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Molecular analysis of endometrial serous carcinoma reveals distinct clinicopathologic and genomic subgroups

Published:January 05, 2022DOI:https://doi.org/10.1016/j.ygyno.2021.12.030

      Highlights

      • 22% of endometrial serous carcinoma (EMSC) may harbor homologous recombination deficiency (HRD).
      • BRCA1/2 mutations are enriched in HRD-EMSC.
      • HRD-EMSC exhibited unique solid tumor morphology.
      • CCNE1 amplification was enriched in EMSC of patients from African descent.

      Abstract

      Objectives

      Endometrial serous carcinoma (EMSC) is an aggressive variant of uterine cancer with limited therapeutic options. We sought to define distinct clinicopathologic and genomic EMSC subgroups.

      Methods

      We retrospectively analyzed 2159 EMSC and 2346 endometrioid-type endometrial carcinomas (EEC) tissue specimens that had undergone comprehensive genomic profiling (CGP) via the FoundationOne CDx assay during routine clinical care. High tumor mutational burden (TMB) was defined as ≥10mut/Mb using the FDA-approved CDx cutoff for pembrolizumab. Microsatellite instability (MSI) was determined on 95 loci. Evidence of homologous recombination deficiency (HRD) was determined via genomic loss of heterozygosity (gLOH), a validated HRD detection method for predicting PARP inhibitor effectiveness in ovarian carcinoma. High gLOH was defined as ≥16%.

      Results

      A genomic analysis of 2159 EMSCs revealed a predominance of TP53 mutations, microsatellite stability, low tumor mutational burden (TMB), and recurrent alterations of PIK3CA, PPP2R1A, ERBB2, CCNE1, FBXW7 and MYC. Evidence of HRD via high gLOH was identified in 22% of EMSCs. BRCA1 and BRCA2 alterations, as well as unique SET (solid, pseudo-endometrioid, and transitional cell-like) variant morphology, were enriched in HRD-EMSC. There was an increased frequency of CCNE1 amplification, a lower prevalence of PIK3CA and PPP2R1A alterations, and no differences in HRD, MSI or TMB biomarker frequencies in patients of predicted African ancestry. EMSC exhibited distinct gene mutation frequencies and MSI, TMB and gLOH biomarker signatures compared to a cohort 2346 EEC.

      Conclusions

      Molecularly defined subgroups provide a framework to test the susceptibility of EMSC to targeted therapies in specific genetic settings (e.g. HRD, PIK3CA, PPP2R1A, ERBB2, MYC, CCNE1).

