Finding Endometrial Cancer Subtypes With Universal Testing With NGS

The use of next-generation sequencing (NGS) to determine microsatellite status allows for simultaneous screening for Lynch Syndrome and categorization of endometrial cancer by molecular subtypes, with prognostic and therapeutic implications.

The four molecular subtypes outlined in the Proactive Molecular Risk Classifier for Endometrial Cancer are:

  • Polymerase epsilon (POLE; ultramutated)
  • Microsatellite instability (MSI, hypermutated)
  • p53 abnormal
  • p53 wild-type/no specific molecular subtype (NSMP)

The association of molecular classification with survival has been demonstrated in several retrospective studies and may assist clinicians in testing therapies in the adjuvant setting. This strategy is currently undergoing prospective evaluation in clinical trials.

Researchers at the University of Washington in Seattle implemented a universal screening algorithm using MSI assessment by NGS in 2018. In JCO Precision Oncology, The researchers, led by Isabel V. Rodriguez, MD, now report the results of a retrospective cohort study using NGS results to classify patients by molecular subtype of endometrial cancer and compare it to screening algorithm of previous methods.

None of the authors were available for an interview, and the answers to this Q&A are taken from the text of the report.

What does this study add to the literature?

A retrospective review was performed on 408 patients with newly diagnosed endometrial cancer: 140 patients who underwent universal screening by NGS and 268 who underwent screening by mismatch repair immunohistochemistry (MMR IHC) as part in a historical screening paradigm. The use of an NGS-based assay allowed for simultaneous Lynch Syndrome screening and molecular subtype classification in one test, providing important prognostic and therapeutic information at a lower cost than IHC.

What were the highlights of the study?

In the NGS cohort, 38 patients (27%) had MSI-high endometrial cancer, 100 (71%) had microsatellite stable endometrial cancer, and two (1%) had indeterminate results. Lynch Syndrome was diagnosed in two patients (1%), and all but five completed genetic screening (96%).

Molecular subtypes were determined: eight had POLE-ultramutated endometrial cancer, 28 had TP53-mutated endometrial cancer (20%), and 66 (47%) had NSMP. MSI-high and TP53-Mutated endometrial cancer has worse prognostic features compared to NSMP endometrial cancer. Comparison of historical cohorts showed a significant increase in follow-up testing after an initial positive genetic screen in the MSI NGS cohort.

What is the value of NGS for simultaneous molecular subtype classification?

Universal Lynch Syndrome screening using MSI by NGS in patients with newly diagnosed endometrial cancer yielded an initial screen result for 99% of the study group, with 96% of subjects completing genetic screening and two (1%) were diagnosed with Lynch Syndrome. It allows the use of NGS for simultaneous molecular subtype classification, which is currently recommended by several consensus guidelines.

NGS MSI testing is less expensive at our institution than IHC MMR testing, with IHC for the four MMR proteins charged at approximately $800 and NGS MSI testing at approximately $500 .

What are the clinical implications?

The molecular classification has current implications for the treatment of endometrial cancer, with several immune checkpoint inhibitors carrying FDA approvals for mismatch repair deficiency or MSI-high malignancies. Similarly, POLE mutation leads to an ultramutated phenotype that is also amenable to treatment with immune checkpoint inhibition.

Because of the prognostic differences, clinical decision-making regarding therapy based on molecular subtype, including potential deregulation of therapy, is an area of ​​ongoing investigation. Considering that NGS is not available in all institutions, molecular classification can also be determined using a combination of MMR and p53 IHC with POLE exonuclease domain-mutant hotspot sequencing.

What are the common barriers for patients to complete genetic screening?

Attendance at genetic counseling visits after referrals was consistently low in the three cohorts, which is consistent with findings from other studies reporting 40-80% attendance rates for endometrial cancer. Commonly cited barriers to completing genetic screening include concerns about cost or insurance coverage, confusion about the need for and implications of testing, and difficulty accessing genetic counseling services.

These factors may disproportionately affect minority populations, and further investigation is needed to identify effective interventions to improve access to care. Our current screening paradigm limits referrals to those at highest risk of germline genetic mutations and thus provides an opportunity to allocate support to those in greatest need.

What are the limitations of the study?

There are several limitations to this study. The catchment area for our institution covers several states. Many patients are seen for initial consultations and surgery, then eventually complete surveillance visits and additional follow-up closer to home. This limits the availability of long-term follow-up and survival data. Our analysis of genetic counseling attendance may also have excluded patients seen at an outside institution where records were not available for review, and this represents a barrier to genetic counseling for patients who travel. away for visits.

What is the main take home message for practicing oncologists?

The use of an NGS-based assay allows for the identification of somatic mutations with prognostic and therapeutic value and low cost. Universal MSI by NGS facilitates seamless integration of molecular profiling into routine pathologic assessment for all patients with endometrial cancer.

Read the study here.

Rodriguez reports no potential conflicts of interest.

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