Top

22-08-2017 | Ovarian cancer | Article

Contemporary Treatment Strategies for Rare Epithelial Ovarian Cancers

Journal: Current Obstetrics and Gynecology Reports

Authors: Jennifer E. Bergstrom, Amanda N. Fader, David M. Gershenson

Abstract

Purpose of Review

Epithelial ovarian carcinoma consists of not one but five distinct histologic subtypes which include high-grade and low-grade serous carcinomas, clear cell, endometrioid, and mucinous carcinoma. Until recently, women with all histologic subtypes have been “grouped together” in cooperative group trials and treated in a similar fashion.

Recent Findings

Recent advances have demonstrated that each subtype differs in molecular and genetic differentiation, pathogenesis, clinical behavior, and response to treatments. Since the establishment of the Gynecologic Oncology Group (GOG) Rare Tumor Committee in 2005, there has been increasing emphasis placed upon novel treatment strategies for these low incidence malignancies. There has been mounting evidence to suggest that a “one-size-fits-all” treatment approach is not appropriate—especially for low-grade serous, clear cell, endometrioid, and mucinous carcinomas as they all tend to be relatively chemoresistant to typical platinum/taxane-based chemotherapy regimens utilized for high-grade serous carcinomas.

Summary

We present a review of the rare epithelial ovarian cancer subtypes, including current best clinical practices for the management of each tumor type.

Ovarian Cancer. American Cancer Society, Inc. https://www.cancer.org/cancer/ovarian-cancer.html. Accessed May 2017.

National Cancer Institute (NCI). Cancer Stat Facts: Ovarian Cancer. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed May 2017.

Cho KR, IeM S. Ovarian cancer. Annu Rev Pathol. 2009;4:287–313. doi:10.1146/annurev.pathol.4.110807.092246.CrossRefPubMedPubMedCentral

Gynecologic Oncology Group. Newsletter. 86th Semi-Annual Meeting. San Diego - Spring 2013. http://www.gog.org/Spring2013newsletter.pdf. Accessed May 2017.

Kurman R, Shih I. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34(3):433–43.CrossRefPubMedPubMedCentral

Vang R, Levine DA, Soslow RA, Zaloudek C, IeM S, Kurman RJ. Molecular alterations of TP53 are a defining feature of ovarian high-grade serous carcinoma: a rereview of cases lacking TP53 mutations in the cancer genome atlas ovarian study. Int J Gynecol Pathol. 2016;35(1):48–55.CrossRefPubMedPubMedCentral

Farley J, Ozbun L, Birrer M. Genomic analysis of epithelial ovarian cancer. Cell Res. 2008;18(5):538–48.CrossRefPubMed

National Comprehensive Cancer Network. Ovarian. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed May 2017.

Bodurka D, Deavers M, Tian C, Sun C, Malpica A, Coleman R, et al. Reclassification of serous ovarian carcinoma by a 2-tier system. Cancer. 2011;118(12):3087–94.CrossRefPubMed

10.

Malpica A, Deavers M, Lu K, Bodurka D, Atkinson E, Gershenson D, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28(4):496–504.CrossRefPubMed

11.

Gershenson D, Sun C, Lu K, Coleman R, Sood A, Malpica A, et al. Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary. Obstet Gynecol. 2006;108(2):361–8.CrossRefPubMed

12.

Tsilidis KK, Allen NE, Key TJ, Dossus L, Lukanova A, Bakken K, et al. Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer. 2011;105:1436.CrossRefPubMedPubMedCentral

13.

Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet. 2008;371(9609):303–14. doi:10.1016/S0140-6736(08)60167-1.CrossRefPubMed

14.

Cibula D, Widschwendter M, Májek O, Dusek L. History of breast feeding. Hum Reprod Update. 2011;17:55.CrossRefPubMed

15.

Medeiros F, Muto M, Lee Y, Elvin J, Callahan M, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006;30(2):230–6.CrossRefPubMed

16.

