Targeted therapy largely remains an unmet therapeutic need for low-grade serous ovarian carcinomas. However, recent advances in molecular characterization are beginning to change the landscape. A recent article highlights the association of genetic alterations with clinical outcomes, widening the scope of novel targeted therapies.

See related article by Manning-Geist et al., p. 4456

In this issue of Clinical Cancer Research, Manning-Geist and colleagues (1) report the result from a retrospective, correlative study that characterizes the tumor mutational landscape by panel-based sequencing in a large cohort of patients with low-grade serous ovarian carcinomas (LGSOC). Correlation of somatic and germline mutations with clinicopathologic features showed dominant mutated genes (KRAS, NRAS, EIF1AX, BRAF) in the MAPK pathway among 60% of patients (n = 71), concordant with previous studies (2–4). The authors highlight the association between KRAS alterations and platinum sensitivity and also demonstrate independent associations between improved overall survival (OS) in patients with MAPK pathway alterations and platinum-sensitive disease. Germline mutation was present in a small proportion of patients (9%), including RB1, BAP1, MUTYH, CHEK2, APC, and FANCA, but its correlation with LGSOC remains unclear. The molecular findings presented can potentially be leveraged for therapy.

LGSOC has characteristics which distinguish it from high-grade serous ovarian cancer (HGSOC). LGSOC is a rare epithelial ovarian cancer subtype which in some cases has been suggested to arise from adenofibromas or borderline tumors. A current hypothesis indicates that the origin is epithelial cells from the fallopian tube which migrate into the ovaries (2). In contrast with HGSOC, LGSOC is rarely associated with BRCA mutations and lacks TP53 mutation (3). Nevertheless, activating mutations in the MAPK pathway are commonly found, including BRAF, ERBB2, NRAS, and NF1. Other potential driver mutations were identified in PIK3CA, USP9X, FFAR1, and EIF1AX (4). LGSOCs have longer survival than HGSOCs but are less chemotherapy responsive. Recognizing the pathway alterations is essential for developing more effective and better tolerated targeted therapies (Fig. 1).

Figure 1.

Activated signaling pathways in LGSOC and therapeutic opportunities. Focal adhesion kinase (FAK) is a cytoplasmatic tyrosine kinase activated by integrins through disruption of the auto-inhibitory mechanism. FAK can directly phosphorylate SRC family kinases and form a heterodimer complex with SRC. Subsequently, multiple downstream signaling events, including activation of the PI3K-AKT-mTOR pathway, induce tumor cell proliferation. Activation of receptor tyrosine kinase triggers the RAS-RAF-MEK-ERK pathway. ERK signaling induces cyclin D overexpression and stimulates cyclin-dependent kinases 4 and 6 (CDK4/6) to promote tumor proliferation. Estrogen stimulates tumor cell survival by multiple mechanisms. The estrogen receptor (ER) complex combines with coregulator proteins and DNA to promote the transcription of genes that participate in the cell cycle regulation, DNA replication, and apoptosis. One of these gene products is cyclin D1, which activates CDK4/6. Other growth factors and cytokine signaling pathways can promote ER phosphorylation and activate the receptor even in the absence of estradiol, triggering cell proliferation. (Adapted from an image created with BioRender.com.)

Figure 1.

Activated signaling pathways in LGSOC and therapeutic opportunities. Focal adhesion kinase (FAK) is a cytoplasmatic tyrosine kinase activated by integrins through disruption of the auto-inhibitory mechanism. FAK can directly phosphorylate SRC family kinases and form a heterodimer complex with SRC. Subsequently, multiple downstream signaling events, including activation of the PI3K-AKT-mTOR pathway, induce tumor cell proliferation. Activation of receptor tyrosine kinase triggers the RAS-RAF-MEK-ERK pathway. ERK signaling induces cyclin D overexpression and stimulates cyclin-dependent kinases 4 and 6 (CDK4/6) to promote tumor proliferation. Estrogen stimulates tumor cell survival by multiple mechanisms. The estrogen receptor (ER) complex combines with coregulator proteins and DNA to promote the transcription of genes that participate in the cell cycle regulation, DNA replication, and apoptosis. One of these gene products is cyclin D1, which activates CDK4/6. Other growth factors and cytokine signaling pathways can promote ER phosphorylation and activate the receptor even in the absence of estradiol, triggering cell proliferation. (Adapted from an image created with BioRender.com.)

