Comprehensive analysis of PD-L1 expression, HER2 amplification, ALK/EML4 fusion, and mismatch repair deficiency as putative predictive and prognostic factors in ovarian carcinoma

  • Elisa SchmoeckelEmail author
  • Sophie Hofmann
  • Daniel Fromberger
  • Miriam Rottmann
  • Beate Luthardt
  • Alexander Burges
  • Udo Jeschke
  • Thomas Kirchner
  • Sigurd F. Lax
  • Doris Mayr
Original Article


Most ovarian carcinomas (OC) are characterized by poor prognosis, particularly the most frequent type high-grade serous carcinoma. Besides PARP inhibitors, target-based therapeutic strategies are not well established. We asked the question which other therapeutic targets could be of potential value and, therefore, analyzed a large cohort of OC for several predictive factors. Two hundred eighty-eight (288) cases of OC including the major histological types were analyzed by immunohistochemistry for PD-L1HER2, ALK, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. HER2 amplification and ALK/EML4 fusion were assessed by fluorescence in situ hybridization. The most frequent finding was PD-L1 expression ≥ 1% in 19.5% of the cases, which correlated with a significantly better overall survival in multivariate analysis (p < 0.001). HER2 amplification was detected in 11 cases (4%), all high-grade serous carcinomas. Amplification of HER2 did not correlate with patients’ survival. ALK/EML4 fusion was found in two cases (0.74%): one high-grade serous and one endometrioid carcinoma. MMR deficiency was only present in one case of stage IV high-grade serous carcinoma. Subsets of high-grade serous carcinomas show PD-L1 expression and HER2 amplification, respectively, and, therefore, could qualify for immune checkpoint inhibitor therapy or anti HER2 therapy. PD-L1 is also of prognostic impact. ALK/EML4 fusion is very rare in OC and not a putative therapeutic target.


Ovarian carcinoma HER2 ALK/EML4 PD-L1 Mismatch repair deficiency Microsatellite instability 


Author’s contributions

Doris Mayr designed the study. Elisa Schmoeckel designed the study and wrote the first draft of the manuscript. Elisa Schmoeckel, Sophie Hofmann, Daniel Fromberger, and Beate Luthardt carried out the research work and analyzed the data. Miriam Rottmann supported the statistical analyses. Doris Mayr, Alexander Burges, Udo Jeschke, Miriam Rottmann, Thomas Kirchner, and Sigurd F. Lax reviewed and edited the manuscript. All authors gave final approval for publication.

Elisa Schmoeckel takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Compliance with ethical standards

All patients’ data were fully anonymized, and the study was performed according to the standards set in the Declaration of Helsinki 1975. The current study was approved in writing by the Ethics Committee of the Ludwig-Maximilians-University, Munich, Germany (approval number 18-130).

Conflict of interest

There are no business relationships that might lead to a conflict of interest.

Supplementary material

428_2019_2528_MOESM1_ESM.docx (23 kb)
ESM 1 (DOCX 22 kb)


