Highlights
- High tumour pERK expression (histoscore >140) is a significant predictor of prolonged progression-free survival (PFS) for patients treated with trametinib, reaching a median of 20.1 months.
- Canonical RAS-RAF-MAPK mutations (KRAS/BRAF/NRAS) are strongly associated with higher objective response rates (50.0%) to MEK inhibition.
- The presence of KRAS amplifications and non-canonical MAPK mutations expands the identifiable defect pool to 55.2% of cases, though these do not further refine predictive accuracy for trametinib benefit.
- Chromosome 1p loss is identified as a potential biological modulator of lower pERK expression in LGSOC.
Background: The Unique Challenge of Low-Grade Serous Ovarian Cancer
Low-grade serous ovarian carcinoma (LGSOC) represents a distinct clinical and molecular entity from the more common high-grade serous ovarian carcinoma (HGSOC). While HGSOC is characterized by near-universal TP53 mutations and significant genomic instability, LGSOC typically occurs in younger women, follows a more indolent but persistent clinical course, and exhibits a notable resistance to traditional platinum-based chemotherapy. At the molecular level, LGSOC is frequently driven by aberrations in the Mitogen-Activated Protein Kinase (MAPK) pathway, making it a prime candidate for targeted therapies such as MEK inhibitors.\n
Historically, treatment options for recurrent LGSOC were limited to hormonal therapies or cytotoxic agents with relatively low response rates. The landscape shifted with the GOG281/LOGS trial (NCT02101788), a landmark phase II/III study that demonstrated the superiority of the MEK inhibitor trametinib over physician’s choice standard of care (SOC). However, as with many targeted therapies, clinical response varies among patients. Identifying which individuals derive the most benefit is essential for optimizing treatment sequences and improving long-term outcomes.\n\n
Study Design: The GOG281/LOGS Translational Cohort
The GOG281 trial enrolled 260 patients with recurrent or persistent LGSOC who had received at least one prior platinum-based regimen but no more than three previous lines of chemotherapy. Patients were randomized to receive either oral trametinib (2 mg daily) or a standard-of-care regimen (including letrozole, tamoxifen, pegylated liposomal doxorubicin, paclitaxel, or topotecan).\n
This translational sub-study focused on 170 patients from the original trial for whom adequate tumour specimens were available. The research team employed whole exome sequencing (WES) to identify somatic mutations and copy-number alterations, alongside immunohistochemistry (IHC) for phospho-ERK (pERK) to assess the activation state of the MAPK pathway. The primary objective was to correlate these molecular features with clinical endpoints, specifically progression-free survival (PFS) and objective response rate (ORR), to identify predictive biomarkers.
Key Findings: pERK as a Potent Predictor of PFS
One of the most significant findings from this analysis was the role of pERK expression. The researchers used a histoscore (ranging from 0 to 300) to quantify pERK levels. Patients with ‘high’ pERK expression—defined as a score greater than the median of 140—experienced a dramatic benefit from trametinib. In this subgroup, the median PFS was 20.1 months with trametinib compared to just 5.6 months with SOC (log-rank P < 0.0001). The statistical test for interaction (P = 0.023) confirmed that pERK expression was specifically predictive of the trametinib treatment effect rather than merely being a general prognostic marker for better outcomes across all treatments.
Conversely, patients with low pERK expression (histoscore ≤ 140) did not show the same magnitude of benefit, suggesting that the baseline activation level of the MAPK pathway is a critical determinant of how much a patient will respond to its inhibition.
The Role of MAPK Mutations in Orchestrating Response
The study also scrutinized the mutational status of the canonical RAS-RAF-MAPK genes (KRAS, BRAF, and NRAS). These mutations were found in 32.8% of the analyzed cases (44 out of 134). The presence of these mutations was a powerful predictor of the objective response rate. Patients with canonical mutations who received trametinib achieved an ORR of 50.0%, a stark contrast to the 8.3% response rate seen in patients without these mutations (Barnard’s P = 0.0004).
Interestingly, while these mutations predicted the likelihood of the tumour shrinking (ORR), they were not significantly predictive of prolonged PFS (test for interaction P = 0.719). This suggests a nuanced clinical reality: while RAS/RAF mutations may make a tumour more likely to hit a response threshold, other factors—perhaps including the pERK activation levels mentioned above—govern how long that response or disease stabilization lasts.
Expanding the Genomic Portrait
Beyond the canonical mutations, the researchers investigated whether expanding the definition of MAPK pathway defects would improve patient stratification. They identified KRAS amplifications in five patients (without other canonical mutations) and mutations in other MAPK-associated genes in an additional 25 patients. This expanded the group with identifiable MAPK pathway defects to 55.2% of the cohort. However, including these additional genetic events did not improve the ability to discriminate which patients would respond best to trametinib. This highlights the primary importance of the core KRAS/BRAF/NRAS mutations in LGSOC biology.
The analysis also touched upon chromosomal alterations. Chromosome 1p loss was observed in 49% of cases and was significantly associated with lower pERK expression (P = 0.021). This finding suggests that large-scale genomic deletions might play a role in modulating pathway activity and, by extension, sensitivity to MEK inhibition.
Expert Commentary: Clinical Implications and Future Directions
The results of this molecular profiling study are highly relevant for the management of LGSOC. For years, the oncology community has sought to move beyond a ‘one-size-fits-all’ approach for rare ovarian cancers. The GOG281 trial established trametinib as a standard option, but these new data provide clinicians with a potential roadmap for personalization.
The strong predictive value of pERK IHC is particularly interesting because IHC is a relatively accessible and cost-effective tool in most pathology laboratories compared to comprehensive genomic sequencing. If validated in further prospective cohorts, pERK testing could become a routine part of the diagnostic workup for recurrent LGSOC to guide the timing and selection of MEK inhibitor therapy.
However, some limitations must be acknowledged. This was an exploratory analysis, and the thresholds used (such as the median pERK histoscore) require independent validation. Furthermore, the lack of correlation between KRAS/BRAF mutations and PFS—despite the strong correlation with ORR—suggests that the biology of resistance in LGSOC is complex. It is possible that compensatory pathways or clonal heterogeneity eventually lead to disease progression even in tumours that initially show a robust response to trametinib.
Conclusion
The molecular analysis of the GOG281/LOGS trial provides a much-needed evidence base for precision medicine in low-grade serous ovarian cancer. By demonstrating that pERK expression and canonical RAS-RAF-MAPK mutations are candidate biomarkers for PFS and objective response, respectively, this study brings us closer to a future where treatment for LGSOC is tailored to the individual molecular profile of the tumour. As we move forward, integrating these biomarkers into clinical practice and exploring combination therapies to overcome resistance will be the next frontier in improving the lives of women with this challenging disease.
Funding and ClinicalTrials.gov
This study was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award numbers U10CA180821 and U10CA180868, and by Novartis. The clinical trial is registered at ClinicalTrials.gov with the identifier NCT02101788.
References
- Hollis RL, Miller A, Lankes HA, et al. Molecular profiling and tumour biomarker analysis of GOG281/LOGS: a positive late-phase trial of trametinib for recurrent/persistent low grade-serous ovarian cancer. Clin Cancer Res. 2025.
- Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet Oncol. 2022;23(2):205-216.
- Grisham RN. Low-grade serous carcinoma of the ovary. Oncology (Williston Park). 2016;30(7):650-652.
