A pan-tumor approach to cancer treatment represents a modern shift in oncology. This method focuses on the unique genetic and molecular characteristics of a tumor, rather than its origin in a specific organ or tissue. It recognizes that cancers from different parts of the body can share underlying genetic abnormalities that drive their growth. By identifying these shared molecular features, doctors can target specific alterations, regardless of where the cancer first appeared. This approach aims to personalize cancer care by matching therapies to an individual’s tumor.
The Genetic Basis of Pan-Tumor Analysis
The pan-tumor approach is based on the understanding that various cancers, despite diverse origins, can exhibit identical genetic mutations or molecular biomarkers. These shared anomalies act as common drivers, influencing how cancer cells grow. For instance, Microsatellite Instability-High (MSI-H) is a biomarker with a high number of mutations within short, repeated DNA sequences. This instability often arises from a defect in the cell’s DNA mismatch repair (MMR) system, which corrects errors during DNA replication. While MSI-H is frequently found in colorectal, gastric, and endometrial cancers, it can also appear in other tumor types, indicating a common genetic vulnerability.
Another pan-tumor biomarker is Tumor Mutational Burden (TMB), which quantifies the total number of genetic mutations in a cancer cell’s DNA. Tumors with high TMB are believed to produce more abnormal proteins that the immune system can recognize. TMB levels vary widely across cancer types, with some, like melanoma and lung cancer, often exhibiting higher burdens. Additionally, specific gene fusions, such as those involving the Neurotrophic Tyrosine Receptor Kinase (NTRK) genes, are pan-tumor targets. These fusions occur when an NTRK gene joins with another, producing abnormal TRK fusion proteins that drive uncontrolled cell growth. While rare, NTRK fusions have been identified in over 25 different types of solid tumors, including those of the brain, head and neck, thyroid, and lung.
Identifying Pan-Tumor Targets
Determining specific genetic alterations within a tumor requires advanced diagnostic methods. Comprehensive genomic profiling (CGP) is a primary technology used to identify these pan-tumor biomarkers. CGP employs next-generation sequencing (NGS) to simultaneously analyze hundreds of cancer-related genes. This allows for the detection of various genetic changes, including mutations, insertions, deletions, gene amplifications, and fusions.
These genetic analyses are typically performed on a tumor tissue sample obtained through a biopsy. If a tissue biopsy is not feasible or to monitor disease progression, a liquid biopsy can be used. A liquid biopsy analyzes a blood sample for circulating tumor DNA (ctDNA), fragments shed by tumor cells. NGS applied to liquid biopsies provides a non-invasive way to gain insights into a tumor’s genetic makeup.
Pan-Tumor Therapeutic Approaches
Once a pan-tumor biomarker is identified, clinicians can use “tumor-agnostic” or “histology-independent” drugs. These therapies target the shared molecular alteration, rather than the cancer’s anatomical location. The main categories are targeted therapies and immunotherapies.
Targeted therapies interfere with specific molecules involved in cancer growth. For example, larotrectinib is approved for tumors with NTRK gene fusions. This drug selectively inhibits the abnormal TRK fusion proteins that drive cancer cell proliferation, blocking signaling pathways and inducing cell death. It binds to TRK proteins, preventing their activation and halting uncontrolled growth.
Immunotherapies harness the patient’s own immune system to fight cancer. Pembrolizumab, an immune checkpoint inhibitor, is a tumor-agnostic immunotherapy approved for MSI-H or high TMB cancers. Cancer cells often express proteins like PD-L1 that bind to PD-1 receptors on immune T-cells, allowing cancer to evade detection. Pembrolizumab blocks this PD-1/PD-L1 interaction, reactivating the immune system’s ability to recognize and destroy cancer cells. Tumors with MSI-H or high TMB often have more mutations, leading to abnormal proteins the reactivated immune system can target.
Distinguishing from Traditional Cancer Models
The pan-tumor approach fundamentally differs from traditional cancer models in classification and treatment. Historically, cancer was classified and treated based on its organ or tissue of origin. This conventional model categorizes cancers as, for instance, “lung cancer” or “breast cancer,” with treatment protocols determined by the anatomical site and microscopic appearance. Therapies were developed for specific organ-defined cancers, often using broad treatments like chemotherapy or radiation.
In contrast, the pan-tumor model transcends anatomical boundaries. It redefines cancer by its shared molecular targets or genetic alterations, irrespective of the tumor’s site of origin. Under this approach, a patient with a rare tumor might receive the same therapy as a patient with a common cancer if both tumors share an identical underlying genetic mutation. This shift allows for a more personalized and effective treatment strategy, focusing on the specific biological drivers of the disease.