The patient's clinical course was illustrated in  Figure 1A . A 52-year-old female patient presented at the hospital in June, 2018 in a good physical condition, complaining of pain in the middle and upper abdomen accompanied by acid reflux and heartburn over the past 5 months. Her serum CA19.9, SCC, and CEA levels were 65.82 U/ml, 25.5 ng/ml, and 11.65 ng/ml, respectively. An abdomen computed tomography (CT) indicated a tumor measuring 7 x 6 cm located in the tail of the pancreas that invaded the posterior wall of the stomach and the splenic artery, accompanied by multiple hepatic and lymph node metastases in the left supraclavicular fossa ( Figure 1B ). Subsequently an endoscopic ultrasound (EUS)-guided biopsy was performed on the pancreatic lesion and the histological and immunohistochemically tests confirmed a cT4N1M1 primary pure squamous cell carcinoma ( Figure 2A ).
A sequencing performed on the biopsied specimen revealed a stop-gain mutation in BRCA2 exon 11 (c.1830A>T, p.K944*) ( Figure S1 ), which has been reported as a pathogenic germline mutation. In addition, the patient had a tumor mutational burden (TMB) of 5.4 mut/Mb and a stable microsatellite status (MSS). Based on the genetic results, a regimen of nanoparticle albumin-bound paclitaxel (125 mg/m2) combined with cisplatin (75 mg/m2) was eventually decided after a multi-disciplinary panel discussion.
The combined chemotherapy was initiated in July, 2018 ( Figure 1A ). After five cycles of treatment, the patient achieved partial response (PR) on primary pancreatic and metastatic lesions revealed by a total abdomen CT scan ( Figure 1B ) and the serum biomarkers (CA19.9, SCC, and CEA) declined into a normal range. She remained as PR after eight cycles. A magnetic resonance imaging (MRI) was performed in March, 2019 after 10 cycles of combined chemotherapy and showed that both hepatic and lymph node metastases (regional and distanced lymph nodes) achieved complete response (CR) and the primary pancreatic lesion shrank from the initial 5.7 to 1.5 cm in diameter ( Figure 1B ).
Since the imaging examination indicated tumor downstaging, which might be qualified for surgical resection, a preoperative laparoscopy was conducted in April, 2019, and detected multiple nodules on the liver surface. No hepatic space-occupying lesion was detected by the intraoperative US. The nodules on hepatic segments 2, 3, and 4 were resected and sent for histopathological test, and results showed a few malignant tumor cells in the S2 nodule. A laparotomy continued under the request of the patient's family and revealed a lesion of 4 x 3cm in the pancreatic tail and multiple hepatic lesions. Subsequently, a posterior radical antegrade modular pancreatosplenectomy was performed and hepatic metastatic lesions were also resected. Histological examination of the resected specimens revealed severe tumor degeneration after the combined chemotherapy ( Figure 2B ) with vital tumor cells present only in small areas of primary and liver metastatic lesions. Two of the four peripancreatic lymph nodes had severe degeneration; no residual tumor cells were found in lymph nodes (n = 12). The pathological classification of pT3N0M1 was defined. The sequencing on the tumor tissue showed the retaining of BRCA2 K944*, a TMB of 8 mut/Mb and MSS.
The patient experienced postoperative thrombocytopenia (platelet account: 6-9 x 109/L) of unknown cause and the platelet account returned to normal (50-60 x 109/L) 3 months later without any treatment. A repeat PET-CT in July, 2019 showed a liver recurrent lesion of 3.3 cm in diameter. The patient was then treated with olaparib (200 mg per day) combined with pembrolizumab (100 mg per 21 days) and achieved stable disease (SD) on her liver lesion 6 months later. The plasma and matched white blood cell samples of the patient were sent for sequencing using a panel with 520-cancer-related genes. The results confirmed BRCA2 K944* as a somatic mutation, and showed a TMB of 7.98 mut/Mb and MSS status. The patient experienced hepatic artery embolization and severe low platelet count. She died from a cerebral hemorrhage in March, 2020 with an OS of 21 months.