Racial differences in the molecular profile of endometrial carcinoma
thesisposted on 16.07.2020, 15:13 by Konstantinos Polymeros
Endometrial cancer (EC) is the commonest gynaecologic malignancy in developed countries and its incidence is rising. Although excellent prognosis is associated with early stage disease, treatment for late stage cases is challenging and the treatment options limited.
Racial differences have been shown in Black and Caucasian women diagnosed with EC however, evidence for other racial groups is limited with Asian patients being particularly under-represented in the literature.
The aims of the study were to propose effective targeted drug treatments suitable for subsequent testing in animal models of EC and to identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women.
CUDC-907, a PI3K and HDAC inhibitor, was the most effective monotherapy treatment in EC cells. Several combination treatments showed synergism and efficacy in EC cell lines with the most efficacious being CUDC-907 and S63845 (MCL1 inhibitor) combined with the MEK inhibitor PD0325901.
Although there was no significant difference in the overall mutation frequency of the 10 genes analyzed, numerous differences were observed between the two racial groups. PIK3CA and PTEN mutations were positively associated in the BSA but not in the BW group. On the contrary, BW women had co-existent ARID1A and PI3K pathway mutations, which was not shown in BSA women. BSA women had higher grade disease in our cohort and survival data are eagerly anticipated.
A range of targeted inhibitory drugs emerged from this study showing in vitro efficacy, alone or in combination, in endometrial cancer cells. Further validation of these therapeutic options in animal models is needed prior to confirming their suitability for use in EC. This study, the first to attempt a comparison between a Caucasian and South Asian cohort of women in genes frequently driving carcinogenesis in EC, showed several differences with translational and clinical relevance.