  1. 1.
    Anglesio MS, Kommoss S, Tolcher MC, Clarke B, Galletta L, Porter H, Damaraju S, Fereday S, Winterhoff BJ, Kalloger SE, Senz J, Yang W, Steed H, Allo G, Ferguson S, Shaw P, Teoman A, Garcia JJ, Schoolmeester JK, Bakkum-Gamez J, Tinker AV, Bowtell DD, Huntsman DG, Gilks CB, McAlpine JN (2013) Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. J Pathol 229:111–120. CrossRefGoogle Scholar
  2. 2.
    Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M, Maestri I, Guerzoni L, Roncucci L, Menigatti M, Roncari B, Maffei S, Rossi G, Ponti G, Santini A, Losi L, Di Gregorio C, Oliani C, Ponz de Leon M, Lanza G (2005) Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 11:8332–8340. CrossRefGoogle Scholar
  3. 3.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. CrossRefGoogle Scholar
  4. 4.
    Cancer Genome Atlas Research N (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615. CrossRefGoogle Scholar
  5. 5.
    Cancer Genome Atlas Research N (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–550. CrossRefGoogle Scholar
  6. 6.
    Darb-Esfahani S, Kunze CA, Kulbe H, Sehouli J, Wienert S, Lindner J, Budczies J, Bockmayr M, Dietel M, Denkert C, Braicu I, Johrens K (2016) Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget 7:1486–1499. Google Scholar
  7. 7.
    Dellas A, Puhl A, Schraml P, Thomke SE, Ruschoff J, Mihatsch MJ, Moch H (2004) Molecular and clinicopathological analysis of ovarian carcinomas with and without microsatellite instability. Anticancer Res 24:361–369Google Scholar
  8. 8.
    du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, Bauknecht T, Richter B, Warm M, Schroder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J, Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study G (2003) A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320–1329CrossRefGoogle Scholar
  9. 9.
    Gadducci A, Guerrieri ME (2017) Immune checkpoint inhibitors in gynecological cancers: update of literature and perspectives of clinical research. Anticancer Res 37:5955–5965. Google Scholar
  10. 10.
    Gasljevic G, Lamovec J, Contreras JA, Zadnik V, Blas M, Gasparov S (2013) HER2 in gastric cancer: an immunohistochemical study on tissue microarrays and the corresponding whole-tissue sections with a supplemental fish study. Pathol Oncol Res 19:855–865. CrossRefGoogle Scholar
  11. 11.
    Gavin PG, Paik S, Yothers G, Pogue-Geile KL (2013) Colon cancer mutation: prognosis/prediction-response. Clin Cancer Res 19:1301. CrossRefGoogle Scholar
  12. 12.
    Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E (2010) Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 46:2788–2798. CrossRefGoogle Scholar
  13. 13.
    Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577–581. CrossRefGoogle Scholar
  14. 14.
    Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, Mori Y, Matsumoto S, Chikuma S, Matsumura N, Abiko K, Baba T, Yamaguchi K, Ueda A, Hosoe Y, Morita S, Yokode M, Shimizu A, Honjo T, Konishi I (2015) Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol 33:4015–4022. CrossRefGoogle Scholar
  15. 15.
    Howitt BE, Strickland KC, Sholl LM, Rodig S, Ritterhouse LL, Chowdhury D, D'Andrea AD, Matulonis UA, Konstantinopoulos PA (2017) Clear cell ovarian cancers with microsatellite instability: a unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology 6:e1277308. CrossRefGoogle Scholar
  16. 16.
    Huang XX, Xie FF, Hou LJ, Chen XX, Ou RY, Yu JT, Qiu JG, Zhang WJ, Jiang QW, Yang Y, Zheng DW, Chen Y, Huang JR, Wang K, Wei MN, Li WF, Shi Z, Yan XJ (2017) Crizotinib synergizes with cisplatin in preclinical models of ovarian cancer. Am J Transl Res 9:1667–1679Google Scholar
  17. 17.
    Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Sasada S, Watanabe S, Asamura H, Tamura T, Ohe Y (2015) Reliability of small biopsy samples compared with resected specimens for the determination of programmed death-ligand 1 expression in non-small-cell lung cancer. Clin Lung Cancer 16:385–390. CrossRefGoogle Scholar
  18. 18.
    Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703. CrossRefGoogle Scholar
  19. 19.
    Le Quesne J, Maurya M, Yancheva SG, O'Brien M, Popat S, Wotherspoon AC, de Castro DG, Nicholson AG (2014) A comparison of immunohistochemical assays and FISH in detecting the ALK translocation in diagnostic histological and cytological lung tumor material. J Thorac Oncol 9:769–774. CrossRefGoogle Scholar
  20. 20.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. CrossRefGoogle Scholar
  21. 21.
    Ledermann JA (2016) PARP inhibitors in ovarian cancer. Ann Oncol 27(Suppl 1):i40–i44. CrossRefGoogle Scholar
  22. 22.
    Lee JM, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, Cao L, Harrell MI, Swisher EM, Houston N, Botesteanu DA, Taube JM, Thompson E, Ogurtsova A, Xu H, Nguyen J, Ho TW, Figg WD, Kohn EC (2017) Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women’s cancers: a dose-escalation, phase I study. J Clin Oncol 35:2193–2202. CrossRefGoogle Scholar
  23. 23.
