The two main findings of the present work are the quasi-absence of PSMA expression within serous epithelial ovarian cancers, whatever its degree of resistance to chemotherapy and the non-evolution of PSMA expression during the treatment course.
Contradictorily Wernicke et al. [13] described a PSMA expression in the neovasculature of primary ovarian tumours, 31% of tumours exhibiting an expression of more than 50% in tumour vasculature. Regarding the tumour cellular expression of PSMA, they found that nearly 50% of primary ovarian tumours they studied were positive. Similarly to our study, all were high grade serous carcinomas, in which 10 to 50% of the cells were positive with both cytoplasmic and membrane expression. We definitely did not find such results in our population, which is very wondering. Our immunohistochemical protocol cannot be incriminated since we detected strong PSMA expression in other normal (prostate) or tumour (thyroid) tissues, used as positive internal controls, as exemplified on the Fig. 3. Besides, looking carefully at figures from the paper of Wernicke AG et al., the chosen iconographies do not seem to fully support the point, visually showing weak cellular and neovascular expressions. Wernicke AG et al. also described more intense neovascular expression of PSMA in metastases than primary lesions. In contrast, the majority of them were negative at the cellular level. Even if we did not explore this specific point, it is worth noticing that we had a larger data bank from which to support our findings and that it was the first time that the evolution of PSMA staining during the course of treatment was explored.
Conversely, our results are concordant with Kinoshita Y. et al. demonstrating that ovary stromal cells stained strongly, whereas ovary carcinoma did not express PSMA [14]. However, this study included only 5 normal ovaries and 1 ovarian carcinoma tissue sample. Also, data from the human protein atlas, which is a Swedish-based program initiated in 2003 with the aim to map all the human proteins in cells, tissues and organs using integration of various omics technologies [15], seems to confirm that ovarian carcinomas are PSMA negative cancers (see: https://www.proteinatlas.org/ENSG00000086205-FOLH1/pathology/ovarian+cancer).
On the other hand, a preclinical study demonstrated that a low level of PSMA expression in non-prostatic tumours was sufficient for in vivo tumour targeting and imaging [16]. However, investigations were conducted on melanoma and non-small cell lung cancer that in this specific study displayed higher PSMA expression than ovarian cancer, questioning the SPECT/CT images and quantification that could have been obtained with ovarian carcinoma xenografts. It is worth noticing that the number of patients included in the present study is limited, but it comes from a centre of reference for management of ovarian cancers and it is for now the largest currently available database exploring PSMA expression in ovarian cancers. In view of these preliminary results which left us with little hope of conclusive results, we decided not to pursue our investigation with a PET clinical trial as it was originally planned. However, PSMA probes are currently being investigated in clinical trials now recruiting in North America and to be completed next year (NCT03857087, NCT03811899, NCT03302156). We are looking forward to seeing if they will confirm our findings.