      Keywords

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      References

        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2020.
        CA Cancer J. Clin. 2020; 70: 7-30https://doi.org/10.3322/CAAC.21590
        • Henley S.J.
        Uterine cancer incidence and mortality — United States, 1999–2016.
        MMWR Morb. Mortal. Wkly Rep. 2020; 67: 1333-1338https://doi.org/10.15585/MMWR.MM6748A1
        • Bogani G.
        • Ray-Coquard I.
        • Concin N.
        • et al.
        Uterine serous carcinoma.
        Gynecol. Oncol. 2021; 162: 1https://doi.org/10.1016/j.ygyno.2021.04.029
        • Fader A.N.
        • Boruta D.
        • Olawaiye A.B.
        • Gehrig P.A.
        Uterine papillary serous carcinoma: epidemiology, pathogenesis and management.
        Curr. Opin. Obstet. Gynecol. 2010; 22: 21-29https://doi.org/10.1097/GCO.0B013E328334D8A3
        • Fader A.N.
        • Roque D.M.
        • Siegel E.
        • et al.
        Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu.
        J. Clin. Oncol. 2018; 36: 2044-2051https://doi.org/10.1200/JCO.2017.76.5966
        • Bruchim I.
        • Amichay K.
        • Kidron D.
        • et al.
        BRCA1/2 germline mutations in Jewish patients with uterine serous carcinoma.
        Int. J. Gynecol. Cancer. 2010; 20: 1148-1153https://doi.org/10.1111/IGC.0b013e3181ef622d
        • Lavie O.
        • Ben-Arie A.
        • Segev Y.
        • et al.
        BRCA germline mutations in women with uterine serous carcinoma--still a debate.
        Int. J. Gynecol. Cancer. 2010; 20: 1531-1534https://doi.org/10.1111/IGC.0b013e3181cd242f
        • Pennington K.P.
        • Walsh T.
        • Lee M.
        • et al.
        BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.
        Cancer. 2013; 119: 332-338https://doi.org/10.1002/cncr.27720
        • Swisher E.M.
        • Lin K.K.
        • Oza A.M.
        • et al.
        Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2017; 18: 75-87https://doi.org/10.1016/S1470-2045(16)30559-9
        • Coleman R.L.
        • Oza A.M.
        • Lorusso D.
        • et al.
        Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2017; 390: 1949-1961https://doi.org/10.1016/S0140-6736(17)32440-6
        • Moore K.N.
        • Nickles Fader A.
        Uterine papillary serous carcinoma.
        Clin. Obstet. Gynecol. 2011; 54: 278-291https://doi.org/10.1097/GRF.0b013e318218c755
        • Bitler B.G.
        • Watson Z.L.
        • Wheeler L.J.
        • Behbakht K.
        PARP inhibitors: clinical utility and possibilities of overcoming resistance.
        Gynecol. Oncol. 2017; 147: 695-704https://doi.org/10.1016/j.ygyno.2017.10.003
        • Bregar A.J.
        • Alejandro Rauh-Hain J.
        • Spencer R.
        • et al.
        Disparities in receipt of care for high-grade endometrial cancer: A National Cancer Data Base analysis.
        Gynecol. Oncol. 2017; 145: 114-121https://doi.org/10.1016/J.YGYNO.2017.01.024
        • Long B.
        • Liu F.W.
        • Bristow R.E.
        Disparities in uterine cancer epidemiology, treatment, and survival among African Americans in the United States.
        Gynecol. Oncol. 2013; 130: 652-659https://doi.org/10.1016/j.ygyno.2013.05.020
        • Goundiam O.
        • Gestraud P.
        • Popova T.
        • et al.
        Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma.
        Int. J. Cancer. April 2015; https://doi.org/10.1002/ijc.29568
        • Petersen S.
        • Wilson A.J.
        • Hirst J.
        • et al.
        CCNE1 and BRD4 co-amplification in high-grade serous ovarian cancer is associated with poor clinical outcomes.
        Gynecol. Oncol. 2020; 157: 405-410https://doi.org/10.1016/j.ygyno.2020.01.038
        • Soslow R.A.
        • Han G.
        • Park K.J.
        • et al.
        Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.
        Mod. Pathol. 2012; 25: 625-636https://doi.org/10.1038/modpathol.2011.183
        • Howitt B.E.
        • Hanamornroongruang S.
        • Lin D.I.
        • et al.
        Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.
        Am. J. Surg. Pathol. 2015; 39: 287-293https://doi.org/10.1097/PAS.0000000000000369
        • Ritterhouse L.L.
        • Nowak J.A.
        • Strickland K.C.
        • et al.
        Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas.
        Mod. Pathol. 2016; 29: 893-903https://doi.org/10.1038/modpathol.2016.82
        • Lipson D.
        • Capelletti M.
        • Yelensky R.
        • et al.
        Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.
        Nat. Med. 2012; 18: 382-384https://doi.org/10.1038/nm.2673
        • He J.
        • Abdel-Wahab O.
        • Nahas M.K.
        • et al.
        Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting.
