DURHAM, NC — Chemotherapy has long been a component in the first-line treatment for advanced or metastatic colorectal cancer (mCRC). A number of studies in recent years indicate that a subset of patients with specific genetic mutations do not respond well to the recommended 5-fluorouracil-based regimens, such as FOLFOX (5-FU, oxaliplatin, and leucovorin) or FOLFIRI (5-FU, irinotecan, and leucovorin) alone or in combination with other agents.
For patients with both mismatch-repair deficiency (dMMR) and high microsatellite instability (MSI-H), recent research shows that immunotherapies provide a better option and longer survival. About 15% of CRC patients have dMMR which makes cells unable to recognize and fix errors introduced when DNA is copied. When the mutations cannot be repaired, they start accumulating and may become cancerous. When more than 30% of short, repeated sequences of DNA (microsatellites) in cancer cells have a high number of mutations, they are considered to be MSI-H.
Generally, dMMR is associated with MSI-H, but the two biomarkers are assessed by different methods, which sometimes show that one is present without the other. Immunohistochemical (IHC) staining uses biopsied tissue to detect dMMR, while polymerase chain reaction (PCR) tests compare biopsied tissue to normal tissue to assess microsatellite instability. MSI-H can also be determined by next-generation sequencing (NGS).
Researchers from the Durham, NC, Albuquerque, NM, and Tampa, FL, VAMCs sought to determine whether immune checkpoint inhibitors (ICIs) were effective in patients with discordant dMMR and MSI-H.
To do so, they accessed records for veterans with colorectal cancer and an MSI-H biomarker determined by NGS in the VA National Precision Oncology Program Database. Of the 1,276 patients with CRC, 71 (5.6%) had MSI-H by NGS. Among the 71 patients, 29 had dMMR IHC testing, while eight had MSI-H PCR testing and one had both types of testing. The remainder had only NGS testing.1
The researchers found that NGS and PCR testing were completely consistent, but eight of the 29 IHC tests were discordant with NGS results. Of those eight, five received an ICI and four responded, with three having durable response without progression at a median of 8.5 months.
Based on these results, proceeding with NGS in patients with discordant PCR/IHC testing will likely resolve the discrepancy. “In a cohort of NGS MSI-H colorectal cancer patients, there was a high rate of discordant IHC results,” the VA researchers noted. “Clinical benefit is seen in patients treated with ICI with discordant testing results, suggesting that NGS testing identifies patients with false-negative dMMR IHC testing in the real-world clinical setting.”
- Isaacs J, Guo A, Vashistha V, Katsoulakis E, Boswell E, Strickler JH, Ahmed S, Kelley MJ. Clinical outcomes of immune checkpoint inhibitor (ICI) therapy among Veterans Affairs patients with colorectal cancer and discordant dMMR/MSI-H status. J Clin Oncol. 2022;40 (suppl 16; abstr 3534).