Gastrointestinal stromal tumor (GIST)

GIST is the most common mesenchymal tumor of the gastrointestinal tract, arising from the interstitial cells of Cajal and typically driven by activating mutations in KIT (CD117) or PDGFRA.

Oncology Pharmacist Key Points

• Molecular driver: KIT (~75–80%) or PDGFRA mutations
• Common sites: Stomach > small intestine
• Targeted therapy backbone:
  • Imatinib (first-line for sensitive mutations)
• Mutation subtype determines:
  • Dose (e.g., KIT exon 9 may need higher dose)
  • Resistance patterns
  • Sequencing strategy

Genomic Drivers and Biomarkers

The management of gastric and esophageal cancers relies heavily on molecular testing to guide targeted therapy:

• HER2-neu: This protein is amplified in approximately 12–23% of gastric cancer patients and 15–30% of esophageal adenocarcinoma patients. It is more common in intestinal-type histology and gastroesophageal junction (GEJ) tumors. All patients with advanced adenocarcinoma should be tested for HER2 expression.
• PD-L1: Expression of Programmed Death 1 Ligand (PD-L1) is reported using the Combined Positive Score (CPS). It predicts response to immunotherapy; for example, PD-L1 CPS ≥5 or ≥10 often indicates a better response to checkpoint inhibitors like nivolumab or pembrolizumab.
• dMMR/MSI-H: Patients with mismatch repair deficiency or high microsatellite instability are candidates for neoadjuvant or perioperative immunotherapy.
• CDH1: Germline mutations in this gene are associated with hereditary diffuse gastric cancer, for which prophylactic total gastrectomy is recommended between ages 18 and 40.

Treatment Regimens for Gastric Cancer

The primary goal for localized disease is cure through surgery, often accompanied by systemic therapy.

• Perioperative Standard: The FLOT regimen (5-FU, leucovorin, oxaliplatin, and docetaxel) is the Category 1 preferred standard of care for medically fit patients with localized gastric cancer. It replaced older regimens like ECF/ECX because it significantly improved overall survival.
• Postoperative Care: Patients who receive less than a D2 lymph node dissection may require postoperative chemoradiation. For those who have had a D2 dissection, capecitabine + oxaliplatin is a standard chemotherapy option.

Treatment Regimens for Esophageal Cancer

Esophageal cancers are treated based on their histology: adenocarcinoma or squamous cell carcinoma (SCC).

• Preoperative Approach: For localized adenocarcinoma of the thoracic esophagus or EGJ, preoperative chemoradiation is the preferred approach. The CROSS trial established that carboplatin and paclitaxel combined with radiation doubled overall survival compared to surgery alone.
• Adjuvant Immunotherapy: For patients with residual pathologic disease after preoperative chemoradiation and surgery, nivolumab is recommended to improve disease-free survival.
• Definitive Chemoradiation: This may be curative for patients who are not surgical candidates or for those with cervical esophageal cancer.

Metastatic and Subsequent-Line Therapy

For advanced disease, the focus shifts to palliative treatment to improve quality of life and survival.

• First-Line: Treatment usually consists of a platinum-based doublet (e.g., FOLFOX or CAPEOX) combined with trastuzumab (if HER2 positive) and/or an immunotherapy agent like nivolumab or pembrolizumab.
• Subsequent-Line: Options include ramucirumab (an anti-VEGFR2 antibody) alone or with paclitaxel, fam-trastuzumab deruxtecan-nxki for HER2-positive cases, and trifluridine/tipiracil for those who have progressed on at least two prior lines of therapy