Cancer Treatment Guidelines Shift to Biomarker-First
The standard of care for advanced gastroesophageal cancer is now fully biomarker-driven, according to a summary of the 2026 ASCO update. Medical oncologist Dr. Rishabh Jain notes that clinicians must now test for HER2, PD-L1, MMR/MSI, and CLDN18.2 at diagnosis. This represents a major shift from a chemo-first approach to one where biological markers dictate the initial treatment plan.
For decades, the standard approach for many cancers was chemotherapy, a treatment concept that originated from studies on nitrogen mustard during World War II. This method uses powerful drugs to kill rapidly dividing cells, but its lack of specificity means it also damages healthy cells, causing significant side effects. The new biomarker-driven model is a form of "targeted therapy," which works more like a smart missile than a bomb. These drugs are designed to attack specific molecules that help cancer cells grow and spread, such as the HER2 protein, which, when overproduced, fuels cancer growth in some patients. This targeted approach often leads to fewer side effects than traditional chemotherapy. Two of the newly mandated biomarkers, PD-L1 and MMR/MSI status, focus on harnessing the body's own immune system. Some cancer cells use the PD-L1 protein to hide from immune cells, and drugs that block PD-L1 can reveal the cancer to the immune system. A deficient mismatch repair (dMMR) system, leading to high microsatellite instability (MSI-H), is another flag that a tumor may be vulnerable to immunotherapy. The inclusion of Claudin 18.2 (CLDN18.2) highlights the rapid pace of discovery. CLDN18.2 is a protein that appears on the surface of some gastroesophageal cancer cells, and its presence makes the tumor a target for new drugs like zolbetuximab, which was approved after showing it could improve survival when added to chemotherapy. Approximately one-third of patients with this cancer have high expression of CLDN18.2. Identifying these intricate molecular targets is the work of professionals in bioinformatics and computational biology. They design and use complex software to sift through enormous sets of genomic and proteomic data, searching for the unique genetic mutations or protein expressions that can be turned into a drug target. This data-driven work is the essential first step in creating personalized medicines. That data is then used by clinical researchers to design and run the multi-phase trials that test new targeted drugs for safety (Phase I), effectiveness (Phase II), and superiority to existing treatments (Phase III). Finally, medical oncologists and genetic counselors work directly with patients, using the biomarker test results to move away from a one-size-fits-all approach and select the specific treatment most likely to work for that individual's cancer.
