Next-Generation Sequencing Finds More Immunotherapy-Eligible Patients

Research has found that next-generation sequencing may be better able to detect DNA mismatch repair.

Most patients with endometrial or colorectal cancer undergo immunohistochemistry (IHC) testing to determine if they have DNA mismatch repair (dMMR), and therefore would benefit from treatment with immunotherapy. However, recent research published in Cancer Cell found that another type of tumor testing — next-generation sequencing — may be better able to detect dMMR.

The researchers analyzed data from a large cohort of patients with colorectal or endometrial cancer who underwent both IHC testing and next-generation sequencing.

dMMR Status Indicates Immunotherapy Eligibility

Findings showed that in approximately 2% of cases, the next-generation sequencing came up positive for dMMR, while the IHC did not. Further, patients who only tested positive on next-generation sequencing tended to have a better response to immunotherapy than other treatments.

“If this were to be applied across the whole United States, this would result in identifications of thousands of patients who would otherwise benefit from immunotherapy,” Dr. Elias Farhat, study author and postdoctoral research fellow at Brigham and Women’s Hospital said in an interview with CURE®. “But if we only do IHC (also known as) tumor staining, they would not begin this (treatment type).”

In fact, in March 2023, the Food and Drug Administration (FDA) approved the immunotherapy agent, Keytruda (pembrolizumab), for the treatment of adults and children with pretreated dMMR or microsatellite instability-high solid tumors.

READ MORE: FDA Approves Keytruda for Adults, Children with MSI-H or dMMR Solid Cancers

Of note, approximately 6% of patients with endometrial cancer and 1% of patients with colorectal cancer are positive for dMMR.

Difference Between IHC and Next-Generation Sequencing

IHC testing is still widely used, however, because it has a quick turnaround time of approximately 48 hours and tends to be more affordable than next-generation sequencing, explained study author, Dr. Amin Nassar, a second-year oncology fellow at Yale Cancer Center.

“It's the first line tests that we typically go for. And it's also recommended by older guidelines in the US, and also in Europe,” Nassar said in an interview with CURE®.

Next-generation sequencing is the “new kid on the block,” according to Nassar. Although it has existed for over 20 years, it has become popular in recent years as more targeted cancer treatments have become available.

The cost of next-generation sequencing has also come down, too, Nassar explained, noting that the test used to cost thousands of dollars, while it is now below $300.

Nevertheless, turnaround time with next-generation sequencing tends to still be longer than what is observed with IHC staining. Waiting one to three weeks for the results can lead to treatment delays and be a prohibitive factor for some patients.

For patients who have a short window of opportunity for a potential cure, Farhat recommends against waiting for next-generation sequencing to determine a treatment plan. For other patients who have treatable but not curable cancers, it might be worth seeing what the next-generation sequencing determines before starting therapy, he mentioned.

Nassar added that newer next-generation sequencing platforms have shorter turnaround times, and many doctors are now doing both IHC and next-generation sequencing — both of which are done via tumor tissue samples — at the same time. Doctors now may not wait for IHC testing to come back to decide to do further next-generation sequencing.

“For now we would not recommend (next-generation sequencing) as a replacement (to IHC testing); we would recommend it as a complementary test to IHC,” Nassar said.
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