Molecular Classification &
Risk Stratification of
BC-based research team develops a novel molecular classifier for endometrial cancer that is opening doors for precision oncology.
The Need for Molecular Classification
Endometrial cancer (EC) is the most common gynecologic cancer and the 6th most common female cancer North America (Sigel et al., 2022).
Histopathology (appearance under the microscope) is traditionally used to diagnose EC. However, key features of ECs are difficult to tell apart and predicting which patients are most likely to recur from their disease and need more treatment a longstanding challengeThus, it became evident that a more reproducible and biologically relevant system for diagnosing and classifying EC was needed.
Developing a ProMisE-ing Molecular Classification System
In 2015, Drs. Jessica McAlpine, Aline Talhouk, and their team developed assays that could replicate molecular classification of ECs in a more pragmatic and cost-effective manner to bring this tool into the clinical use (Talhouk et al., 2015). Their molecular classification system later became known as the Proactive M olecular Risk Classifier for Endometrial Cancer ( ProMisE).
ProMisE is used to classify a patient’s endometrial carcinoma into one of four distinct molecular subtypes– each of which have distinguishable disease characteristics and outcomes. Classification is based on immunohistochem istry (identifying the presence or absence of certain proteins such as mismatch repair (MMR) and p53) and Next-Generation Sequencing (looking for specific mutations in POLE ).
Check out our video on Molecular Classification:
The molecular categorization of ECs allows for improved stratification. Clinicians can better determine patient prognosis, which patients may qualify for certain clinical trials, benefit from targeted treatments, genetic testing, or even de-escalation of treatments.
ProMisE has been widely accepted by institutions across the world and has had a tremendous impact on clinical care. Since 2020, the World Health Organization (WHO) has recommended that molecular classification be incorporated into routine EC reporting. The clinical impact can also be seen in the incorporation of molecular classification into the 2020 ESGO/ESTRO/ESP EC risk stratification and treatment algorithms . Shortly after, other clinical resources, such as UpToDate and the National Comprehensive Cancer Network , updated their guidelines for EC care accordingly.
Thanks to collaborative work with the Provincial BC Cancer Gyne Tumor Group, routine MMR and p53 IHC, and POLE testing available for free (centralized testing in Vancouver) for cases where the results will impact treatment decisions. These tests are considered the standard of care here in BC (BCCancer, 2023). Similarly, members of the BC-based team have also played a direct role in the creation of guidelines to support the rollout of ProMisE testing in the United Kingdom and in other parts of Canada.
Molecular Classification is now required for Endometrial Cancer triage and decisions regarding when and how a patient is managed in BC.
Future Directions: Refining the Breadth of Classification and Stratification
Last year, the ProMisE research team received the 2022 Terry Fox New Frontiers Program Project Grant to support their goal of refining the breadth, efficacy, and impact of the existing ProMisE classifier. Learn more about their ongoing projects here .
Overall, molecular classification and risk stratification using the ProMisE system has provided a critical framework for research and clinical care in EC. This team is eagerly working to refine this stratification further, ensure equal access/implementation and bring precision medicine to more EC patients.
Explore more about ProMisE and our other research projects in our GCI Knowledge Hub below.
Talhouk, A., McConechy, M. K., Leung, S., Li-Chang, H. H., Kwon, J. S., Melnyk, N., Yang, W., Senz, J., Boyd, N., Karnezis, A. N., Huntsman, D. G., Gilks, C. B., & McAlpine, J. N. (2015). A clinically applicable molecular-based classification for endometrial cancers. British journal of cancer, 113(2), 299–310. https://doi.org/10.1038/bjc.2015.190.
Talhouk A, Hoang LN, McConechy MK, Nakonechny Q, Leo J, Cheng A, Leung S, Yang W, Lum A, Köbel M, Lee CH, Soslow RA, Huntsman DG, Gilks CB, McAlpine JN. Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment. Gynecol Oncol. 2016 Oct;143(1):46-53. doi: 10.1016/j.ygyno.2016.07.090.
Talhouk, A., McConechy, M. K., Leung, S., Yang, W., Lum, A., Senz, J., Boyd, N., Pike, J., Anglesio, M., Kwon, J. S., Karnezis, A. N., Huntsman, D. G., Gilks, C. B., & McAlpine, J. N. (2017). Confirmation of promise: A simple, genomics-based clinical classifier for endometrial cancer. Cancer, 123(5), 802–813. https://doi.org/10.1002/cncr.30496.
Kommoss S, McConechy MK, Kommoss F, Leung S, Bunz A, Magrill J, Britton H, Kommoss F, Grevenkamp F, Karnezis A, Yang W, Lum A, Krämer B, Taran F, Staebler A, Lax S, Brucker SY, Huntsman DG, Gilks CB, McAlpine JN, Talhouk A. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol. 2018 May 1;29(5):1180-1188. doi: 10.1093/annonc/mdy058.
Tailored adjuvant therapy in pole-mutated and p53-wildtype early stage endometrial cancer (TAPER). ClinicalTrials.gov. (2021). https://classic.clinicaltrials.gov/ct2/show/NCT04705649
RAINBO Research Consortium (2022). Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 33(1), 109–117. Advance online publication. https://doi.org/10.1136/ijgc-2022-004039.
Siegel, R., Miller, K., Fuchs, H., & Jemal, A. (2022). Cancer statistics, 2022. CA: A Cancer Journal for Clinicians , 72(1), 7–33. https://doi.org/10.3322/caac.21708.
BC Cancer. (2023). Endometrium. In Cancer Management Manual . Provincial Health Services Authority. http://www.bccancer.bc.ca/health-professionals/clinical-resources/cancer-management-manual/gynecology/endometrium#:~:text=ECs%20in%20BC.-,POLE%20testing%20has%20been%20approved%20in%20BC%20since%20May%202022,see%20POLE%20testing%20section%20below).&text=Mismatch%20repair%20is%20a%20DNA%20repair%20pathway.
Jamieson, A., Huvila, J., Chiu, D., Thompson, E. F., Scott, S., Salvador, S., Vicus, D., Helpman, L., Gotlieb, W., Kean, S., Samouelian, V., Köbel, M., Kinloch, M., Parra-Harran, C., Offman, S., Grondin, K., Irving, J., Lum, A., Senz, J., … McAlpine, J. N. (2023). Grade and estrogen receptor expression identify a subset of no specific molecular profile endometrial carcinomas at a very low risk of disease-specific death. Modern Pathology, 36 (4). https://doi.org/10.1016/j.modpat.2022.100085.
Interested in collaboration or implementation of ProMisE in your institution?
Reach out to Dr. Jessica McAlpine at firstname.lastname@example.org.