Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer

Aline Talhouk, Melissa K. McConechy, Samuel Leung, Winnie Yang, Amy Lum, Janine Senz, Niki Boyd, Judith Pike, Michael Anglesio, Janice S. Kwon, Anthony Karnezis, David G. Huntsman, C. Blake Gilks, Jessica N. McAlpine

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P <.001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802–13.

Original languageEnglish (US)
Pages (from-to)802-813
Number of pages12
JournalCancer
Volume123
Issue number5
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

Fingerprint

Endometrial Neoplasms
Genomics
Medical Oncology
Proteins
DNA Mismatch Repair
Neoplasms
Immunohistochemistry
Hereditary Nonpolyposis Colorectal Neoplasms
Exonucleases
Decision Trees
Survival
Atlases
Missense Mutation
Disease-Free Survival
Disease Progression
Clinical Trials
Genome
Mutation

Keywords

  • endometrial carcinoma
  • histotype
  • mismatch repair
  • p53
  • polymerase-ɛ (POLE)
  • prognostic
  • risk-stratification system
  • The Cancer Genome Atlas (TCGA)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Talhouk, A., McConechy, M. K., Leung, S., Yang, W., Lum, A., Senz, J., ... 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

Confirmation of ProMisE : A simple, genomics-based clinical classifier for endometrial cancer. / Talhouk, Aline; McConechy, Melissa K.; Leung, Samuel; Yang, Winnie; Lum, Amy; Senz, Janine; Boyd, Niki; Pike, Judith; Anglesio, Michael; Kwon, Janice S.; Karnezis, Anthony; Huntsman, David G.; Gilks, C. Blake; McAlpine, Jessica N.

In: Cancer, Vol. 123, No. 5, 01.03.2017, p. 802-813.

Research output: Contribution to journalArticle

Talhouk, A, McConechy, MK, Leung, S, Yang, W, Lum, A, Senz, J, Boyd, N, Pike, J, Anglesio, M, Kwon, JS, Karnezis, A, Huntsman, DG, Gilks, CB & McAlpine, JN 2017, 'Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer', Cancer, vol. 123, no. 5, pp. 802-813. https://doi.org/10.1002/cncr.30496
Talhouk A, McConechy MK, Leung S, Yang W, Lum A, Senz J et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017 Mar 1;123(5):802-813. https://doi.org/10.1002/cncr.30496
Talhouk, Aline ; McConechy, Melissa K. ; Leung, Samuel ; Yang, Winnie ; Lum, Amy ; Senz, Janine ; Boyd, Niki ; Pike, Judith ; Anglesio, Michael ; Kwon, Janice S. ; Karnezis, Anthony ; Huntsman, David G. ; Gilks, C. Blake ; McAlpine, Jessica N. / Confirmation of ProMisE : A simple, genomics-based clinical classifier for endometrial cancer. In: Cancer. 2017 ; Vol. 123, No. 5. pp. 802-813.
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abstract = "BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P <.001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89{\%}) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802–13.",
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T2 - A simple, genomics-based clinical classifier for endometrial cancer

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AU - McConechy, Melissa K.

AU - Leung, Samuel

AU - Yang, Winnie

AU - Lum, Amy

AU - Senz, Janine

AU - Boyd, Niki

AU - Pike, Judith

AU - Anglesio, Michael

AU - Kwon, Janice S.

AU - Karnezis, Anthony

AU - Huntsman, David G.

AU - Gilks, C. Blake

AU - McAlpine, Jessica N.

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N2 - BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P <.001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802–13.

AB - BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P <.001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802–13.

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