Deficient DNA Mismatch Repair in Rectal Cancer

A recent study’s findings provide a starting point for assessing the efficacy of immunotherapy in rectal cancer patients with deficient DNA mismatch repair (dMMR).

dMMR status has long been established as an important prognostic biomarker in colorectal cancer, but breakthroughs in therapy for dMMR associated disease have been slow in coming, said Y. Nancy You, M.D., an associate professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center and the study report’s senior author. However, recent developments in cancer immunotherapy are changing this paradigm. Early trials in patients with colorectal and other cancers have demonstrated that patients with dMMR have better responses to immunotherapy drugs, particularly immune checkpoint inhibitors, than do those without dMMR. Now, additional clinical trials of immunotherapy with or without conventional therapy for patients with dMMR-associated colorectal cancer are rapidly gathering on the horizon.

“All of a sudden, several forces are coming together: we have this cohort of patients with a genetically defined syndrome, and there’s this phenomenal approach to treatment that’s becoming available to them,” Dr. You said. “But at the same time, it’s never been established how the subset of patients with dMMR rectal cancer specifically do with just conventional therapy.”

Thus, Dr. You and her colleagues designed a retrospective study to assess the outcomes of patients with dMMR rectal cancer following standard multimodality therapy. This information can provide a baseline for comparison when such patients are enrolled in the upcoming clinical trials of new immunotherapies. Although the implications of dMMR status in colon cancer patients have been largely defined—in general, patients with dMMR have a better prognosis than do those without dMMR—these implications were not known in rectal cancer patients. The recent study showed that the prognosis of rectal cancer patients with dMMR tended to be much better than that of rectal cancer patients without dMMR.

The study also demonstrated that currently available multimodality therapy for dMMR rectal cancer offers a chance at a cure. Patients with stage I or II disease had a 5-year rectal cancer– specific survival rate of 100%, and those with stage III and IV disease had 5-year rectal cancer–specific survival rates of 85% and 60%, respectively. The vast majority of patients (95%) underwent surgical resection with curative intent, and most of those patients (66%) received adjuvant chemotherapy. About three-fourths of the patients with stage III or IV disease also received neoadjuvant fluoropyrimidine-based chemotherapy and pelvic radiation therapy; this regimen was associated with a complete pathological response rate of 28%.

The study’s findings also confirmed the importance of screening rectal cancer patients for dMMR. dMMR is the hallmark of Lynch syndrome (previously known as hereditary nonpolyposis colorectal cancer), a hereditary cancer disorder that increases patients’ lifetime risk for colorectal and other cancers and has implications for patients’ blood relatives. Lynch syndrome is caused by defects in mismatch repair genes including MLH1, MSH2, MSH6, and PMS2. Most patients in the study had Lynch syndrome, and most of these patients had pathogenic germline mutations in the MSH2 or MSH6 genes. Defects in the MSH2 and MSH6 genes can predispose patients to colorectal cancer, but they are also associated with other cancers. About one-fifth of the dMMR rectal cancer patients in the study had a history of at least one non-colorectal cancer before their diagnosis, and another fifth developed at least one noncolorectal cancer during the follow-up period.

“These patients need lifelong surveillance for other cancers in other organs, and their family members need to be evaluated for dMMR to help ensure that they take appropriate preventive measures,” Dr. You said (see Hereditary gastrointestinal cancer syndrome clinic).

Because the patient population is so well defined genetically, the experience with dMMR rectal cancer is a preview of what could be possible with other cancers, according to Dr. You.

“Since we can precisely define the key genetic defects that drive this cancer, we can more accurately predict its prognosis, the drugs or other therapies it will respond to, and the implications in terms of patients’ long-term survivorship,” she said. “We’re testing other cancers for various mutations to find new pathways to target therapeutically, but dMMR screening in patients with rectal cancer is an example that’s here today.”

For more information, contact Dr. Y. Nancy You at 713-794-4206.

Further Reading

de Rosa N, Rodriguez-Bigas MA, Chang GJ, et al. DNA mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics. J Clin Oncol. 2016;34:3039–3046.

OncoLog, October 2016, Volume 61, Issue 10