Rare case of human epidermal growth factor receptor 2-positive gastric remnant cancer after bariatric surgery—case report

Gastric cancer is among the most common malignant solid tumors. Men are approximately twice as likely to be affected as women. The incidence varies significantly by country and continent. Annually about 1.1 million cases of gastric cancer are diagnosed worldwide. Acquired risk factors include, among others, obesity, Helicobacter pylori infection of the gastric mucosa, diet, alcohol, and nicotine consumption [1].

Early gastric cancers are often asymptomatic. Symptoms like dyspepsia, vomiting, weight loss, and gastrointestinal bleeding often only occur in advanced stages [2].

Endoscopy is considered the most sensitive and specific diagnostic method. Therapy depends on the stage and the HER2 and PDL1 status [1].

Trastuzumab as an add-on in first-line therapy significantly improved treatment options of HER2-positive metastatic gastric carcinomas. For second-line treatment, it was recently shown that trastuzumab deruxtecan resulted in a significant benefit over standard chemotherapy [3‐5].

A 58-year-old man with a medical history of bariatric Roux-en‑Y gastric bypass (RYGB) surgery 9 years ago presented at our institution in 2021 with weight loss of 10 kg (body weight at the time of diagnosis: 129 kg), abdominal pain, diarrhea and hematochezia for the prior 2 months. Besides the gastric bypass, the patient had a history of idiopathic pulmonary embolism diagnosed in 2011. Regarding the family history, the patient reported that his father suffered from lung cancer.

Diagnostic workup included upper gastrointestinal (GI) endoscopy, which was unremarkable except for mild reflux esophagitis and colonoscopy, showing hemorrhoids grade 3 as potential cause of the bleeding. Due to persistent abdominal pain, we conducted an abdominal computed tomography (CT) scan with oral and intravenous contrast, which revealed para-aortic and mesenterial lymphadenopathy (Fig. 1). A thoracic CT scan demonstrated mediastinal lymphadenopathy. An endobronchial ultrasound-guided needle biopsy of paratracheal lymph nodes showed no evidence of malignancy. With persisting symptoms and extensive lymphadenopathy, we conducted an 18F-FDG PET-CT scan, detecting several cervical tracer-enriched lymph nodes and suspect lymph node stations in the mediastinum and abdomen. One suspicious, wire-marked supraclavicular lymph node was removed. Histological analysis demonstrated a poorly differentiated adenocarcinoma of gastrointestinal origin with HER2 positivity on FISH testing. Serum levels of CEA (18.3; normal 0–3 ng/mL) and CA72‑4 (11.1; normal 0–6.9 U/mL) were above the normal range. Although previous endoscopy showed normal findings, the histology strongly suggested a malignancy of gastrointestinal origin. Together with the department of nuclear medicine, we re-examined the diagnostic imaging, detecting slight tracer enrichment at the site of the gastric remnant. These results prompted an explorative laparoscopy to confirm the diagnosis. Wedge resection of the anterior wall of the gastric antrum was performed (Fig. 2). No peritoneal carcinosis or dissemination to other organs was detected. Subsequent histology taken from the gastric remnant confirmed the diagnosis of HER2-positive gastric cancer on immunohistochemistry testing (HER2 3+) with distant lymph node metastasis (intestinal type Lauren pT3, NX, L1, V1, R0, M1; UICC IV).

