Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications

Abstract

Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53 . The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.

A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer

“…By comparing the mutant spectra of EOVC and EC (Table 2), many shared mutant genes have been identified: ARID1A, TP53, PTEN, PIK3CA, KRAS, CTNNB1, MMR, POLE, among others (51). However, the frequency of mutation of these genes appears to vary depending on different microenvironmental effects (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60).…”

“…By comparing the mutant spectra of EOVC and EC ( Table 2 ), many shared mutant genes have been identified: ARID1A, TP53, PTEN, PIK3CA, KRAS, CTNNB1, MMR, POLE, among others ( 51 ). However, the frequency of mutation of these genes appears to vary depending on different microenvironmental effects ( 50 – 60 ). PTEN mutations are more frequent in low-grade endometrioid endometrial carcinoma (EEC) and CTNNB1 mutations are more common in low-grade EOVC ( 50 ).…”

“…Summary of most common molecular alterations in EOVC and EEC(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60).…”

Modular self-assembly system for development of oligomeric, highly internalizing and potent cytotoxic conjugates targeting fibroblast growth factor receptors

“…By engineering the ligands towards site-specific drug conjugation and biotinylation followed by self-assembly with SA tetramers, oligomeric conjugates of selected specificity can be easily and rapidly developed. In numerous tumors different cell surface proteins are overexpressed and their simultaneous targeting with multi-specific oligomers could enhance efficiency of the therapy and overcome cancer drug resistance [ 51 – 55 ]. Furthermore, some cancer biomarkers, such as HER2, are well known for their poor internalization, which limits their targeting with cytotoxic conjugate [ 56 , 57 ].…”

Glycomic-Based Biomarkers for Ovarian Cancer: Advances and Challenges

“…OvCas are classified into five major types based on their histological and molecular genetics. They are high-grade serous type, which is the most abundant, followed by endometrioid, clear cell, mucinous and the least abundant, the low-grade serous ovarian carcinoma [ 2 , 3 ].…”