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Molecular classification of endometrial cancer , Time to clinical implication

Basel Refky A.Fattah ,MD,MRCS

European board of surgical oncology

ESGO exam certificate

Ass.prof of Surgical oncology

Oncology center-Mansoura University

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Breast Cancer

Patient A

Patient B

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NGS

  • Lung
    • EGFR mutations and ALK fusions
  • Breast
    • ER/PR/HER2neu
  • Ovary
    • BRCA/HRD status

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FUNDAMENTAL FRAMEWORK

IN OUR DISCUSSION OF

ENDOMETRIAL CANCER

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Type I

Type II

Adjuvant or no

Treat based on traditional risk factors

Treat

Treatment based on molecular features

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The Cancer Genome Atlas (TCGA)

  • Collaboration between National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI)
  • Genomic data on a very large scale
  • Gynecologic cancers including
    • Serous ovarian (2011)
    • Endometrial carcinoma (2013)
    • Cervical cancer (2017)
    • Uterine carcinosarcoma (2017)

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TCGA Endometrial Cancer

  • Defined 4 molecular subtypes
    • POLE
    • MSI
    • Copy number low (endometrioid-like)
    • Copy number high (serous-like)

Prognostic implications for molecular classes

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G Getz et al. Nature 497, 67-73 (2013) doi:10.1038/nature12113

Mutation spectra across endometrial carcinomas.

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Endometrial cancer new molecular classification

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specimens

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POLE mutated

  • Best prognosis

Best prognosis

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MMR deficient

loss of nuclear expression of one or more MMR proteins (MLH1, MSH2, MSH6 and PMS2) within tumour cell

Intermediate prognosis

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Copy number low ,P53 wild , NSMP

Intermediate prognosis

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Copy number high , P53 mutant

Worse prognosis

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PORTEC trials

  • PORTEC 1. 2000

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  • PORTEC 2. 2010

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  • PORTEC 3. 2018-2019

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  • PORTEC 4a Ongoing

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Intermediate risk

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High intermediate risk

Lymph node staging performed

Lymph node staging not performed

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High risk

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Target Therapy

Both MSI and POLE mut subtypes express essential immunogenicity because of a high mutational burden.

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Addition of PDL1 or anti PD-1 agents (atezolizumab, nivolumab or pembrolizumab) can be effective in recurrent or metastatic MSI or POLE mutations EC.

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In EC cases, showing the amplification of ERBB2 gene and overexpression of HER2, trastuzumab therapy may be used. Trastuzumab is a monoclonal antibody directed against the HER2 receptor

Advanced

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Early detection ?

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Take home message

  • The new (no longer new )molecular classification should be known by all specialties related to gynecological oncology.

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  • It has been already implanted in clinical practice, will need time to be resources compliant .

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  • Will it change surgical practice ? ( hot area for research )

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  • Not one size fits all.

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