Our interdisciplinary tumor board discussed the treatment plan for this patient. We indicated a first-line therapy with trastuzumab, 5‑fluorouracil (5-FU), and oxaliplatin. Due to potential changes in the pharmacokinetics of orally administered 5‑FU after gastric resection, we chose intravenous administration using the FLO protocol in combination with trastuzumab (4 mg/kg) every 2 weeks, given the HER2 positivity. We excluded a DPD mutation before starting chemotherapy. After 7 cycles of FLO and trastuzumab, the patient’s tumor marker levels returned to normal. Restaging with PET-CT showed near-complete response. The patient developed grade 3 neuropathy as a side effect, prompting us to stop treatment. Maintenance therapy with trastuzumab was omitted in accordance with the patient’s wish to take a treatment break. Restaging with PET-CT 3 months after discontinuing therapy revealed progressive disease with lymphadenopathy and cholestasis, and a rise in tumor marker levels. The patient presented with painless jaundice due to malignant stenosis of the main bile duct and was transferred to a tertiary care hospital. Lumen-apposing metal stent (LAMS) gastrogastrostomy and endoscopic retrograde cholangiopancreatography (ERCP) were performed with stenting of the main bile duct. Unfortunately, the patient presented at our clinic shortly after this intervention with acute abdomen and sepsis. We presumed acute cholecystitis with a consecutive concealed perforation of the gallbladder as the cause in the CT scan. Therefore, we performed an emergency laparotomy showing an extensive peritonitis and biliary ascites due to a retroperitoneal leakage. Due to the findings after intra-abdominal lavage an abdominal-VAC was placed. Two days later a second look with conventional cholecystectomy was performed. We could not see any sign of gallbladder perforation, which is why, with the spontaneous cessation of the retroperitoneal leakage, a microperforation following ERCP was assumed. Apart from antibiotic therapy, no further intervention was necessary. The postoperative recovery was uneventful.

Therefore, a second line of chemotherapy treatment was commenced. There was no biopsy taken at the acute interventions but because of the previously known HER2 positivity we initiated treatment with trastuzumab deruxtecan through a named patient program. After three cycles, imaging and tumor levels showed partial remission, and the patient experienced no severe side effects. As of the last staging in October 2024, after 26 cycles, the disease remains stable.

Bariatric surgery offers benefits for patients suffering from obesity [6].

On the other hand, as this case shows, diagnosis and therapy of gastric cancer are more complex due to the changed anatomic situation. This affects surgical procedures as well as pharmacokinetics especially regarding absorption. While the reduction in overall cancer incidence after bariatric surgery is well-documented [7, 8], evidence regarding the incidence of gastric tumors is controversial. However, a recent large cohort study was able to show a decrease in incidence [9, 10]. HER2 positivity was found in 22.1% patients with gastric cancer screened for the Toga trial [3]. The Toga trial demonstrated that adding trastuzumab to chemotherapy (capecitabine plus cisplatin or fluorouracil plus cisplatin) significantly improves overall survival and progression-free survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer [3]. Although those patients had a good therapeutic option for first-line therapy, there were negative trials for second-line therapy (e.g. tyrosine kinase inhibitor, trastuzumab emtansine) [11].

The antibody–drug conjugate trastuzumab deruxtecan has shown high efficacy in HER2-positive breast cancer [12]. After that, efficacy was also shown in other entities like lung cancer and gastric cancer [4, 5, 13]. The profile of side effects resembles chemotherapy more than the typical antibody adverse effects. Beside typical chemotherapy side effects like nausea, anemia, and neutropenia, one has to be aware of the risk of pneumonitis during the first year of treatment [4]. In this case, the therapy with trastuzumab deruxtecan has been well tolerated over a long period and has kept the disease stable. No severe side effects occurred. Because of gastrointestinal side effects and fatigue, we eventually reduced the dose to 75% and extended the dosing interval to 4 weeks.

In the event of progression, there is no guideline for third-line therapy. Irinotecan, paclitaxel/ramucirumab or ramucirumab monotherapy are available as standard treatment options [14, 15]. Several studies are ongoing for HER2-positive gastric cancer ranging from immune activation with checkpoint inhibitors or novel substances like evorpacept to small molecules like pyrotinib, regorafenib or apatinib [15‐20].

Diagnosis of gastric cancer can be challenging after prior surgery. Consistent follow-up after bariatric surgery is required and physicians must be aware of diagnostic challenges after bariatric surgery. For patients with HER2-positive gastric cancer who progress after first-line treatment, trastuzumab deruxtecan is a therapeutic option that in some cases leads to rather long progression-free survival.