        Blood. 2016; 127: 3004-3014https://doi.org/10.1182/blood-2015-08-664649
        • Frampton G.M.
        • Fichtenholtz A.
        • Otto G.A.
        • et al.
        Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.
        Nat. Biotechnol. 2013; 31: 1023-1031https://doi.org/10.1038/nbt.2696
        • Chalmers Z.R.
        • Connelly C.F.
        • Fabrizio D.
        • et al.
        Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
        Genom. Med. 2017; 9: 34https://doi.org/10.1186/s13073-017-0424-2
        • FDA approves pembrolizumab for adults and children with TMB-H solid tumors
        FDA.
        (Accessed July 15)
        • Connelly C.F.
        • Carrot-Zhang J.
        • Stephens P.J.
        • Frampton G.M.
        Abstract 1227: Somatic genome alterations in cancer as compared to inferred patient ancestry.
        in: Cancer Research. vol 78. American Association for Cancer Research (AACR), 2018: 1227https://doi.org/10.1158/1538-7445.am2018-1227
        • Sun J.X.
        • He Y.
        • Sanford E.
        • et al.
        A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal. Dunbrack RL, ed.
        PLoS Comput. Biol. 2018; 14: e1005965https://doi.org/10.1371/journal.pcbi.1005965
        • Getz G.
        • Gabriel S.B.
        • Cibulskis K.
        • et al.
        Integrated genomic characterization of endometrial carcinoma.
        Nature. 2013; 497: 67-73https://doi.org/10.1038/nature12113
        • Cerami E.
        • Gao J.
        • Dogrusoz U.
        • et al.
        The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
        Cancer Discov. 2012; 2: 401-404https://doi.org/10.1158/2159-8290.CD-12-0095
        • Gao J.
        • Aksoy B.A.
        • Dogrusoz U.
        • et al.
        Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
        Sci. Signal. 2013; 6: pl1https://doi.org/10.1126/scisignal.2004088
        • Buza N.
        • English D.P.
        • Santin A.D.
        • Hui P.
        • Buza N.
        Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice.
        Mod. Pathol. 2013; 26: 1605-1612https://doi.org/10.1038/modpathol.2013.113
        • Fader A.N.
        • Roque D.M.
        • Siegel E.
        • et al.
        Randomized phase II trial of carboplatin–paclitaxel compared with carboplatin–paclitaxel–trastuzumab in advanced (stage III–IV) or recurrent uterine serous carcinomas that overexpress Her2/Neu (NCT01367002): updated overall survival analysis.
        Clin. Cancer Res. 2020; 26: 3928-3935https://doi.org/10.1158/1078-0432.CCR-20-0953
        • André F.
        • Ciruelos E.
        • Rubovszky G.
        • et al.
        Alpelisib for PIK3CA -mutated, hormone receptor–positive advanced breast cancer.
        N. Engl. J. Med. 2019; 380: 1929-1940https://doi.org/10.1056/NEJMoa1813904
        • Remmerie M.
        • Janssens V.
        PP2A: a promising biomarker and therapeutic target in endometrial cancer.
        Front. Oncol. 2019; 9: 462https://doi.org/10.3389/fonc.2019.00462
        • Delmore J.E.
        • Issa G.C.
        • Lemieux M.E.
        • et al.
        BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
        Cell. 2011; 146: 904-917https://doi.org/10.1016/j.cell.2011.08.017
        • Bandopadhayay P.
        • Bergthold G.
        • Nguyen B.
        • et al.
        BET bromodomain inhibition of MYC-amplified medulloblastoma.
        Clin. Cancer Res. 2014; 20: 912-925https://doi.org/10.1158/1078-0432.CCR-13-2281
        • Lovén J.
        • Hoke H.A.
        • Lin C.Y.
        • et al.
        Selective inhibition of tumor oncogenes by disruption of super-enhancers.
        Cell. 2013; 153: 320-334https://doi.org/10.1016/j.cell.2013.03.036
        • Otto C.
        • Schmidt S.
        • Kastner C.
        • et al.
        Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells.
        Neoplasia (United States). 2019; 21: 1110-1120https://doi.org/10.1016/j.neo.2019.10.003
        • Murali R.
        • Davidson B.
        • Fadare O.
        • et al.
        High-grade endometrial carcinomas: morphologic and immunohistochemical features, diagnostic challenges and recommendations.
        Int. J. Gynecol. Pathol. 2019; 38: S40https://doi.org/10.1097/PGP.0000000000000491
        • Anderson C.
        • Bae-Jump V.L.
        • Broaddus R.R.
        • Olshan A.F.
        • Nichols H.B.
        Long-term patterns of excess mortality among endometrial cancer survivors.
        Cancer Epidemiol. Biomark. Prev. 2021; 30: 1079-1088https://doi.org/10.1158/1055-9965.EPI-20-1631
        • Mills A.M.
        • Liou S.
        • Ford J.M.
        • Berek J.S.
        • Pai R.K.
        • Longacre T.A.
        Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer.
        Am. J. Surg. Pathol. 2014; 38: 1501-1509https://doi.org/10.1097/PAS.0000000000000321