Groen R, Gershenson D, Fader A. Updates and emerging therapies for rare epithelial ovarian cancers: one size no longer fits all. Gynecol Oncol. 2015;136(2):373–83.CrossRefPubMed

17.

Mishra S, Crasta J. An immunohistochemical comparison of P53 and Bcl-2 as apoptotic and MIB1 as proliferative markers in low-grade and high-grade ovarian serous carcinomas. Int J Gynecol Cancer. 2010;20(4):537–41.CrossRefPubMed

18.

Singer G, Cope L, Dehari R, Hartmann A, Cao D, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis. Am J Surg Pathol. 2005;29(2):218–24.CrossRefPubMed

19.

Singer G, Kurman RJ, Chang HW, Cho SK, IeM S. Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol. 2002;160(4):1223–8.CrossRefPubMedPubMedCentral

20.

Risch H, McLaughlin J, Cole D, Rosen B, Bradley L, Kwan E, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700–10.CrossRefPubMedPubMedCentral

21.

Press J, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer. 2008;8(1):17.CrossRefPubMedPubMedCentral

22.

Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20(5):1248–59.CrossRefPubMed

23.

Nickles Fader A, Java J, Ueda S, Bristow R, Armstrong D, Bookman M, et al. Survival in women with grade 1 serous ovarian carcinoma. Obstet Gynecol. 2013;122(2, PART 1):225–32.CrossRef

24.

Santillan A, Kim Y, Zahurak M, Gardner G, Giuntoli R, Shih I, et al. Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma. Int J Gynecol Cancer. 2007;17(3):601–6.CrossRefPubMed

25.

Schmeler KM, Sun CC, Bodurka DC, et al. Neoadjuvant chemotherapy for low-grade serouscarcinoma of the ovary or peritoneum. Gynecol Oncol. 2008;108:510–4. CrossRef , Medline CrossRefPubMed

26.

Ansquer Y, Leblanc E, Clough K, Morice P, Dauplat J, Mathevet P, Lhommé C, Scherer C, Tigaud JD, Benchaib M, Fourme E, Castaigne D, Querleu D, Dargent D. Neoadjuvant chemotherapy for unresectable ovarian carcinoma: a French multicenter study. Cancer. 2001;91(12):2329–34.CrossRefPubMed

27.

•• Grabowski JP, Harter P, Heitz F, Pujade-Lauraine E, Reuss A, Kristensen G, Ray-Coquard I, Heitz J, Traut A, Pfisterer J, du Bois A. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. Gynecol Oncol. 2016;140(3):457–62. doi:10.1016/j.ygyno.2016.01.022. This paper reiterated that advanced LGSC of the ovary have low response rates to conventional chemotherapy. CrossRefPubMed

28.

Gershenson D, Sun C, Iyer R, Wong K, Kavanagh J, Malpica A, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125:S35.CrossRef

29.

Wong KK, Lu KH, Malpica A, et al. Significantly greater expression of ER, PR, and ECAD in advanced-stage low-grade ovarian serous carcinoma as revealed by immunohistochemical analysis. Int J Gynecol Pathol. 26:404–9. 200

30.

Escobar J, Klimowicz AC, Dean M, et al. Quantification of ER/PR expression in ovarian low-grade serouscarcinoma. Gynecol Oncol. 2013;128:371–6.CrossRefPubMed

31.

•• Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35(10):1103–11. doi:10.1200/JCO.2016.71.0632. This study demonstrated the benefits of hormonal maintenance therapy in women with LGSC in the primary disease setting. CrossRefPubMed

32.

•• Fader-newest data to be published (this will be published within the next month). This is the first description of hormonal monotherapy in the primary disease setting for women with LGSC.

33.

Dalton HJ, Fleming ND, Sun CC, Bhosale P, Schmeler KM, Gershenson DM. Activity of bevacizumab-containing regimens in recurrent low-grade serous ovarian or peritoneal cancer: a single institution experience. Gynecol Oncol. 2017;145(1):37–40. doi:10.1016/j.ygyno.2017.01.027.CrossRefPubMed

34.

