Next-Generation Sequencing May Help Improve Access to Immunotherapy Among Patients With Cancer and Mismatch Repair Deficiency

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Next-generation sequencing may help better identify patients with cancer and mismatch repair deficiency who may benefit from immunotherapy, according to a recent study published by Farhat et al in Cancer Cell. The new findings indicated that treating more patients with immunotherapy may require revisions to the current cancer care guidelines.


Over 150,000 and 65,000 patients in the United States are diagnosed with colorectal cancer and endometrial cancer per year, respectively. Patients with these types of cancers often have higher rates of mismatch repair deficiency—a genetic state where errors in the DNA caused by a lack of certain repair proteins can impair the DNA’s ability to repair itself and lead to the development of cancer. Previous studies have found that immunotherapy may be highly effective in patients whose tumors harbor mismatch repair deficiency.

Immunohistochemistry is the current standard-of-care test to identify patients with mismatch repair deficiency. However, the test is only capable of detecting mutations that affect the antigen, whereas next-generation sequencing is a more sensitive test because it senses more mutation characteristics.

“In colorectal cancer and endometrial cancer, which are the two types of cancer where mismatch repair deficiency is most commonly seen, immunotherapy is not the standard treatment unless a patient has this condition,” explained lead study author Elias Bou Farhat, MD, a postdoctoral research fellow in the Division of Pulmonary and Clinical Care Medicine at Brigham and Women’s Hospital. “[However], in patients with this condition, even in late-stage cancer, those who receive immunotherapy can live for years and in some cases be potentially cured. Including next-generation sequencing as a complimentary testing practice could benefit patients in all phases of cancer, from pretreatment to advanced stages,” he emphasized.

Study Methods and Results

In the new study, investigators analyzed the data of 1,655 patients with colorectal cancer or endometrial cancer who received both immunohistochemistry and next-generation sequencing tests. They discovered that about 6% of the patients with endometrial cancer and 1% of the patients with colorectal cancer who had mismatch repair deficiency were missed by immunohistochemistry. In these cases, the condition was successfully detected by next-generation sequencing.

These patients responded better to immunotherapy than other treatments and their survival and treatment outcomes were similar to those who were found deficient by both tests. In patients with the same cancer type and stage, those who did not receive immunotherapy had worse outcomes than those who did receive the treatment. The investigators estimated that the novel strategy could identify 6,000 additional U.S. patients with cancer who would otherwise not be offered immunotherapy.


Although the new research suggested that next-generation sequencing could be a more sensitive diagnostic tool in patients with mismatch repair deficiency, further studies may be needed to validate the findings. The investigators plan to examine whether their new findings apply to other sequencing panels and other cancer types. They also hope to investigate the potential role of other genetic deficiencies involved in mismatch repair deficiency.

“We don’t want to miss these patients or we could be depriving them of a treatment that can have long-term benefits,” underscored senior study author Amin Nassar, MD, a member of Yale Cancer Center. “We also want to avoid giving patients treatments that could be more toxic and/or less effective; we want to treat patients with the appropriate therapy,” he concluded.

Disclosure: For full disclosures of the study authors, visit

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