Genomic profiling in low grade serous ovarian cancer: Identification of novel markers for disease diagnosis and therapy

• Published in: Gynecologic oncology 2022-11, Vol.167 (2), p.306-313
• Main Authors: ElNaggar, Adam, Robins, David, Baca, Yasmine, Arguello, David, Ulm, Michael, Arend, Rebecca, Mantia-Smaldone, Gina, Chu, Christina, Winer, Ira, Holloway, Rob, Krivak, Tom, Jones, Nathaniel, Galvan-Turner, Valerie, Herzog, Thomas J., Brown, Jubilee
• Format: Article
• Language: English
• Subjects: Cystadenocarcinoma, Serous - diagnosis; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - therapy; Female; Genomics; Hormones; Humans; Low grade serous ovarian cancer; Molecular profiling; Mutation; Neoplasm Grading; Next generation sequencing; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - genetics; Ovarian Neoplasms - therapy; Precision medicine; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2022.09.022

Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort. Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens. Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent. BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents. •Low grade serous ovarian cancer has a unique mutational profile relative to high grade and borderline serous ovarian cancers.•BRAF mutations are rare (6.6%) and nearly a third were RAS dependent (a.k.a Class III)•Estrogen receptor expression is seen in 80% and commonly co-exist with NRAS and BRAF mutations.•Clinical biomarkers associated with response to immune checkpoint inhibitors are largely absent.