Immunohistochemical expression of Nectin-4 and potential implications for enfortumab vedotin therapy in germ cell tumors of the testis: a preliminary study

A subset of germ cell tumors of the testis (GCTT) shows an aggressive clinical behavior, with chemo-resistance, metastases, and recurrences. Recently, enfortumab vedotin (EV), an antibody-drug conjugate (ADC) targeting Nectin-4, has been shown to improve the survival in urothelial carcinoma and has been approved for the locally advanced or metastatic cases. We stained for Nectin-4 (EPR15613-68 rb, Abcam) 46 cases (42 chemo-naive primary testicular tumors and 4 post-chemotherapy metastatic recurrences) and adopted the H-score and the specific Nectin-4 score (negative (H-score 0-14), weak (H-score 15-99), moderate (H-score 100-199), and strong (H-score 200-300)) for both the cytoplasm and the membrane. The expression of Nectin-4 was compared between different histotypes by adopting the specific Nectin-4 score and Fisher's exact test. Nectin-4 membrane expression was positive in 14/89 (15.7%) GCTT components, with median H-score of 0 (range 0-120; IQR 0-10). Choriocarcinoma (CHC) (median H-score 29 (range 20-40, IQR 21.25-38.25)) and isolated syncytiotrophoblast cells (iSTCs) [median H-score 65 (range 0-90; IQR 10-147.5)) showed statistically significant higher Nectin-4 membrane expression than the other GCTT components (p < 0.001), with staining mostly observed in syncytiotrophoblasts in CHC and thus mirroring what found in "normal" syncytiotrophoblasts of placental tissue (adopted as positive control). Additionally, 2/4 (50%) post-chemotherapy metastatic recurrences (one Tpt and one YSTpt) and 3/25 (12%) EC showed positive weak Nectin-4 membrane expression. To summarize, our study reveals that only a small minority of GCTT exhibit positive weak Nectin-4 membrane expression. However, a subgroup of potentially aggressive GCTT (especially CHC and post-chemotherapy metastatic recurrences) more frequently exhibits Nectin-4 membrane expression, thus prompting future studies to assess whether these patients may be potentially eligible for EV therapy.