Farley J, Brady W, Vathipadiekal V, Lankes H, Coleman R, Morgan M, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. The Lancet Oncology. 2013;14(2):134–40.CrossRefPubMedPubMedCentral

35.

Array BioPharma. A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer. https://clinicaltrials.gov/ct2/show/NCT01849874. Accessed May 2017.

36.

National Cancer Institute (NCI). Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer. https://clinicaltrials.gov/ct2/show/NCT02101788?term=NCT02101788&rank=1. Accessed May 2017.

37.

Olivia Newton-John Cancer Research Institute. A Phase II Trial of Ipilimumab and Nivolumab for the Treatment of Rare Cancers. https://clinicaltrials.gov/ct2/show/NCT02923934?term=NCT02923934&rank=1. Accessed May 2017.

38.

Itamochi H, Kigawa J, Terakawa N. Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci. 2008;99(4):653–8.CrossRefPubMed

39.

Chan J, Teoh D, Hu J, Shin J, Osann K, Kapp D. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol. 2008;109(3):370–6.CrossRefPubMed

40.

Kennedy A, Biscotti C, Hart W, Webster K. Ovarian clear cell adenocarcinoma. Gynecol Oncol. 1989;32(3):342–9.CrossRefPubMed

41.

Mizuno M, Kikkawa F, Shibata K, Kajiyama H, Ino K, Kawai M, et al. Long-term follow-up and prognostic factor analysis in clear cell adenocarcinoma of the ovary. J Surg Oncol. 2006;94(2):138–43.CrossRefPubMed

42.

Barakat R. Principles and practice of gynecologic oncology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.

43.

Kobayashi H. Toward an understanding of the pathophysiology of clear cell carcinoma of the ovary (review). Oncology Letters. 2013.

44.

Kurian AW, Balise RR, McGuire V, Whittemore AS. Histologic types of epithelial ovarian cancer: have they different risk factors? Gynecol Oncol. 2005;96(2):520–30.CrossRefPubMed

45.

Wu RC, Wang TL, Shih IM. The emerging roles of ARID1A in tumor suppression. Cancer Biol Ther. 2014;15(6):655–64.CrossRefPubMedPubMedCentral

46.

Samartzis E, Noske A, Dedes K, Fink D, Imesch P. ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas. IJMS. 2013;14(9):18824–49.CrossRefPubMedPubMedCentral

47.

Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, et al. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. PLoS One. 2013;8(3):e57724.CrossRefPubMedPubMedCentral

48.

Zorn KK, Bonome T, Gangi L, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11:6422–30.CrossRefPubMed

49.

Takahashi A, Sasaki H, Kim SJ, et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994;54:4233–7.PubMed

50.

Jenison E, Montag A, Griffiths C, Welch W, Lavin P, Greer J, et al. Clear cell adenocarcinoma of the ovary: a clinical analysis and comparison with serous carcinoma. Gynecol Oncol. 1989;32(1):65–71.CrossRefPubMed

51.

Takano M, Tsuda H, Sugiyama T. Clear cell carcinoma of the ovary: is there a role of histology-specific treatment? J Exp Clin Cancer Res. 2012;31(1):53.CrossRefPubMedPubMedCentral

52.

Savvari P, Peitsidis P, Alevizaki M, Dimopoulos MA, Antsaklis A, Papadimitriou CA. Paraneoplastic humorally mediated hypercalcemia induced by parathyroid hormone-related protein in gynecologic malignancies: a systematic review. Onkologie. 2009;32(8–9):517–23. doi:10.1159/000226209.CrossRefPubMed

53.

Rose P. Gemcitabine reverses platinum resistance in platinum-resistant ovarian and peritoneal carcinoma. Int J Gynecol Cancer. 2005;15(s1):18–22.CrossRefPubMed

54.

Brown A, Jhingran A, Klopp A, Schmeler K, Ramirez P, Eifel P. Involved-field radiation therapy for locoregionally recurrent ovarian cancer. Gynecol Oncol. 2013;130(2):300–5.CrossRefPubMedPubMedCentral

55.

