MMR/MSI Testing in Colorectal Cancer 'Alarmingly' Low

Alexander M. Castellino, PhD

November 14, 2017

The most recent guidelines recommend that all patients with colorectal cancer (CRC) be tested for deficient DNA mismatch repair (MMR), but until recently, this testing was recommended specifically for two groups of patients ― those at high risk, determined on the basis of personal or family history of CRC, and CRC patients younger than 50 years.

But testing rates have been woefully low, and the latest study shows that the picture remains bleak. Researchers from the Fox Chase Cancer Center, Philadelphia, Pennsylvania, using available data for 152,993 adults with CRC, found that the rate of testing rate was just 28.2%. Only 43.1% of younger patients were tested for MMR/microsatellite instability (MSI) status.

Suboptimal testing rates were reported at academic centers, cancer networks, and across all regions in the United States.

These alarmingly low testing rates are another example of our healthcare system's failure. Dr Nestor Esnaola

"These alarmingly low testing rates are another example of our healthcare system's failure to reliably implement evidence-based best practices and tells us that we are not doing a good job as clinicians, even at cancer networks," corresponding author Nestor F. Esnaola, MD, MPH, MBA, from the Department of Surgical Oncology at the Fox Chase Cancer Center, told Medscape Medical News. "Per guidelines in place when this study was initiated, all younger patients with CRC needed to be tested. It's disappointing that testing rates were as low as 43% in these patients," he added.

These results from the largest study to date were published online November 9 in JAMA Oncology.

"The findings are worrying," writes Stanley R. Hamilton, MD, from the Division of Pathology and Laboratory Medicine at the University of Texas MD Anderson Cancer Center, Houston, writing in an invited commentary.

The study "provides important, national baseline data regarding utilization of MMR deficiency testing in patients with CRC and identifies significant groups at risk for potential nonadherence to newly implemented universal testing guidelines moving forward," write the authors.

Dr Hamilton concurs and notes that the analyses invovled patients with a diagnosis of CRC between 2010 and 2012. "The data are not contemporaneous [testing is currently required for all patients with CRC] but provide a good baseline to determine how testing behavior will change in the future," he told Medscape Medical News.

Dr Hamilton said that he was optimistic that recent approvals of immunotherapy for use in patients with these genetic defects will bring seismic changes in MMR/MSI testing. As reported byMedscape Medical News, earlier this year saw the approval of pembrolizumab (Keytruda, Merck) in May 2017 to treat any tumor associated with a high risk for MSI (MSI-H), and in August 2017, nivolumab (Opdivo, Bristol-Myers Squibb) was approved for use in patients with CRC and MMR/MSI defects.

The Fox Chase Cancer Center Study

For their study, the Fox Chase researchers used the National Cancer Database, which includes data for 70% of all newly diagnosed cases in the United States, to identify patients diagnosed with CRC. The study was conducted from March 2016 to March 2017 ― prior to the approval of any immunotherapy for MSI-H cancer.

The database provided information on MMR/MSI-H testing derived on pathology reports, laboratory reports, admission notes, or consultation notes. "Information was not available as to who ordered the testing," Dr Esnaola told Medscape Medical News.

There were 152,993 patients newly diagnosed with CRC (mean age, 66.9 years; 51% men).

Higher testing rates were seen at academic centers (35.4%), in patients with private insurance (33%), in patients with stage II or III disease (32.7% and 31.5%, respectively), and in patients who underwent examination of 12 or more lymph nodes (33.3%). Testing rates also increased during the 3-year period, from 22.3% in 2010 to 33.1% in 2012 and from 36.1% in 2010 to 48% in 2012 in the younger subset of patients.

"Associations are difficult to explain, such as the higher frequency of testing with larger number of lymph nodes," Dr Hamilton comments. However, Dr Esnaola told Medscape Medical News that the observed association between the number of lymph nodes harvested at colectomy and testing suggests that the association may be a proxy for better cancer care.

Dr Hamilton also noted that some of the associations are actionable. These include the lower frequency of testing in individuals with lower education levels and the underuse of testing associated with older age, residence in a nonmetropolitan county, care at a nonacademic center, and geographic location. "Expanded education of physicians and patients about MSI-H testing could improve adherence to the current guidelines," he writes.

MMR/MSI Testing Should Be Reflexive, Experts Say

Four gene products are predominantly associated with the MMR system responsible for correction of errors in DNA replication ― MLH1, MSH2, MSH6, and PMS2. However, methylation in one of the genes, MLH1, results in most of the cases of MMR-deficient CRC. Mutational defects in the germline of any of the four can result in the accumulation of DNA errors when the second copy is inactivated in the tumor, Dr Hamilton pointed out.

