# Dbrutinib Could Suppress CA-125 in Ovarian Cancer: A Hypothesis
## 2 Case Report  
A 61-year-old woman was referred to our department in 2010 for further treatment of an enlarged ovary, which had been an incidental finding in a follow-up CT scan for CLL. The CLL had previously been treated with chlorambucil and prednisone. Secondary diagnosis included arterial hypertension and dyslipidemia. Upon referral, transvaginal sonography revealed an ovarian tumor of 57 \(\times\) 30 mm containing solid and cystic components. Blood serum analysis was negative for CA-125. Surgical treatment was performed as follows: hysterectomy, adnexectomy, pelvic and para-aortal lymphadenectomy, incidental appendectomy, and radical omentectomy. Histological workup revealed a papillary serous borderline tumor with transition to a low-grade ovarian cancer, stage FIGO (Federation internationale de gynecologie obstetricique) IIIb. Postoperatively, an adjuvant platinum-based therapy (6 cycles of carboplatin/paclitaxel) was administered as standard of care.  
In 2011, the patient was diagnosed with sarcoidosis. Systemic steroids were administered from December 2011 until April 2012, resulting in total remission. In 2013, the patient suffered her first recurrence of CLL. The treatment regimen included 2 cycles of ribomustin and rituximab.  
In 2014, rising levels of CA-125 marked recurrent ovarian cancer, and a re-laparotum for tumor-debulking and partial colon resection with end-to-end anastomosis was performed in October 2014. Second-line chemotherapy contained 6 cycles of carboplatin and gemcitabine until March 2015. In July 2016, sixteen months after second-line chemotherapy, elevated CA-125 levels were recorded, without further clinical or radiological findings, allowing for expectant management of the asymptomatic patient (Figure 1). Gynecological follow-up visits were continued every 3 months.  
A second recurrence of CLL was diagnosed in May 2017. Repeated therapy with ribomustin and rituximab showed minimal response. Therefore, an oral therapy with brtutinib (140 mg, alternating 2\(\times\)/3\(\times\) daily) was established in November 2017, which allowed for hematological disease control.  
Following the initiation of brtutinib, the CA-125 levels started to decrease continuously, with normalization after 12 months of therapy. During the continued therapy, the patient had no laboratory, radiological, or clinical signs of recurring ovarian cancer.  
Figure 1: Development of CA-125 levels in recurrent disease. An increase was seen during the course of the disease, and debulking surgery with second-line chemotherapy was performed (grey arrow and grey bar). CA-125 monitoring was not continued postoperatively until July 2016, when elevated levels suggested recurrent (subclinical) disease. During expectant management, CA-125 dropped sharply after the initiation of brtutinib therapy for a different indication (green arrow). After termination of brtutinib intake (red arrow), a marked increase was seen.  
We initiated genetic testing of the cancer sampled in the second surgery via Foundation One CDx (Foundation Medicine Inc., Cambridge, MA, USA; Hoffmann La Roche AG, Basel, Switzerland). The molecular profile showed the genomic signature of a microsatellite-stable carcinoma with a loss-of-heterozygosity score of 0.0% and a low tumor mutational burden (3 Muts/Mb). Gene alterations were found in ARID1A and MUTYH, as well as an activating oncogenic KRAS G12V mutation. None of the mutations offered any therapeutic consequences, as confirmed by our molecular tumor board.  
In January 2020, ibrutinib was stopped by the treating hematologist after 26 months of therapy due to laboratory signs of hepatitis. The patient was hospitalized due to a deterioration of general condition shortly thereafter. The signs and symptoms were interpreted in the context of relapsing sarcoidosis and treated accordingly. In February 2020, six weeks after discontinuation of ibrutinib, an elevated CA-125 level was registered, without any clinically or radiologically apparent tumor.