Revolutionizing Endometrial Cancer Classification and Disease Monitoring Using NGS

Next Generation Sequencing (NGS) technology is an invaluable tool for personalized oncology. In this article, we highlight recent successes using Avitia’s NGS platform to address clinical challenges in Endometrial Cancer (EC). Drs. Jessica McAlpine and Amy Jamieson are both esteemed gynecological cancer surgeons at Vancouver General Hospital. The pair developed and implemented an innovative diagnostic and monitoring tool based on Avitia’s tests. Now they are sharing the important insights from their recent studies in patient care. 

The traditional system of categorizing tumors based on histomorphology, or how they look under a microscope, worked well in ovarian cancer (OC). However, it’s been problematic in endometrial cancer (EC). Expert pathologists often disagree on how to classify tumors, particularly high-grade ones. This leads to inconsistent pathology diagnoses, challenges in interpretations of treatment efficacy in clinical trials, and an inability to accurately provide prognostic information. This hindered research and patient care and highlighted the need for a more objective — as well as reproducible — classification system.

In 2013, a breakthrough came with The Cancer Genome Atlas project (TCGA), a study that provided in-depth profiling of endometrial cancer, identifying four subtypes:1) POLE mutated (POLEmut), 2) mismatch repair deficient (MMRd), 3) p53 abnormal (p53abn) and 4) no specific molecular profile (NSMP). However, methods used by the TCGA were not practical and were impractical to be transferred to the clinic. 

“Our team started to work on developing a pragmatic classifier (ProMisE) that could use standard pathology material to identify these four molecular subtypes of endometrial cancer with prognostic value”, says Dr. McAlpine. “In our earlier work (Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer - PubMed), we utilized simple immunohistochemistry and focused sequencing, to assess three key molecular features, including POLE mutations, p53, and MMR status. Taken together, these molecular features enable classification and can be executed reliably by any pathology lab.”

However, the uptake of this classifier has been limited primarily because its components are typically done at different time points of patient care, and often at different labs, with only a small percentage of patients presenting more than one of the 3 molecular features. As a result, patients miss an opportunity to use this valuable information to guide care.

To address this challenge, in collaboration with Avitia’s team, Drs. McAlpine and Jamieson developed a single-test DNA-based targeted NGS molecular classifier (ProMisE NGS) that leverages Avitia’s targeted Find It NGS test. In the 2023 study in Gynecological Oncology (Harmonized molecular classification; assessment of a single-test ProMisE NGS tool - PubMed), they demonstrated that the ProMisE NGS had high concordance with the original ProMisE classifier — which also maintained prognostic value in EC. In their following study in Gynecological Cancer (Validation and clinical performance of a single test, DNA based endometrial cancer molecular classifier - PubMed), the ProMisE NGS has been rigorously clinically validated using an independent multi-institutional cohort of 545 ECs patients. It demonstrates 95% concordance with the original classifier and full maintenance of prognostic value. This classification tool was positioned to become a practical option in clinical practice for centers where immunohistochemistry may not be performed routinely.

“The clinical significance of the Endometrial Promise Classifier has been tremendous,” says Dr. Amy Jamieson. “The World Health Organization recommended its incorporation into routine endometrial cancer pathology reporting in 2020, and the same year the European clinical management guidelines had changed to incorporate molecular classification for treatment decisions with other international organizations following (NCCN, FIGO). Molecular classification has impacted patient care by guiding preoperative imaging, surgical decisions, and treatment plans.” Dr. McAlpine adds: “In British Columbia alone it has become indispensable for EC patients for whom ProMisE NGS information has been routinely used to guide clinical decisions.”

Avitia’s NGS assay has also been instrumental in addressing the prognostic challenge of the no molecular profile (NSMP) subtype of EC. NSMP is the most common molecular type, and although most patients with this cancer type have excellent outcomes, there is tremendous variability in prognosis. In the 2023 issue of Modern Pathology, Dr. McAlpine and Dr. Jamieson published a study that demonstrated two key features — tumor grade, and estrogen receptor status. This enabled clinical outcome stratification within NSMP endometrial cancers and can be used to direct care.

