Patients with DNA mismatch repair deficiency rectal cancer may not necessarily have Lynch syndrome. Expert Yi-Qian Nancy You weighs in on the topic.
It is important to have a well-rounded understanding of the molecular and clinical causes and risks for patients with DNA mismatch repair deficiency (dMMR) rectal cancer, said Yi-Qian Nancy You, M.D., M.H.Sc., an author on a report published in the Journal of Clinical Oncology, which addressed gene alterations and treatment for patients with dMMR rectal cancer.
For patients with colorectal cancer, identification of dMMR triggers the need for genetic testing for the detection of a potential heritable germline deficiency in the DNA mismatch repair system. The implications of dMMR status are still unknown in rectal cancer, however, meaning that genetic testing has rarely occurred.
When genetic testing is performed on dMMR rectal cancer patients, a separation occurs between patients who present with mutations in their tumors in the mismatch repair system as well as the same mutations in the germline, and those who do not show the same mutations in the germline as can be found in their tumors.
Historically, this group has been clinically considered to have Lynch syndrome because there’s been no evidence to the contrary. Therefore, this subgroup of patients, along with their family members, would be considered to have a high lifetime risk of developing cancer and would subsequently require extensive screening.
“At some point when we figure out what’s going on with these people—what led to their tumor mutation if it’s not in the germline...then maybe we won’t need to keep them in this high-risk screening program and test them for all of these other Lynch-associated tumors,” said You, associate professor of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, in an interview with CURE.
However, this group, often termed “Lynch-like syndrome” by many reports, stands apart from those with Lynch syndrome. These patients have nonsporadic high microsatellite instability tumors, abnormal immunohistochemistry of the MMR proteins in the tumor, and no evidence of MLH1 hypermethylation or BRAF mutation. Also, genetic testing in these patients show various unclassified variants that are likely nonpathogenic, or results are inconclusive, whereas patients with true Lynch syndrome have identifiable pathogenic mutations. It is possible that these patients may not require as extensive screening as those with Lynch syndrome would.
One population-based study examined the risk of cancer in families of patients with “Lynch-like syndrome” in comparison with families of Lynch syndrome patients. The study found that the familial risk is reduced with Lynch-like syndrome compared with Lynch syndrome. The standardized incidence ratio (SIR) for colorectal cancer (CRC) for Lynch-like syndrome was 2.12 compared with 6.04 for classic Lynch syndrome. However, the SIR for Lynch-like syndrome was higher than the SIR for sporadic CRC of 0.48, confirming the need for surveillance of these families, although not to the extent of Lynch syndrome families.
The community does not yet have a consensus on not only how to manage these patients, but also regarding what to call this subgroup, commented You. She has proposed that these patients be termed “mutation-negative Lynch syndrome.” This phrase would differentiate these patients from the classic Lynch syndrome and nod to the fact that genetic testing shows unknown MMR genes in these patients.
The basis for “mutation-negative Lynch syndrome” needs to be understood in order to differentiate cancer treatment and surveillance for these patients and their family members. You and colleagues’ study of dMMR in rectal cancer aimed to begin to identify the molecular basis of this patient population compared with Lynch syndrome patients, and to begin to identify which treatment would most benefit these patients.
In the study a selection of 62 patients over the age of 18 years old with dMMR rectal adenocarcinoma, who were diagnosed between 1992 and 2012, were tested for tumor MMR status, microsatellite instability, and immunohistochemistry of the MLH1, MSH2, MSH6 and PMS2 proteins.
Patients with detected deficiency in MLH1, MSH2, MSH6 or PMS2 underwent genetic counseling for confirmatory germline mutation testing. Forty-two patients had true Lynch syndrome and 15 patients had mutation-negative Lynch syndrome, seven of which had presented with a variant of unknown significance (VUS), all of which were missense mutations and eight had uninformative negative results. The remaining five patients had declined genetic testing.
Ninety-eight percent of the patients met the revised Bethesda criteria while only 15 percent met Amsterdam criteria 1 or 2. The median PREMM 1,2,6 score for all of the patients was 25.6.
Following testing, it was found that a majority of the patients had a mutation in either MSH2 (53 percent) or MSH6 (23 percent). Expectations had favored the MLH1 gene for the majority of defects in MMR, study authors noted in a statement, as this is commonly found in patients with dMMR colon cancer. However, only 16 percent of patients in the study had a mutated MLH1 gene and 8 percent had a mutation in PMS2.
Thirty of 40 patients (75 percent) with stage 2 or 3 rectal cancer were treated with neoadjuvant uoropyrimidine-based chemotherapy and long-course pelvic radiation. All but one of these patients underwent surgical resection. Eight patients (27.6 percent) experienced a pathological complete response and 16 patients (55.5 percent) were downstaged following treatment.
For the entire patient population, the five-year overall survival (OS) rate was 87 percent and the rectal cancer-specific survival (RC-SS) rate was 90.6 percent overall. For patients with stage 1 and 2 disease, the RC-SS rate was 100 percent, 85.1 percent for stage 3, and 60 percent for stage 4. Recurrence occurred in 18.6 percent (11 of 59) of the patients who had curative-intent resection. Eleven of the patients died, six due to rectal cancer and five due to extracolorectal cancers after a median of 17.3 years. Although all of the patients with VUS mutation-negative Lynch syndrome were still alive as of last follow-up.
Fourteen patients (22.6 percent) developed a total of 22 extra-colorectal cancers. Study authors noted that the MSH2 and MSH6 MMR genes have been associated with higher incidences of extracolorectal cancers.
“Our data basically established what the results are with current therapy. That provides a baseline for developing trials that include new drugs because you have to have something to compare it against to see whether the new drugs are going to add any benefit,” You said.
Future trials may examine the effect of immunotherapy and targeted therapy agents on patients with dMMR rectal cancer. You noted that clinical trials are already underway examining PD-1 blockade in tumors with DNA dMMR, which have already shown substantial results. It is suggested that dMMR is predictive of response to immune checkpoint blockade treatment.
The trial also provides implications for the underlying genetics of dMMR rectal cancers. “Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies,” the study authors emphasized in their abstract.
In dMMR colon cancers, genetic testing is more common right off the bat to identify patients with Lynch syndrome. However, dMMR is different in rectal cancer than in colon cancer, You pointed out.
“We think if you find rectal cancer, the likelihood that someone is actually Lynch is much, much higher than if it’s a colon cancer because there are other ways of causing it in colon cancer. The other known mechanisms that cause tumor dMMR we can’t find in rectal cancer.”
Subsets of colon cancers that develop DNA dMMR are caused by other mechanisms, such as hypermethylation of a gene, typically MLH1. On the other hand, there is no methylation or other known mechanisms causing the deficiency in rectal cancer patients. The causes are still unknown for rectal cancer.
In the meantime, there is a better indication of the long-term prognosis of these patients. The long-term multiorgan follow-up of patients with dMMR rectal cancers is very important, You urged, especially since many will develop extracolonic cancers as their germline mutations put them at a lifelong risk for developing other cancers.
This follow-up extends beyond the patient to members of their family as well. Once a patient has been diagnosed with a genetic mutation it can affect the entire family as they will all need to be continually screened for associated cancers.
“Precision medicine is good for this one patient, of course, but it’s so much more powerful if you think of the implications for all of the generations,” You said.