    Li C, Huang C, Mok TS, Zhuang W, Xu H, Miao Q, Fan X, Zhu W, Huang Y, Lin X, Jiang K, Hu D, Chen X, Huang P, Lin G (2017) Comparison of 22C3 PD-L1 expression between surgically resected specimens and paired tissue microarrays in non-small cell lung cancer. J Thorac Oncol 12:1536–1543. CrossRefGoogle Scholar
  24. 24.
    Luo H, Xu X, Ye M, Sheng B, Zhu X (2018) The prognostic value of HER2 in ovarian cancer: a meta-analysis of observational studies. PLoS One 13:e0191972. CrossRefGoogle Scholar
  25. 25.
    McGuire WP 3rd, Markman M (2003) Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer 89(Suppl 3):S3–S8. CrossRefGoogle Scholar
  26. 26.
    Muller V, Clemens M, Jassem J, Al-Sakaff N, Auclair P, Nuesch E, Holloway D, Shing M, Bang YJ (2018) Long-term trastuzumab (Herceptin(R)) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer. BMC Cancer 18:295. CrossRefGoogle Scholar
  27. 27.
    Nakamura K, Banno K, Yanokura M, Iida M, Adachi M, Masuda K, Ueki A, Kobayashi Y, Nomura H, Hirasawa A, Tominaga E, Aoki D (2014) Features of ovarian cancer in Lynch syndrome (review). Mol Clin Oncol 2:909–916. CrossRefGoogle Scholar
  28. 28.
    Perren TJ (2016) Mucinous epithelial ovarian carcinoma. Ann Oncol 27(Suppl 1):i53–i57. CrossRefGoogle Scholar
  29. 29.
    Pfisterer J, Du Bois A, Bentz EK, Kommoss F, Harter P, Huober J, Schmalfeldt B, Burchardi N, Arnold N, Hilpert F (2009) Prognostic value of human epidermal growth factor receptor 2 (Her-2)/neu in patients with advanced ovarian cancer treated with platinum/paclitaxel as first-line chemotherapy: a retrospective evaluation of the AGO-OVAR 3 trial by the AGO OVAR Germany. Int J Gynecol Cancer 19:109–115. CrossRefGoogle Scholar
  30. 30.
    Pujade-Lauraine E, Fujiwara K, Dychter SS, Devgan G, Monk BJ (2018) Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. Future Oncol 14:2103–2113. CrossRefGoogle Scholar
  31. 31.
    Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, Christie M, Allan PE, Stephens AN, Bowtell DD, Australian Ovarian Cancer Study G, Campbell IG, Gorringe KL (2015) Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. Genome Med 7:87. CrossRefGoogle Scholar
  32. 32.
    Scheel AH, Dietel M, Heukamp LC, Johrens K, Kirchner T, Reu S, Ruschoff J, Schildhaus HU, Schirmacher P, Tiemann M, Warth A, Weichert W, Fischer RN, Wolf J, Buettner R (2016) Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol 29:1165–1172. CrossRefGoogle Scholar
  33. 33.
    Scott LJ (2017) Niraparib: first global approval. Drugs 77:1029–1034. CrossRefGoogle Scholar
  34. 34.
    Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T (2013) CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 14:590–598. CrossRefGoogle Scholar
  35. 35.
    Tang S, Yang F, Du X, Lu Y, Zhang L, Zhou X (2016) Aberrant expression of anaplastic lymphoma kinase in ovarian carcinoma independent of gene rearrangement. Int J Gynecol Pathol 35:337–347. CrossRefGoogle Scholar
  36. 36.
    Thunnissen E, Bubendorf L, Dietel M, Elmberger G, Kerr K, Lopez-Rios F, Moch H, Olszewski W, Pauwels P, Penault-Llorca F, Rossi G (2012) EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Arch 461:245–257. CrossRefGoogle Scholar
  37. 37.
    Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461. CrossRefGoogle Scholar
  38. 38.
    Wang Q, Lou W, Di W, Wu X (2017) Prognostic value of tumor PD-L1 expression combined with CD8(+) tumor infiltrating lymphocytes in high grade serous ovarian cancer. Int Immunopharmacol 52:7–14. CrossRefGoogle Scholar
  39. 39.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, LM MS, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. CrossRefGoogle Scholar
  40. 40.
    Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. Arch Pathol Lab Med 142:1364–1382. CrossRefGoogle Scholar
  41. 41.
    Wright CM, Dent OF, Barker M, Newland RC, Chapuis PH, Bokey EL, Young JP, Leggett BA, Jass JR, Macdonald GA (2000) Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg 87:1197–1202. CrossRefGoogle Scholar
  42. 42.
    Yuza K, Nagahashi M, Watanabe S, Takabe K, Wakai T (2017) Hypermutation and microsatellite instability in gastrointestinal cancers. Oncotarget 8:112103–112115. CrossRefGoogle Scholar
  43. 43.
    Zhu J, Wen H, Bi R, Wu Y, Wu X (2017) Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma. J Gynecol Oncol 28:e77. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Elisa Schmoeckel
    • 1
    Email author
  • Sophie Hofmann
    • 1
  • Daniel Fromberger
    • 1
  • Miriam Rottmann
    • 2
  • Beate Luthardt
    • 1
  • Alexander Burges
    • 3
  • Udo Jeschke
    • 3
  • Thomas Kirchner
    • 1
  • Sigurd F. Lax
    • 4
  • Doris Mayr
    • 1
  1. 1.Institute of PathologyLudwig-Maximilians-University (LMU)MunichGermany
  2. 2.Munich Cancer Registry (MCR) of the Munich Tumor Centre (TZM), Institute for Medical Information Processing, Biometry, and Epidemiology (IBE)University Hospital of Munich, Ludwig-Maximilians-UniversityMunichGermany
  3. 3.Department of Gynaecology and ObstetricsLudwig-Maximilians-University (LMU)MunichGermany
  4. 4.Department of PathologyHospital Graz II and Medical University GrazGrazAustria

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