# Dbrutinib Could Suppress CA-125 in Ovarian Cancer: A Hypothesis
## 4 Discussion  
There are several limitations to our hypothesis. It is important to stress that the observed correlation does not imply causation. Nevertheless, the absence of other concomitant oncological medication during the time of the CA-125 decrease in our case report suggests at least a partial effect of brtutinib.  
Randomly elevated CA-125 levels due to sarcoidosis have sporadically been described in case reports [13]. These reports are rare, implying a correlation due to the absence of differential diagnosis or due to involvement of serosal surfaces. In our patient, sarcoidosis was primarily cutaneous and pulmonal, without pleural or peritoneal effusions, and CA-125 was not elevated during the initial diagnosis of sarcoidosis in 2011. The tumor marker has not since been established for monitoring sarcoidosis activity. Concerning the observed decline of CA-125, spontaneous regression is extremely rare in epithelial ovarian cancer. A PubMed search (1 May, 2020) revealed only one case report of spontaneous regression in recurrent disease after radiation of a single nodal metastasis [14]. As spontaneous regression and sarcoidosis fail to explain the serum marker fluctuation, the kinase inhibitor's possible role needs to be investigated.  
Few in vitro experiments have studied brtutinib's effect on ovarian cancer. Papillary serous cells, such as in the present case, displayed drug response in ex vivo drug sensitivity testing [15]. Ovarian cancer stem cells have been shown to express Btk, with brtutinib diminishing their self-renewal capacities [5].  
Regarding other kinase inhibitors, recent case reports describe disease response and declining CA-125 after therapy with trametinib, a MEK inhibitor affecting the MAPK/ERK pathway [12]. Furthermore, we found a case report about a patient harboring the same KRAS mutation who experienced an impressive clinical response after treatment with binimetinib, another MEK inhibitor [16]. Animal studies found overexpression of p65 BTK, an isoform of Btk, in KRAS-mutant cell lines. Btk inhibitors proving effective against cell viability in these experiments offers another molecular explanation for our findings [17].  
CA-125 expression shows a high correlation with serous subtype borderline and malignant ovarian tumors [18], and we conclude that the varying levels of CA-125 in our patient were a direct result of brtutinib's effect on subclinical ovarian cancer. The absence of a radiologically or clinically detectable tumor during this period is consistent with this conclusion, as low tumor volumes typically elevate serum levels before they become clinically evident. The observed decrease in CA-125 during brtutinib intake can be explained by a cytotoxic effect, a metabolic effect (suppression of CA-125 production in sub-apoptotic serum levels), or a combination of these.  
Further research is needed to test this hypothesis in low- and high-grade ovarian cancer, and we encourage the conduction of in vitro experiments exploiting the underlying pathways for tumor suppression. In this context, our work can be seen as an additional puzzle piece in this widely unexplored area, bridging the gap toward more clinically relevant research.