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Despite the advances in cancer therapeutics, rare gynecologic malignancies still have chemotherapy as the mainstay of treatment despite poor response rates (3). A high frequency of activating mutations in the MAPK pathway was identified in LGSOC and targeting RAS-RAF-MEK-ERK to control tumor growth has been investigated. In 2013, the first evidence of the benefit of a MEK inhibitor in LGSOC was reported in a single-arm phase II study of selumetinib (5). The overall response rate (ORR) was modest at 15%, and the median progression-free survival (PFS) was 11 months. The activity was not restricted by the presence of BRAF/KRAS mutation. On the basis of this, two randomized phase III trials, MILO-ENGOT-ov11 (6) and GOG 281/LOGS (7), were designed to evaluate the role of MEK inhibitors in patients with LGSOC. Patients were not selected for MAPK mutation upfront.

MILO-ENGOT-ov11 (6) compared binimetinib with the investigator's choice chemotherapy. Among 303 patients enrolled, 33% had KRAS mutation. The primary endpoint of improvement in PFS for the experimental agent was not met, with 9.1 months [95% confidence interval (CI), 7.3–11.3] in the binimetinib group and 10.6 months (95% CI, 9.2–14.5) in the control group. The study stopped early due to crossing the futility boundary. Nevertheless, an exploratory analysis suggested a positive association between KRAS mutation and treatment with binimetinib, with better PFS and response rate. GOG 281/LOGS trial (7) compared trametinib to the investigator's choice standard of care (SOC), including hormonal therapy. The rate of KRAS, NRAS, and BRAF mutations was 33% among 134 of 260 patients sequenced. Treatment with trametinib significantly improved PFS compared with SOC, regardless of mutational status. The ORR was 26.2% on trametinib versus 6.2% on SOC. The limitation of MEK inhibitors is the higher burden of toxicities leading to worse quality of life. In MILO-ENGOT-ov11 study, 76% of patients had grade ≥3 adverse events reported with binimetinib, including diarrhea, rash, nausea, and fatigue. In GOG 281/LOGS trial, 36% of patients discontinued trametinib due to toxicity. Trametinib, when used as targeted therapy in metastatic melanoma in a phase III trial, reported dose interruption and dose reduction due to adverse events, however, toxicities were managed with short dose interruptions i.e., 2- to 3-day hold period (8).

This result demonstrates the importance of targeting the MAPK pathway even in negative KRAS, BRAF, or NRAS mutation, but it is unclear if the activity is based on nonspecific tyrosine kinase (TKI)effects or susceptibility to targeting this pathway but not predicted by panel testing for mutations. Further translational studies are ongoing to analyze the activity of MAPK pathway in these patients without the mutation. This could be related to cross-talk with other pathways or posttranscriptional events increasing protein expression. Both studies performed molecular sequencing in archival tissue specimens and might not have identified acquired mutations in real-time. Manning-Geist and colleagues (1) conducted panel-based sequencing over multiple sequential time points in 8 patients. Two of five patients without genetic alterations initially were found to have a new driver mutation. These findings indicate that serial sequential samples are needed to comprehensively analyze the pathogenesis and evolution (9). Dr. Gershenson and colleagues (10) presented recent data from tumor sequencing of 215 patients with LGSOC, of whom 112 (53%) were found to have a MAPK mutation. Consistent with Manning-Geist and colleagues (1), the most common activating mutations were KRAS, NRAS, and BRAF, and outcomes were better in MAPK mutated patients with improved PFS and OS. Among these patients, 47.8% received MEK inhibitors, which could be the reason for better outcomes in this population.

There are studies (Table 1) in progress testing different therapeutic targets. However, due to the rarity of this tumor, these drugs are generally studied as part of basket trials. In the first-line setting, the phase III study NRG-GY-019 (NCT04095364) compares platinum-based chemotherapy followed by letrozole or letrozole monotherapy, fundamentally evaluating the role of chemotherapy in this ‘resistant’ disease. An interesting but small phase II pilot study in the neoadjuvant scenario showed favorable results with the combination of fulvestrant and abemaciclib followed by maintenance with letrozole in unresectable LGSOC (11). Fifteen patients were enrolled, 7 patients (47%) had a partial response, and 5 underwent interval debulking surgery. A new strategy has emerged with an RAF/MEK dual inhibitor called VS-6766 with or without defactinib, a FAK inhibitor. The phase I FRAME trial showed durable objective responses in recurrent LGSOC, including patients who had received prior MEK inhibitor treatment. Patients who harbored a KRAS mutation had a higher response rate (64%) than KRAS wild-type (44%). This combination was well tolerated, and grade ≥ 3 adverse events were reported in 32% of patients (12). The phase II RAMP-201 trial evaluating this combination is ongoing (13).

Table 1.

Examples of current active trials in LGSOC.

