In this JCO PO Article Insights episode, Fergus Keane provides a summary on "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice", by Papadopoulou, et al published January 25, 2024

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Fergus Keane: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Fergus Keane, an ASCO Editorial Fellow. Today, I will be providing a summary of the article entitled "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice" by Dr. Eirini Papadopoulou.

The mismatch repair pathway has gained interest in recent years due to advances in precision oncology, the widespread use of immune checkpoint blockade, and next-generation sequencing-based assays to identify microsatellite instability. The mismatch repair pathway has a key role in DNA repair and maintaining genomic stability. Tumor cells, which are MMR deficient are prone to mismatch errors in the microsatellite regions during DNA replication. Microsatellite instable, referred to as MSI-High tumors are observed across a variety of tumor types, most commonly colorectal and endometrial cancers.

Germline Lynch syndrome is caused by inactivating variants in one of five primary MMR genes, namely MSH2, MLH1, MSH6, PMS2, and EPCAM, and is associated with an autosomal dominant pattern of inheritance. Mismatch repair deficiency is observed in most tumors in individuals with Lynch syndrome and can also occur sporadically. In mismatch repair deficient colorectal cancer, sporadic cases are identified by BRAF V600E mutations or MLH1 gene promoter hypermethylation. The absence of both of these findings should raise suspicion for germline Lynch syndrome.

The aim of this study was to report the prevalence of microsatellite instability in a large cohort of patients in Europe, specifically Greek patients. In addition, the authors aimed to evaluate the proportion of patients with microsatellite instability referred for germline testing and what factors appeared to influence clinician decision to refer for germline testing. 4553 patients with metastatic cancer were included between January 2020 and April 2023. All patients were referred for MSI analysis, and at physician discretion, BRAF V600E and MLH1 gene methylation analyses were available. Approximately half of patients included had colorectal cancer. 5.27% of patients exhibited MSI-High in total, of whom 58% were female and 42% were male.

The rates of MSI-High cancers varied according to tumor type, but the highest rates observed in patients with endometrial cancer at 15.69%, gastric cancer at 8.54%, colorectal cancer at 7.4%, and urinary tract cancers at 4.55%. Of the MSI-High patients, with colorectal cancer identified, 24.85% had a BRAF V600E. Excluding these patients, 198 were eligible for genetic testing with a hereditary cancer panel. Of these, only 22.7% were actually referred for a hereditary panel. The median age at diagnosis in this group was 59 years, compared with 66 years for those who were not referred for germline analyses. The age at diagnosis and referral for genetic analyses were significantly correlated.

Beyond colorectal cancer, patients with other cancer types who were also referred for germline testing included nine patients with endometrial cancer, four with gastric cancer, two with ovarian cancer, one with breast cancer, and one with gallbladder cancer, and referral patterns differed by tumor type. Of patients with colorectal and endometrial cancer, 24.4% had a positive germline mismatch repair variant identified. Of note, while the median age of patients with a pathogenic or likely pathogenic germline result was 48.5 years, over 40% of patients with a pathogenic germline result were aged over 50 years, highlighting that age alone should not be the only criterion for consideration of a referral for germline analysis in such patients.

This study highlights some important points. First, MSI analysis is an important biomarker for a variety of tumor types, including colorectal, gastric, and endometrial cancer, but also less commonly associated cancer types. Second, only 22.73% of patients eligible for germline analyses were referred in this patient cohort, despite recommendations from international guidelines indicating that a proportion of patients with a possible familial predisposition syndrome may not be tested for same. Third, key features such as age at diagnosis and tumor type influence the clinical decision for referral for genetic analysis.

The authors conclude that the value of MSI testing as a potential screening tool for identification of patients with a higher risk for germline pathogenic variants may be underappreciated and highlights this important biomarker.

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JCO PO Article Insights: Microsatellite Instability as a Biomarker in Clinical Practice

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