Low-grade Serous Tumors: Are We Making Progress?

Pauly, N; Ehmann, Sarah; Ricciardi, Enzo; Ataseven, Beyhan; Bommert, Mareike; Heitz, Florian; Prader, Sonia; Schneider, Stephanie; Bois, Andreas du; Harter, Philipp; Baert, Thaïs

doi:10.1007/s11912-020-0872-5

Cited by 15 publications

(18 citation statements)

References 54 publications

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“…The grading system for malignant serous ovarian carcinoma has changed and is today binary (i.e. low grade or high grade), which has performed better for outcome prediction than the old three-tier grading (1,19). In low-grade serous ovarian carcinoma the mitogen-activated protein kinase (MAPK) pathway is activated, a kinase cascade that mediates the transmission of growth signals into the nucleus, via mutations in KRAS and BRAF, the upstream regulators of the MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

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Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma

Tholander

Koliadi

Botling

et al. 2020

Upsala Journal of Medical Sciences

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More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.

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Section: Discussionmentioning

confidence: 99%

“…Low-grade serous ovarian carcinoma (LGSOC) is a less common subtype, affecting around 5% of all patients with epithelial ovarian cancer (1). However, in contrast to high-grade serous ovarian carcinoma (HGSOC), LGSOC more often affects young, fertile women.…”

Section: Introductionmentioning

confidence: 99%

Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma

Tholander

Koliadi

Botling

et al. 2020

Upsala Journal of Medical Sciences

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“…MEKi will soon be commonly prescribed, for the treatment of LGSOC, as an alternative to the standard chemotherapy and anti-hormone therapy in patients with recurrent disease [74]. To identify robust biomarkers that predict MEKi response, we used transcript/protein expression to evaluate MAPK pathway regulation.…”

Section: Discussionmentioning

confidence: 99%

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

Shrestha

Fernández

Dawson

et al. 2020

Preprint

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Background: Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates. As such, there is a pressing need to develop more effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use a multiomics approach to interrogate a collection of LGSOC patient-derived cell lines to elucidate novel biomarkers and therapeutic vulnerabilities.Methods: Fourteen LGSOC cell lines were interrogated using whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics. Somatic mutation, copy-number aberrations, gene and protein expression were analyzed and integrated using different computational approaches.LGSOC cell line data was compared to publicly available LGSOC tumor data (AACR GENIE cohort), and also used for predictive biomarker identification of MEK inhibitor (MEKi) efficacy. Protein interaction databases were evaluated to identify novel therapeutic targets. Results: KRAS mutations were exclusively found in MEKi-sensitive and NRAS mutations mostly in MEKiresistant cell lines. Analysis of COSMIC mutational signatures revealed distinct patterns of nucleotide substitution mutations in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes (chromosome 9p21) were much more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. For in-vitro MEKi efficacy prediction, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines.Conclusions: Our LGSOC cell lines are representative models of the most common molecular aberrations found in LGSOC tumors. This study highlights the importance of using proteomic data in multiomics assessment of drug prediction and identification of potential therapeutic targets. CDKN2A/B and MTAP deficiency offer an opportunity to find synthetically lethal candidates for novel treatments.Multiomics approaches are crucial to improving our understanding of the molecular aberrations inLGSOC, establishing effective drug prediction programs and identifying novel therapeutic targets inLGSOC. BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer with a poor prognosis. Women with LGSOC are usually diagnosed with advanced-stage disease and only 10-20% are alive 10 years after diagnosis [1,2]. Research on LGSOC is challenging due to its low prevalence, uncertain etiology, and the limited availability of research models. However, in the last 5-10 years investigators have elucidated many key genomic aberrations, leading to major advancements in the molecular characterization and classification of LGSOC [3,4]. In contrast to other ovarian cancer subtypes, LGSOC are genetically characterized by high frequency of oncogenic mutations in KRAS, NRAS, and BRAF (20-40%, 7-26%, 5-33%, respectively) [5-7], a very low prevalence of TP53 mutatio...

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“…However, the MEKi selumetinib has shown little activity in patients with low-grade serous cancers (15%), where the response did not always correlate with KRAS/BRAF mutation status [22]. With another MEKi, clinical response to the BRAF inhibitor, dabrafenib, has been demonstrated thus far clinically in 20% women with BRAF V600E mutated low-grade carcinomas [23].…”

Section: Histologic Subtypes Of Ovarian Cancer Molecular Correlatesmentioning

confidence: 99%

“…Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutation (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (see below) may not be effective in mucinous ovarian cancer, as only one out of 191 had a high homologous recombination deficiency score [23,35].…”

Section: Histologic Subtypes Of Ovarian Cancer Molecular Correlatesmentioning

confidence: 99%

The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

Dion

Carton

Jaillard

et al. 2020

JCM

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Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20–30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.

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Low-grade Serous Tumors: Are We Making Progress?

Cited by 15 publications

References 54 publications

Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma

Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

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