Study/NCTPathway/TargetTreatmentPopulationPhase
BOUQUET (NCT04931342) MAPK mutation MAPK, PTEN/PIK3CA/AKT1, ERBB2 mutation or amplification not matched Cobimetinib, ipatisertib + paclitaxel, T-DM1, atezolizumab + bevacizumab Biomarker-driven therapies in patients with recurrent rare ovarian tumors II 
FRAME (NCT03875820) RAF-MEK, FAK VS-6766 + defactinib Advanced LGSOC II 
ENGOT-ov60/GOG-3052/RAMP-201 (NCT04625270) RAF-MEK, FAK VS-6766 with or without defactinib Recurrent LGSOC with or without KRAS mutation II 
PERCEPTION/ NOGGO-ov44 (NCT04575961) PD-1, DDR Pembrolizumab + platinum-based chemotherapy Recurrent platinum-sensitive LGSOC II 
KRYSTAL-1 NCT03785249 KRAS G12C Adagrasib Advanced solid tumors I/II 
NCT03673124 ER, CDK4/6 Letrozole + ribociclib Recurrent LGSOC II 
NCT04092270 DNA-PK Peposertib + liposomal doxorubicin Recurrent LGSOC I/Ib 
NCT05113368 Multiple protein kinases Regorafenib + fulvestrant Recurrent LGSOC II 
NRG-GY019 (NCT04095364) DDR, ER Carboplatin + paclitaxel + maintenance letrozole vs. letrozole Stage II-IV LGSOC III 
MATAO (NCT04111978) ER Letrozole maintenance Stage II-IV LGSOC III 
Study/NCTPathway/TargetTreatmentPopulationPhase
BOUQUET (NCT04931342) MAPK mutation MAPK, PTEN/PIK3CA/AKT1, ERBB2 mutation or amplification not matched Cobimetinib, ipatisertib + paclitaxel, T-DM1, atezolizumab + bevacizumab Biomarker-driven therapies in patients with recurrent rare ovarian tumors II 
FRAME (NCT03875820) RAF-MEK, FAK VS-6766 + defactinib Advanced LGSOC II 
ENGOT-ov60/GOG-3052/RAMP-201 (NCT04625270) RAF-MEK, FAK VS-6766 with or without defactinib Recurrent LGSOC with or without KRAS mutation II 
PERCEPTION/ NOGGO-ov44 (NCT04575961) PD-1, DDR Pembrolizumab + platinum-based chemotherapy Recurrent platinum-sensitive LGSOC II 
KRYSTAL-1 NCT03785249 KRAS G12C Adagrasib Advanced solid tumors I/II 
NCT03673124 ER, CDK4/6 Letrozole + ribociclib Recurrent LGSOC II 
NCT04092270 DNA-PK Peposertib + liposomal doxorubicin Recurrent LGSOC I/Ib 
NCT05113368 Multiple protein kinases Regorafenib + fulvestrant Recurrent LGSOC II 
NRG-GY019 (NCT04095364) DDR, ER Carboplatin + paclitaxel + maintenance letrozole vs. letrozole Stage II-IV LGSOC III 
MATAO (NCT04111978) ER Letrozole maintenance Stage II-IV LGSOC III 

The combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) has demonstrated impressive results in terms of ORR of 68% compared with 55% in monotherapy with dabrafenib in patients with BRAF-mutant metastatic melanoma (14). New studies investigating diverse targets such as BCL-2/XL and FAK inhibitors are ongoing. There is preclinical evidence that BRAF/MEK inhibitors modulate the immune microenvironment by increasing CD8+ T cells and decreasing the activity of immunosuppressive cytokines (15). Randomized phase II and III trials evaluating triplet combinations of immunotherapy and BRAF/MEK inhibitors showed a benefit in terms of PFS; however, an increased rate of grade 3 and 4 adverse events was noted (16, 17). In contrast, LGSOC has a low tumor mutation burden (18), and strategies to promote a favorable immune microenvironment are needed. Immunotherapies including checkpoint inhibitors and adoptive T-cell therapy are important frontiers to explore.

Overall, these recent advances in molecular genomics are beginning to pave the way toward precision therapy in LGSOC. Manning-Geist and colleagues (1) demonstrated a potential prognostic association of MAPK pathway mutation with platinum sensitivity and better survival outcomes. These findings are important to delineate future clinical trials exploring the pathways involved in LGSOC and perhaps serve as an invitation to reflect on some key questions: Should MEK inhibitors be given to all patients with LGSOC? Should we be exploring combinations with hormonal treatments? An ongoing challenge will be to reduce the toxicity of target specific tyrosine kinase inhibitors without compromising activity.

Fundamentally, we are beginning to voice aloud if it is time to avoid chemotherapy in LGSOC. This transition from a hushed whisper only a short time ago speaks to progress but requires urgent international collaboration to define what is optimal therapy in this disease.

A.M. Oza is noncompensated CEO of Ozmosis Research, a not-for-profit associated with UHN. No disclosures were reported by the other author.

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