He further explained that at MD Anderson, a panel of four antibodies are used in immunohistochemical (IHC) analyses to determine MMR status. A loss in any one of the MMR proteins merits genetic counseling, he said, and the clinician is informed of the results. If an IHC analysis does not detect a loss, polymerase chain reaction assay is conducted for detection of repetitive DNA, if requested.

Knowing MSI status is important in the clinical management of patients with CRC as well as other tumors. "High-level MSI due to somatic MMR gene alterations as well as Lynch syndrome also influences prognosis and therapy decision [in CRC]," Dr Hamilton writes. For example, patients with MSI-H CRC and early-stage disease have a good prognosis. Such patients are likely to live longer with irinotecan-based therapy and are unlikely to respond to fluorouracil-based therapy. In the metastatic setting, patients can be treated with immunotherapies approved to treat MMR/MSI-H tumors.

Dr Hamilton said the increase in testing rates between 2010 and 2012 is a reason for optimism. But Dr Esnaola was more circumspect. "The rates are higher, they but are unacceptably low," he said.

"Although the proportion of patients tested increased during the study period, our results suggest that underutilization of MMR deficiency testing was significant and pervasive, even among young patients with CRC with a well-established risk of Lynch syndrome," Dr Esnaola and colleagues write.

Testing Should Be Routine

Dr Hamilton, a pathologist by training, indicated that testing is ordered across oncology specialties; those who order tests include surgeons, medical oncologists, and treating physicians. At the MD Anderson Cancer Center, pathologists are also involved in determining whether tissue samples are tested even if a test such as MMR/MSI-H is not ordered. "If there is an unbiased recommendation, then a committee votes on allowing a pathologist to do 'reflex' testing," he said. Reflex testing is a test is performed regardless of whether or not it is ordered.

At the Fox Chase Cancer Center, MMR/MSI testing is performed reflexively on all CRC samples, Dr Esnaola said, and he suggested that this is the way forward. "Institutions that aim to optimize colon cancer care should implement reflexive testing," he told Medscape Medical News.

The study identified factors associated with those who are less likely to be tested for MMR/MSI ― increasing age, lower socioeconomic status, being uninsured, and being insured through Medicare. According to the Fox Chase researchers, these data suggest that national guidelines may not be equally implemented across all sociodemographic groups. "This has to change," Dr Esnaola emphasized. "MSI testing should be the standard of care for all CRC patients," he added. With the implementation of reflex testing, the onus is on the hospital to provide MMR testing for all CRC patients, Dr Esnaola noted.

Dr Hamilton told Medscape Medical News that since pembrolizumab was approved to treat all MSI-H tumors, there has been a spike in MMR/MSI testing rates at his institution. He noted that MMR testing is now conducted not only in endometrial, ovarian, and CRC samples but also in pancreatic cancer samples. "Especially in pancreatic cancer, where outcomes are poor, even the approximately 2% of samples that may be MSI-H can benefit from immunotherapy," he said.

Both Dr Esnaola and Dr Hamilton agree that MMR/MSI testing should approach the level of estrogen/progesterone receptor and HER2 testing for breast cancer. "When a woman is diagnosed with breast cancer, these tests are routinely performed," Dr Hamilton noted. It should be the same with MMR/MSI testing for CRC, he said.

Denial of reimbursement for MMR/MSI testing has contributed to the low testing rates, Dr Esnaola and Dr Hamilton indicated. "The guidelines and the FDA approval for these cancers will drive compliance for testing and reimbursement," Dr Hamilton said.

The current endorsement from four societies ― the American Society of Clinical Oncology, the American Society for Clinical Pathology, the Association for Molecular Pathology, and the College of American Pathologists ― of MMR/MSI testing for all CRC patients will help to increase testing. The National Comprehensive Cancer Network and the European Society for Medical Oncology also recommend MMR/MSI testing for all patients with CRC.

The study was supported by the National Institutes of Health and the National Cancer Institute.The study authors have disclosed no relevant financial relationships. Dr Hamilton is a member of the Scientific Advisory Committee of the Fred Hutchison Cancer Center, consultant for LOXO-Oncology, member of the Halio DX Scientific Advisory Committee, and has a financial relationship with the Johns Hopkins University School of Medicine and Merck.

JAMA Oncol. Published online November 9, 2017. Full text, Commentary

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