Mabuchi S, Kawase C, Altomare D, Morishige K, Hayashi M, Sawada K, et al. Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol Cancer Ther. 2010;9(8):2411–22.CrossRefPubMedPubMedCentral

56.

Farley, J, Brady W, Fujiwara K, Nomura H, Yunokawa M, Tokunaga H, et al. A phase II evaluation of temsirolimus in combination with carboplatin and paclitaxel followed by temsirolimus consolidation as first-line therapy in the treatment of Stage III–IV clear cell carcinoma of the ovary. Poster Presentation at ASCO. 2016.

57.

National Cancer Institute (NCI). Sunitinib Malate in Treating Patients With Persistent or Recurrent Clear Cell Ovarian Cancer. https://clinicaltrials.gov/ct2/show/NCT00979992?term=NCT00979992&rank=1. Accessed May 2017.

58.

NHS Greater Glasgow and Clyde. Study Of Nintedanib Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium (NiCCC). https://clinicaltrials.gov/ct2/show/NCT02866370?term=NCT02866370&rank=1. Accessed May 2017.

59.

University Health Network, Toronto. A Study of ENMD-2076 in Ovarian Clear Cell Cancers. https://clinicaltrials.gov/ct2/show/NCT01914510?term=NCT01914510&rank=1. Accessed May 2017.

60.

National Cancer Institute (NCI). Dasatinib in Treating Patients With Recurrent or Persistent Ovarian, Fallopian Tube, Endometrial or Peritoneal Cancer. https://clinicaltrials.gov/ct2/show/study/NCT02059265. Accessed June 2017.

61.

National Cancer Institute (NCI). Cabozantinib-S-Malate in Treating Patients With Recurrent or Progressive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. https://clinicaltrials.gov/ct2/show/NCT02315430. Accessed June 2017.

62.

Seidman J, Horkayne-Szakaly I, Haiba M, Boice C, Kurman R, Ronnett B. The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol. 2004;23(1):41–4.CrossRefPubMed

63.

Kline R, Wharton J, Atkinson E, Burke T, Gershenson D, Edwards C. Endometrioid carcinoma of the ovary: retrospective review of 145 cases. Int J Gynecol Obstet. 1991;36(2):169–70.CrossRef

64.

Tornos C, Silva E, Ordonez N, Gershenson D, Young R, Scully R. Endometrioid carcinoma of the ovary with a prominent spindle-cell component, a source of diagnostic confusion a report of 14 cases. Am J Surg Pathol. 1995;19(12):1343–53.CrossRefPubMed

65.

Yamada Y, Shigetomi H, Onogi A, Haruta S, Kawaguchi R, Yoshida S et al. Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary. International Journal of Gynecological Cancer. 2011:1.

66.

Catasús L, Bussaglia E, Rodriguez I, Gallardo A, Pons C, Irving J, et al. Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas. Hum Pathol. 2004;35(11):1360–8.CrossRefPubMed

67.

Palacios J, Gamallo C. Mutations in beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res. 1998;58:2095.

68.

Obata K, Morlan S, Watson R, Hitchcock A, Chenevix-Trech G, Thomas E. Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res. 1998;58:1334.

69.

Irving J, Catasús L, Gallardo A, Bussaglia E, Romero M, Matias-Guiu X, et al. Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the β-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis. Hum Pathol. 2005;36(6):605–19.CrossRefPubMed

70.

Modesitt S. Ovarian and extraovarian endometriosis-associated cancer. Obstet Gynecol. 2002;100(4):788–95.PubMed

71.

Storey D, Rush R, Stewart M, Rye T, Al-Nafussi A, Williams A, et al. Endometrioid epithelial ovarian cancer. Cancer. 2008;112(10):2211–20.CrossRefPubMed

72.

Chan J, Tian C, Fleming G, Monk B, Herzog T, Kapp D, et al. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(3):301–6.CrossRefPubMed

73.

