Intragenic rearrangement burden: Broadening Access to Immunotherapy Through Innovative Genetic Testing

Intragenic rearrangement burden: Broadening Access to Immunotherapy Through Innovative Genetic Testing

This groundbreaking discovery has the potential to redefine how cancer patients are selected for immunotherapy. Published in Cancer Immunology Research, this advancement introduces a novel genetic marker known as intragenic rearrangement (IGR) burden. IGR refers to subtle but impactful structural changes within a gene’s sequence, such as duplications, deletions, or relocations of large genetic segments—analogous to rearranging entire paragraphs in an encyclopedia entry. In contrast, tumor mutational burden (TMB) represents smaller changes akin to typographical errors or misspelled words. By identifying these cryptic rearrangements, IGR burden offers a powerful new tool for predicting immunotherapy responses across a broader range of cancer types.

Key Advancements in Immunotherapy Response Prediction

This innovative approach reveals that cancers exhibiting a high IGR burden—structural rearrangements within the genetic code—are more likely to respond positively to immune checkpoint blockade therapies. This finding is especially significant for cancer types such as breast, ovarian, esophageal, and uterine, where current predictive tools have shown limited effectiveness.

Expanding Beyond Traditional Biomarkers

While tumor mutational burden (TMB) has been a key biomarker for predicting immunotherapy success, it is largely effective for cancers with high mutation rates, such as melanoma and lung cancer. Many malignancies—including triple-negative breast cancer, ovarian cancer, uterine cancer, and esophageal cancer—exhibit robust responses to ICB despite having inherently low TMB. This phenomenon highlights the existence of cryptic tumor antigens and underscores the critical need for next-generation biomarkers capable of uncovering these hidden vulnerabilities. IGR burden focuses on structural rearrangements within genes, providing a complementary approach to identifying responsive tumors in cancer types with low TMB.

Evidence from Comprehensive Genomic Analyses and Validation Across Multiple Clinical Trials

Analyses of over 1,000 cancer genomes have highlighted an inverse relationship between TMB and IGR burden across various cancer types. High IGR burden correlates strongly with immune activation markers, including elevated CD8+ T-cell and M1 macrophage signatures. This discovery underscores two distinct cancer classes: TMB-dominant and IGR-dominant tumors, offering expanded opportunities for immunotherapy treatment in IGR-dominant tumors.

Clinical trial datasets, including the MEDI4736 trial for esophageal adenocarcinoma, NeoPembrOv trial for high-grade serous ovarian cancer, two clinical trials for metastatic triple-negative breast cancer, and the IMVigor210 trial for urothelial carcinoma, have demonstrated IGR burden’s strong correlation with immune infiltration and its ability to predict immune checkpoint blockade benefits in TMB-low IGR dominant cancers and in platinum-exposed tumors.

Shaping the Future of Precision Immuno-oncology

With the rapid declining cost of whole genome sequencing (WGS), the integration of IGR burden testing into clinical practice is becoming increasingly feasible. As $100 WGS technologies on the horizon, this approach represents a critical step toward expanding personalized treatment options, particularly for patients with cancers that are historically challenging to treat. Efforts are underway to standardize this innovative technology for broader clinical application. This technological advancement exemplifies how cutting-edge genomic insights can transform cancer care, paving the way for precision oncology solutions that address unmet needs in immuno-oncology and improve outcomes for broader patient populations.