Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas

被引：146

作者：

Anglesio, Michael S. ^{[2
]}

Kommoss, Stefan ^{[2
]}

Tolcher, Mary C. ^{[3
]}

Clarke, Blaise ^{[4
]}

Galletta, Laura ^{[5
]}

Porter, Henry ^{[2
]}

Damaraju, Sambasivarao ^{[6
]}

Fereday, Sian ^{[5
]}

Winterhoff, Boris J. ^{[3
]}

Kalloger, Steve E. ^{[7
,8
]}

Senz, Janine ^{[2
]}

Yang, Winnie ^{[9
]}

Steed, Helen ^{[10
,11
]}

Allo, Ghassan ^{[4
]}

Ferguson, Sarah ^{[12
]}

Shaw, Patricia ^{[13
]}

Teoman, Attila ^{[14
]}

Garcia, Joaquin J. ^{[14
]}

Schoolmeester, John K. ^{[14
]}

Bakkum-Gamez, Jamie ^{[14
]}

Tinker, Anna V. ^{[15
]}

Bowtell, David D. ^{[16
,17
,18
,19
]}

Huntsman, David G. ^{[1
,9
]}

Gilks, C. Blake ^{[2
,7
,8
]}

McAlpine, Jessica N. ^{[1
]}

机构：

[1] Univ British Columbia, Dept Gynecol & Obstet, Div Gynecol Oncol, Vancouver, BC V5Z 1M9, Canada

[2] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada

[3] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN USA

[4] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[5] Peter MacCallum Canc Ctr, Australian Ovarian Canc Study Grp, Melbourne, Vic, Australia

[6] Univ Alberta, Canadian Breast Canc Fdn Tumor Bank, Alberta Hlth Serv, Edmonton, AB, Canada

[7] VGH, Genet Pathol Evaluat Ctr, Vancouver, BC, Canada

[8] Univ British Columbia, Vancouver, BC, Canada

[9] BC Canc Agcy, Ctr Translat & Appl Genom, Vancouver, BC, Canada

[10] Univ Alberta, Dept Obstet & Gynecol, Edmonton, AB, Canada

[11] Univ Alberta, Div Gynecol Oncol, Edmonton, AB, Canada

[12] Univ Toronto, Dept Gynecol Oncol, Toronto, ON, Canada

[13] Univ Toronto, Toronto Gen Hosp, Univ Hlth Network, Toronto, ON M5G 1L7, Canada

[14] Mayo Clin, Dept Pathol, Rochester, MN USA

[15] BC Canc Agcy, Dept Med Oncol, Vancouver, BC, Canada

[16] Peter MacCallum Canc Ctr, Canc Genom & Genet Program, Melbourne, Vic, Australia

[17] Univ Melbourne, Dept Oncol, Parkville, Vic 3052, Australia

[18] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia

[19] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia

来源：

JOURNAL OF PATHOLOGY | 2013年 / 229卷 / 01期

基金：

英国医学研究理事会;

关键词：

Ovarian cancer; HER2; KRAS; mutation; heterogeneity; GROWTH-FACTOR RECEPTOR; IMMUNOHISTOCHEMICAL EXPRESSION; ADVANCED-STAGE; ANTI-HER2; ANTIBODY; PREDICTIVE FACTORS; COLORECTAL-CANCER; CLINICAL-TRIALS; HISTOLOGIC TYPE; INTESTINAL-TYPE; GASTRIC-CANCER;

D O I：

10.1002/path.4088

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the similar to 34% of MC cases with neither HER2 amplification nor KRAS mutations. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

引用

页码：111 / 120

页数：10

共 56 条

[41] Primary and metastatic mucinous adenocarcinomas in the ovaries - Incidence in routine practice with a new approach to improve intraoperative diagnosis [J].

Seidman, JD ;

Kurman, RJ ;

Ronnett, BA .

AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2003, 27 (07) :985-993

[42] The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer [J].

Steffensen, K. D. ;

Waldstrom, M. ;

Jeppesen, U. ;

Jakobsen, E. ;

Brandslund, I. ;

Jakobsen, A. .

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, 2007, 17 (04) :798-807

[43]

Sugiyama Toru, 2009, Gan To Kagaku Ryoho, V36, P187

[44] Primary Ovarian Mucinous Carcinoma of Intestinal Type: Significance of Pattern of Invasion and Immunohistochemical Expression Profile in a Series of 31 Cases [J].

Tabrizi, Ali Dastranj ;

Kalloger, Steve E. ;

Koebel, Martin ;

Cipollone, Jane ;

Roskelley, Calvin D. ;

Mehl, Erika ;

Gilks, C. Blake .

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, 2010, 29 (02) :99-107

[45] Strategy for randomised clinical trials in rare cancers [J].

Tan, SB ;

Dear, KBG ;

Bruzzi, P ;

Machin, D .

BRITISH MEDICAL JOURNAL, 2003, 327 (7405) :47-49

[46] Close association between HER-2 amplification and overexpression in human tumors of non-breast origin [J].

Tapia, Coya ;

Glatz, Katharina ;

Novotny, Hedvika ;

Lugli, Alessandro ;

Horcic, Milo ;

Seemayer, Christian A. ;

Tornillo, Luigi ;

Terracciano, Luigi ;

Spichtin, Hanspeter ;

Mirlacher, Martina ;

Simon, Ronald ;

Sauter, Guido .

MODERN PATHOLOGY, 2007, 20 (02) :192-198

[47] Summary and discussion of session recommendations [J].

Trimble, Edward L. ;

Fountain, Jane ;

Birrer, Michael J. .

GYNECOLOGIC ONCOLOGY, 2006, 103 (02) :S23-S25

[48] Reproductive factors and epithelial ovarian cancer risk by histologic type: A multiethnic case-control study [J].

Tung, KH ;

Goodman, MT ;

Wu, AH ;

McDuffie, K ;

Wilkens, LR ;

Kolonel, LN ;

Nomura, AMY ;

Terada, KY ;

Carney, ME ;

Sobin, LH .

AMERICAN JOURNAL OF EPIDEMIOLOGY, 2003, 158 (07) :629-638

[49] Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7 [J].

Vang, Russell ;

Gown, Allen M. ;

Wu, Lee-Shu-Fune ;

Barry, Todd S. ;

T Wheeler, Darren ;

Yemelyanova, Anna ;

Seidman, Jeffrey D. ;

Ronnett, Brigitte M. .

MODERN PATHOLOGY, 2006, 19 (11) :1421-1428

[50]

Vang R, 2006, AM J SURG PATHOL, V30, P1130

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