Because preoperative staging was deemed highly unreliable, a majority of panelists voted for combined pre- and postoperative chemotherapy (even in localized cancers without lymph node involvement, T2N+ or T2N0), combined with a modified D2 resection (i.e., without resection of the pancreatic tail and without routine splenectomy). Adjuvant chemotherapy or radiochemotherapy was considered for patients Smoothened antagonist who had not received perioperative treatment. There were comments that radiochemotherapy should be
preferred in patients with lymph node involvement or inadequate lymphadenectomy. For pre- or perioperative treatment, a doublet of fluoropyrimidine/platinum was the most widely recommended regimen (e.g., cisplatinum/5-FU, cisplatinum/capecitabine and oxaliplatin/capecitabine). Some considered the addition of taxane as appropriate for the preoperative induction regimen. The addition of trastuzumab to a platinum/fluoropyrimidine combination is a new standard first-line therapeutic regimen for patients with advanced
HER2-positive GC. Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor. In the ToGA trial, trastuzumab in addition Dabrafenib research buy to chemotherapy prolonged the median overall survival from 11.8 months to 16.0 months in a selected group of patients with advanced GC overexpressing the HER-2 protein . However, the addition of trastuzumab to chemotherapy in patients with HER2-positive GC led to an additional absolute increase in response rate of only 12%, indicating the existence of a high primary trastuzumab resistance in this subpopulation. Furthermore, the majority of patients who had initially responded to the treatment developed acquired or secondary resistance. The molecular mechanisms underlying trastuzumab resistance are not yet well characterized. New targeted therapies 上海皓元医药股份有限公司 to overcome trastuzumab resistance
as well as to improve the outcome of patients with HER2-negative GC are currently being evaluated in clinical trials. HER2 is the preferred heterodimerization partner of the other HER family members, and the HER2-HER3 heterodimer is the most active HER signaling dimer, playing a critical role in oncogenic transformation in HER2-driven tumors . Dimerization is followed by transactivation of the receptor, which subsequently activates downstream proteins, including members of the Ras/Raf/mitogen-activated protein kinase (Ras/Raf/MAPK) and phosphatidylinositol-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways, as well as gene transcriptional programs . Trastuzumab binds to domain IV of the HER2 extracellular domain and does not inhibit the dimerization of HER2 with ligand-activated HER3 . In contrast, pertuzumab, a humanized monoclonal antibody directed against the extracellular heterodimerization domain II of HER2, effectively blocks HER2/HER3 heterodimerization.