Cracking Cancer’s Code: How Genetic Testing Is Changing the Treatment Game

Cancer treatment has moved beyond the one-size-fits-all approach of chemotherapy and surgery, with genetic testing now leading the shift toward precision medicine. By analyzing a tumor’s genetic makeup, doctors can tailor treatments, including immunotherapy, to each patient and adjust strategies as the disease evolves. However, challenges such as accessibility, data interpretation, and clinical integration remain. To explore these issues, we spoke with Dr. Chien-Feng Li and Senior Specialist Li-Ching Wu, who shared how genetic testing is transforming cancer care, the hurdles that still exist, and what’s needed to maximize its impact.

From One-Time Test to Ongoing Tracking: Genetic Testing’s Role in Personalized Therapies

Genetic testing in cancer treatment has shifted from a single test at diagnosis to continuous monitoring, allowing doctors to track how tumors evolve and adapt. “Cancer is a disease that is difficult to fully understand with just a single test,” explained Dr. Li. “Unlike certain hereditary diseases where genetic mutations are fixed, cancer evolves. Tumors adapt to their environment and mutate, which is why some drugs initially work but later lose their effectiveness. We cannot rely on a single test at diagnosis; instead, we must continuously monitor changes throughout treatment to identify new strategies when therapy fails.”

Despite its potential, widespread adoption of genetic testing faces hurdles, from sample processing to data analysis and clinical application efficiency. To overcome these challenges, modern laboratories are integrating automation and expanding testing methods. Multi-gene panel tests and high-throughput next-generation sequencing (NGS) now incorporate highly sensitive liquid biopsy techniques alongside traditional tissue testing, improving accuracy and efficiency. These advancements ensure genetic testing results are more precise and better aligned with real-time clinical needs.

Tumor Microenvironment: Decoding Cancer’s “Safe Haven”

Genetic testing in cancer has expanded beyond just the tumor itself to include the tumor microenvironment (TME), which acts as a “safe haven” that can influence how tumors evade treatment. “Some tumors are incredibly ‘smart’—they manipulate their surroundings to protect themselves, preventing the immune system from attacking,” Dr. Li explained. “For example, regulatory T cells (T-regs) suppress immune responses, reducing the effectiveness of immunotherapy. In these cases, even if a patient undergoes immunotherapy, the tumor can still find ways to survive. This explains why some patients do not respond well to immunotherapy.”

As research advances, scientists now use RNA sequencing technology to analyze the cellular composition of the TME, enabling more personalized treatment strategies. “We no longer focus solely on tumor genetic mutations; we now examine the surrounding environment to determine what factors influence treatment response. Only by doing so can we truly find ways to combat cancer,” Dr. Li emphasized. This shift in focus is critical as understanding the TME’s role in treatment resistance helps improve outcomes, particularly in immunotherapy.

New Subtypes and Advanced Profiling Techniques in TME Analysis

Research has categorized the TME into four subtypes—immune-enriched with fibrosis (IE/F), immune-enriched without fibrosis (IE), fibrotic (F), and immune-depleted (D)—based on 29 functional gene expression features. These subtypes are closely linked to how patients respond to immunotherapy. Those in immune-favorable subtypes (IE/F and IE) tend to benefit more from immunotherapy, while those in fibrotic (F) and immune-depleted (D) subtypes have weaker responses.

By analyzing TME characteristics, researchers have gained a deeper understanding of both anti-tumor and pro-tumor environments. Anti-tumor environments include cytotoxic T cells, natural killer cells, and anti-tumor cytokines, while pro-tumor environments feature factors like checkpoint inhibition, T-reg cells, and granulocytes. These mechanisms are integrated with angiogenesis, fibrosis, and tumor cell properties to provide a comprehensive view of the TME’s complex structure.

One breakthrough in this area is Gene Expression Profiling (GEP), an 18-gene analysis that characterizes T-cell activation in the TME. This 18-gene analysis model has shown that GEP expression correlates with improved clinical outcomes across nine different cancers treated with anti-PD-1 drugs, such as pembrolizumab. “Higher GEP expression is associated with a greater proportion of treatment responders, indicating superior therapeutic outcomes,” Dr. Li explained. Since GEP and tumor mutational burden (TMB) only have a moderate correlation, combining both metrics offers complementary insights, improving the accuracy of identifying patients who will respond to immunotherapy. TMB reflects the tumor’s mutation rate, while GEP indicates T-cell activation within the TME. Combining both analyses improves the accuracy of identifying patients likely to benefit from anti-PD-1 therapy. This approach, tailored to different TME types, advances precision cancer treatment, bringing us closer to the promise of personalized medicine.

RNA Sequencing: A Key to Understanding Tumors’ “Immune Hide-and-Seek” Strategy

Commercial NGS kits are now available that can analyze tumor microenvironment characteristics through Target RNA sequencing from clinical FFPE samples, providing more insights for immunotherapy research.

Cancer cells don’t simply sit idly by waiting for the immune system to attack—they have evolved sophisticated strategies to evade detection, making treatment more challenging. One of the most well-known methods is the manipulation of regulatory T cells (T-regs), which play a crucial role in suppressing immune responses. “T-regs normally function to prevent autoimmune diseases,” explained Dr. Li, “but in the tumor microenvironment, they become accomplices, suppressing immune responses so that the immune system ‘does not dare to touch the tumor.’” 

As the number of T-regs increases, the effectiveness of immunotherapy declines. This poses a significant challenge for treating cancers with immunotherapy, as these tumors become adept at counteracting treatment efforts. RNA sequencing is crucial for understanding how tumors hide from the immune system. It tracks immune regulators like T-regs, which suppress immune responses and reduce the effectiveness of immunotherapy. Dr. Li emphasized, “As T-reg levels rise, immunotherapy becomes less effective.”

Beyond tracking T-regs, RNA sequencing lets researchers explore how these immune cells interact within the TME. This deeper dive into tumor evasion tactics opens the door for personalized treatments that can overcome these immune escape strategies.

Evasive Tactics for Precision Immunotherapy Through RNA Sequencing

RNA sequencing (RNA-seq) is revolutionizing our understanding of how tumors evade immune attacks. By analyzing tumor and microenvironment RNA profiles, researchers can pinpoint critical immune response genes and the key mechanisms tumors use to avoid detection. “RNA sequencing allows us to identify immune checkpoints tumors exploit, uncover targets for next-gen immunotherapies, and tailor more effective treatments based on tumor specifics,” explained Dr. Li.

As this technology advances, RNA sequencing holds great promise for precision immunotherapy. It helps craft personalized treatment plans by decoding the tumor’s genetic “language” and understanding how it interacts with the immune system. These insights are set to transform cancer care, offering more targeted and effective therapies to patients.

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Author

Bernice Lottering