A 73-year-old Chinese female patient was admitted to our hospital in November 2019, complaining of upper abdominal pain for over 2 months. Physical examination presented mild right upper quadrant tenderness. The patient had a history of left radical mastectomy because of early-stage breast cancer 27 years ago, without postoperative treatment. And there was no special family history. Abdominal enhanced computed tomography (CT) showed gallstones and a thickened wall of gallbladder fundus, with enlargement of lymph nodes around the main portal vein. Thoracic CT suggested no obvious abnormality. After routine preoperative examinations, radical cholecystectomy and regional lymphadenectomy were performed on November 15, 2019. Postoperative pathological diagnosis confirmed moderately differentiated adenocarcinoma from the gallbladder (Figure 1), invading the whole layer, involving peripheral fibrofatty tissue and liver parenchyma, with immunohistochemistry (IHC) staining of CK7 (+), CK19 (+), MOC-31 (small partly +), CEA (+), SATB-2 (-), CDX-2 (small partly +) and MIB-1 (+, about 20%). Incisal edges of the distal common bile duct and right hepatic artery were detected for residue cancer cells. The liver incisal edge was negative. Two lymph nodes involving the para-right hepatic artery and posterior pancreatic head lymph nodes were found to be metastatic. The postoperative stage was pT4N1M0, stage IVA. After discussion with her family, the patient refused postoperative chemotherapy.
About two months after surgery, routine postoperative CT imaging on January 10, 2020 revealed peritoneal nodules and enlarged lymph nodes in the ligamentum hepatogastricum and mesentery regions, which indicated metastases. The patient refused chemotherapy again and accepted the suggestion of a gene test. Next-generation sequencing (NGS) of the operative specimen and plasma were performed and showed germline mutation (c.1352_1364del, p. S451Lfs*20) in BRCA1 and somatic mutation in TP53 (exon7 p. E258G) and MUTYH (exon13 p. E420*) genes (3D Medicines Shanghai, China). Tissue-based tumor mutational burden (TMB) was 6.15. Microsatellite status was stable (MSS) and the IHC result of programmed death-ligand 1 (PD-L1) was negative. No meaningful mutations were found in other genes, including the mismatch repair gene (MMR), ERBB2, IDH1/2 and FGFR1/2. It is worth mentioning that the patient's family members also received gene sequencing using blood samples. As she had no siblings and her parents were dead, her only daughter and daughter's son received gene sequencing. The results showed that her daughter has the same germline mutation of BRCA1, while her grandson harbors no germline mutation.
Given that BRCA1 mutation was proven to be a predictor of the Olaparib effect, we prescribed Olaparib 300mg every 12 hours as a first-line treatment on January 20, 2020. Unfortunately, grade 4 anemia occurred after taking Olaparib for about 1 month and was treated with a blood transfusion. The Olaparib dose was then decreased to 150mg every 12 hours and no severe adverse reaction was found. About three months after Olaparib administration, a CT scan revealed significant shrinkage of the peritoneal nodules (Figure 2), with the largest diameter decreasing from 1.58 cm to 0.98 cm, which indicated a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. After taking Olaparib for 6 months, on July 31, 2020 an abdominal CT scan showed a new lesion in the remnant liver and enlarged peritoneal nodules, which meant progressed disease (PD). Considering the dosage of Olaparib was not enough, we suggested to the patient that the Olaparib dosage be reinstated at 300mg every 12 hours. But after careful discussion with her family, our patient decided to stop anti-tumor treatment and obtained a progression-free survival (PFS) of about 6 months. At the most recent follow-up, on March 8, 2021, she was alive and receiving the best supportive care at the local hospital.