A 52-year-old woman underwent laparoscopic total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and dissection of pelvic and para-aortic lymph nodes in June, 2018. Pathological findings confirmed the diagnosis of stage IIIA serous papillary adenocarcinoma mixed with endometrioid carcinoma with squamous differentiation (~70% for serous carcinoma component and 30% for endometroid carcinoma component, respectively) (Figure 1A), with tumor metastasis to both fallopian tubes. Immunohistochemistry analysis showed loss of MSH2 (Figure 1B) and MSH6 (Figure 1C) protein expression in the EEC component. She received 6 cycles of paclitaxel and carboplatin as adjuvant therapy with complete response. Postoperative routine follow-up examination in May, 2019 showed that serum CA125 was elevated (71.66 U/ml), but CT examination did not reveal any abnormalities. The level of serum CA125 increased to 100.90 U/ml after 1 month, and ultrasound examination also showed enlarged paraaortic lymph node of 2.5 cm in diameter, suggesting tumor recurrence. Rechallenge of paclitaxel and carboplatin for one cycle failed with continued increase of CA125 to 120.1 U/ml. Subsequently, the patient switched to oxaliplatin combined with pegylated liposomal doxorubicin for one cycle with primary progression. Evaluation after the chemotherapy on August 1, 2019 showed serum CA125 level increased to 231.6 U/ml. CT scan suggested an enlarged left para-aortic lymph node (37*30 mm) (Supplementary Figures 1A,E).
The patient came to our hospital for second opinion. To seek for potential targeted therapies and immunotherapies, paired tumor-normal next-generation sequencing of 1,021 cancer-related genes was performed using tumor tissue and peripheral blood. Of great interest, two heterozygous germline mutations in BRCA1 (NM_007294.3 c.3348_3351delAGTT p.V1117Rfs*11) and MSH2 (large deletion of exons 4-16) were identified (Figures 2B-D). Besides, a total of 72 somatic mutations were detected, including putative or known functional mutations in PTEN, ARID1A, TP53, FBXW7, and KRAS (Supplementary Table 1). In addition, genetic testing results showed that microsatellites were highly unstable, and tumor mutation burden was extremely high (51.84 muts/Mb).
To access the cancer risk for the family members of the patient, Sanger sequencing and RT-PCR were performed to confirm the presence of germline BRCA1 and MSH2 mutations in her family members, although she has no family history of cancer. Her younger sister (I-4) and daughter (II-2) carry the BRCA1 and MSH2 mutations, respectively. Unfortunately, her son harbors both the BRCA1 and MSH2 mutations (Figures 2A, Supplementary Figures 2, 3).
The patient was then treated with 200 mg intravenous tislelizumab every 3 weeks from September 4, 2019. Partial remission was achieved at 9 weeks after treatment with the shrinkage of an enlarged left para-aortic lymph node (Supplementary Figures 1B,F). In addition, the normalization of serum CA125 (12.28 U/ml) was observed after 2 months of treatment. CT scan at 15 weeks after treatment demonstrated continuous shrinkage of the enlarged lymph node (Supplementary Figures 1C,G). She has been on treatment for 4 months, and discontinued the treatment for 2 months due to the impact of COVID-19 outbreak. Fortunately, the CT scan did not reveal progression as a result of drug interruption (Supplementary Figures 1D,H). She continued the treatment and is still in follow-up. During the treatment, she experienced grade 1 treatment-related elevation of alanine transaminase (ALT) and aspartate transaminase (AST), which was relieved after symptomatic treatment.