University Hospital, Basel, Switzerland. Endometriosis and Frequency of Endometriosis-associated Ovarian Carcinomas (EAOC) (EAOC). https://clinicaltrials.gov/ct2/results?term=NCT01732432&Search=Search. Accessed May 2017.

74.

75.

Frumovitz M, Schmeler K, Malpica A, Sood A, Gershenson D. Unmasking the complexities of mucinous ovarian carcinoma. Gynecol Oncol. 2010;117(3):491–6.CrossRefPubMedPubMedCentral

76.

Lee K, Scully R. Mucinous tumors of the ovary. Am J Surg Pathol. 2000;24(11):1447–64.CrossRefPubMed

77.

Riopel M, Ronnett B, Kurman R. Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors. Am J Surg Pathol. 1999;23(6):617–35.CrossRefPubMed

78.

Mok S, Bell D, Knapp R, Fishbaugh P, Welch W, Muto M. Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res. 1993;53:1489–92.PubMed

79.

Gemignani M, Schlaerth A, Bogomolniy F, Barakat R, Lin O, Soslow R, et al. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol. 2003;90(2):378–81.CrossRefPubMed

80.

Tonin P, Maugard C, Perret C, Mes-Masson A, Provencher D. A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Familial Cancer. 2007;6(4):491–7.CrossRefPubMed

81.

Schuijer M, Berns E. TP53 and ovarian cancer. Hum Mutat. 2003;21(3):285–91.CrossRefPubMed

82.

Evans D, Young K, Bulman M, Shenton A, Wallace A, Lalloo F. Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet. 2008;73(4):338–45.CrossRefPubMed

83.

McAlpine J, Wiegand K, Miller M, Adamiak A, Koebel M, Vang R, et al. HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. Gynecol Oncol. 2010;116(3):593–4.CrossRef

84.

Seidman J, Kurman R, Ronnett B. Primary and metastatic mucinous adenocarcinomas in the ovaries. Am J Surg Pathol. 2003;27(7):985–93.CrossRefPubMed

85.

Schmeler K, Tao X, Frumovitz M, Deavers M, Sun C, Sood A, et al. Prevalence of lymph node metastasis in primary mucinous carcinoma of the ovary. Obstet Gynecol. 2010;116(2, Part 1):269–73.CrossRefPubMedPubMedCentral

86.

Zaino R, Brady M, Lele S, Michael H, Greer B, Bookman M. Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal. Cancer. 2010;117(3):554–62.CrossRefPubMedPubMedCentral

87.

Hess V. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol. 2004;22(6):1040–4.CrossRefPubMed

88.

Winter W, Maxwell G, Tian C, Carlson J, Ozols R, Rose P, et al. Prognostic factors for stage III epithelial ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2007;25(24):3621–7.CrossRefPubMed

89.

Shimizu Y, Umezawa S, Hasumi K, Yamauchi K, Silverberg S. Efficacy of a combination of irinotecan (CPT-11) with mitomycin-C (MMC) for clear cell carcinoma of the ovary (OCCA) which is intrinsically platinum-resistant. Eur J Cancer. 1997;33:S119.CrossRef

90.

Sato S, Itamochi H, Kigawa J, Oishi T, Shimada M, Sato S, et al. Combination chemotherapy of oxaliplatin and 5-fluorouracil may be an effective regimen for mucinous adenocarcinoma of the ovary: a potential treatment strategy. Cancer Sci. 2009;100(3):546–51.CrossRefPubMed

91.

National Cancer Institute (NCI). Carboplatin and Paclitaxel or Oxaliplatin and Capecitabine With or Without Bevacizumab as First-Line Therapy in Treating Patients With Newly Diagnosed Stage II-IV or Recurrent Stage I Epithelial Ovarian or Fallopian Tube Cancer. https://clinicaltrials.gov/ct2/show/NCT01081262. Accessed May 2017.

Medicine Matters Oncology

Abstract

Purpose of Review

Recent Findings

Summary