A recent study published in Cancer Immunology Research has identified a potential genetic marker that could predict which patients are likely to respond to immunotherapy in cancer types that currently lack such predictive tools. Led by University of Pittsburgh researchers, the study found that tumors with a high number of intragenic rearrangements (IGR) in their genetic code may respond better to immunotherapy. These findings could pave the way for more precise treatment decisions for patients with breast, ovarian, esophageal, and uterine cancers.
Immunotherapy has been a breakthrough in cancer treatment, but only a small subset of patients respond favorably to these treatments. The ability to identify patients who will respond to immunotherapy is crucial, as these treatments can have severe immune-related side effects and may even accelerate cancer progression in some patients. Currently, genetic tests are available that can predict immunotherapy response in melanoma and lung cancer, but they do not work as well in other cancer types.
To bridge this gap, the researchers developed a new approach that analyzes a class of hidden rearrangements in the cancer genome known as IGR. The study analyzed over 1,000 cancer genomes from a diverse range of cancer types using a large database from the International Cancer Genomic Consortium. The findings showed that measuring the overall burden of IGR could potentially predict immune cell infiltration and response to immunotherapy in certain types of cancer.
IGR occurs when there are rearrangements within a gene’s genetic code. In comparison, tumor mutational burden (TMB) measures the number of simple mutations in the DNA of cancer cells. The study found that high TMB, such as in melanoma and lung cancer, is associated with a low IGR burden. On the other hand, breast, ovarian, endometrial, and esophageal cancers have a low TMB but a high IGR burden.
Both high IGR burden and high TMB are correlated with elevated measures of T cell inflammation, indicating that these genetic abnormalities allow immune cells to recognize and possibly destroy cancers more easily. The researchers suggest that there are two distinct classes of cancers: those driven by simple mutations (TMB-dominant) and those driven by intragenic rearrangements (IGR-dominant). This suggests that patients with a high IGR burden may still benefit from immunotherapy even if they have a low TMB.
The researchers tested this hypothesis by examining a clinical trial dataset of patients with esophageal cancer who were treated with the immunotherapy drug durvalumab. The results showed that patients with a higher IGR burden responded better to treatment, while those with disease relapse had a lower IGR burden. They also analyzed a clinical trial dataset of bladder cancer patients treated with the immunotherapy drug atezolizumab and found that TMB, but not IGR burden, predicted response and survival following treatment.
However, among patients whose tumors were exposed to platinum-based chemotherapy before atezolizumab, the IGR burden of the samples collected after platinum predicted immunotherapy response. This suggests that platinum exposure may damage DNA and induce structural rearrangements in the genome.
The researchers believe that these findings could be used by clinicians in different cancer types and contexts to help decide on the best treatment for patients. As the cost of whole-genome sequencing continues to decrease, measuring IGR burden could become feasible and affordable in the near future. The researchers are now working to further develop and standardize their test and algorithm for clinical use.