“The aim of the study was to identify key features associated with outcomes in endometrial cancers with a specific molecular subtype called NSMP, which has diverse features and clinical outcomes,” says Dr. Jamieson. “The study looked at over a thousand cases of NSMP endometrial cancers and analyzed various clinical, pathological, immunohistochemical, and genetic features. Through this analysis, we found that two critical features, tumor grade, and estrogen receptor status could stratify prognosis. The majority (84%) of NSMP endometrial cancers fell into the low-risk group with a five-year disease recurrence rate of 1.6%, which is exciting as it represents a large proportion of patients with excellent outcomes. Combining these ‘low-risk NSMP’ cases with one of the other relatively less common molecular subtypes POLEmut endometrial cancers, together encompass 50% of all endometrial cancer patients with excellent outcomes who may not need any adjuvant treatment (ie who do not need chemotherapy or radiation)”.

Dr. McAlpine adds, “I think this hints at the next frontier in care. We’re so fussed about making sure that we treat those patients who need additional therapy, but you cannot overstate the impact of not having to give someone toxic radiation and toxic chemotherapy with long-term consequences. As a clinician, it makes us really excited if you can safely identify people who after surgery has been performed could step away from any additional therapy and just be followed with routine visits.”

Another clinical challenge in EC (and OC) management is the lack of tools for monitoring the real-time response to therapy and earlier disease detection. Serum tumor marker CA125 has been used for decades in these cancer types; however, its sensitivity and specificity are limited. This is because changes in its levels often lag behind tumor response. Avitia’s liquid biopsy tool, Follow It, allowed us to expand the work to the monitoring and disease recurrence space. In 2024, Drs Jamieson and McAlpine published another groundbreaking study in the Journal of Gynecologic Oncology (Selective utilization of circulating tumor DNA testing enables disease monitoring in endometrial and ovarian carcinomas). This study demonstrated liquid biopsies utility as disease monitoring tool. The study involved 44 patients with OC/EC who underwent primary surgery and were followed up with serial liquid biopsy testing for two years. This demonstrated the tool’s clear clinical benefits. 

“In OC/EC practice, like in any oncology area, accurate disease assessment at the time of diagnosis is detrimental for favourable clinical outcome”,-  says Dr. McAlpine. “Inability to identify patients with clinically occult advanced stage disease unrecognized at the time of diagnosis. This often results in suboptimal tumour debulking at primary surgery and is associated with worse survival outcomes for both OC and EC. In our patient cohort, using liquid biopsy serial testing we found 42% of patients who harbored detectable preoperative ctDNA mutations with clinically apparent stage I disease, that were subsequently found to have stage II/stage III disease at surgery and on final pathology review. Liquid biopsy also helped us to address the clinical challenge of monitoring real-time response to treatment. We saw clearance of postoperative plasma ctDNA mutations in patients receiving adjuvant therapy that by months precedednormalization of the CA125 levels. In addition, we found that liquid biopsy monitoring can identify earlier disease recurrence, where postoperative ctDNA mutation detection preceded clinical, radiological, and conventional tumour biomarker identification of disease recurrence. We also demonstrated that preoperative ctDNA mutations were associated with a higher risk of subsequent disease recurrence. We were stunned to see that the recurrence rate was almost double that of patients who did not have preoperative mutations. So, the presence of preoperative ctDNA can help us flag those patients that need closer monitoring for disease recurrence.”

Taken together, the ProMisE classifier has revolutionized the classification of endometrial cancer, providing a more objective and reproducible system that has a significant impact on patient care. A single test, ProMisE NGS assay provides a streamlined process to obtain molecular classification for patients with EC to direct patient care. With its incorporation into clinical practice and guidelines, it has become an invaluable tool for gynecological cancer surgeons, medical oncologists, and radiation oncologists in making informed treatment decisions for patients with endometrial cancer. The future looks promising as more countries and organizations adopt this innovative classifier to ensure access and equity, further improving patient outcomes in the field of gynecologic cancers.

For additional information about these studies and/or Avitia’s NGS platform and assays, please reach out to Avitia.