342), evaluating the efficacy and safety of biomarker driven therapy in patients with persistent or recurrent rare epithelial ovarian tumors. Patients with PIK3CA/AKT1/PTEN altered tumors will receive ipatasertib (AKT inhibitor) + paclitaxel. Patients with BRAF/NRAS/KRAS/NF1 altered tumors will receive cobimetinib (MEK inhibitor). Patients with ERBB2 amplified/mutant tumors will receive trastuzumab emtansine. Patients without any specific mutations will receive atezolizumab (PDL1 inhibitor) with bevacizumab. Patients with ER positive tumors will receive giredestrant (selective estrogen receptor degrader (SERD)) with abemaciclib (CDK4/6 inhibitor) and LHRH (luteinizing hormone-releasing hormone) agonist if peri- or pre-menopausal. Patients with PIK3CA altered tumors will receive inavolisib (PI3K α inhibitor) with palbociclib (CDK4/6 inhibitor). Patients with ER positive and PIK3CA altered tumors will receive inavolisib, palbociclib, letrozole, and LHRH agonist (if peri- or pre-menopausal.) Patients without specific mutations will receive inavolisib with olaparib (PARP inhibitor.)
Conclusion
Our understanding of low-grade serous carcinomas has changed dramatically as we have distinguished them as a separate entity from high-grade serous cancers. Surgical cytoreduction remains a mainstay of treatment when feasible; however, when disease is unresectable, effective systemic therapy is critical. While chemotherapy has demonstrated minimal effectiveness in this disease, multiple endocrine and MAPK pathway target combination therapies provide promising alternatives for future treatment options.
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References
Footnotes
Contributors In this review article, Drs LC and DG both contributed to the conceptualization, writing, and final approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests DG reports payments made to his institution from the National Cancer Institute (NRG Oncology), Novartis, and the GOG Foundation for research outside the submitted work; royalties from Elsevier and UpToDate outside the submitted work; consulting fees from Genentech, Onconova, Springworks, and Verastem outside the submitted work; and stock from Johnson & Johnson, Bristol Myers Squibb, and Procter and Gamble outside the submitted work. LC has nothing to report.
Provenance and peer review Commissioned; internally peer reviewed.