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

Michael S. Anglesio, Stefan Kommoss, Mary C. Tolcher, Blaise Clarke, Laura Galletta, Henry Porter, Sambasivarao Damaraju, Sian Fereday, Boris J. Winterhoff, Steve E. Kalloger, Janine Senz, Winnie Yang, Helen Steed, Ghassan Allo, Sarah Ferguson, Patricia Shaw, Attila Teoman, Joaquin J. Garcia, J. Kenneth Schoolmeester, Jamie N Bakkum-GamezAnna V. Tinker, David D. Bowtell, David G. Huntsman, C. Blake Gilks, Jessica N. McAlpine

Research output: Contribution to journalArticle

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Abstract

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 ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

Original languageEnglish (US)
Pages (from-to)111-120
Number of pages10
JournalJournal of Pathology
Volume229
Issue number1
DOIs
StatePublished - Jan 2013

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Mucinous Adenocarcinoma
Carcinoma
Neoplasms
Mutation
Immunohistochemistry
Therapeutics
Recurrence
Multivariate Analysis
Guidelines

Keywords

  • HER2
  • heterogeneity
  • KRAS
  • mutation
  • Ovarian cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Anglesio, M. S., Kommoss, S., Tolcher, M. C., Clarke, B., Galletta, L., Porter, H., ... McAlpine, J. N. (2013). Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. Journal of Pathology, 229(1), 111-120. https://doi.org/10.1002/path.4088

Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. / Anglesio, Michael S.; Kommoss, Stefan; Tolcher, Mary C.; Clarke, Blaise; Galletta, Laura; Porter, Henry; Damaraju, Sambasivarao; Fereday, Sian; Winterhoff, Boris J.; Kalloger, Steve E.; Senz, Janine; Yang, Winnie; Steed, Helen; Allo, Ghassan; Ferguson, Sarah; Shaw, Patricia; Teoman, Attila; Garcia, Joaquin J.; Schoolmeester, J. Kenneth; Bakkum-Gamez, Jamie N; Tinker, Anna V.; Bowtell, David D.; Huntsman, David G.; Gilks, C. Blake; McAlpine, Jessica N.

In: Journal of Pathology, Vol. 229, No. 1, 01.2013, p. 111-120.

Research output: Contribution to journalArticle

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, JN, 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', Journal of Pathology, vol. 229, no. 1, pp. 111-120. https://doi.org/10.1002/path.4088
Anglesio, Michael S. ; Kommoss, Stefan ; Tolcher, Mary C. ; Clarke, Blaise ; Galletta, Laura ; Porter, Henry ; Damaraju, Sambasivarao ; Fereday, Sian ; Winterhoff, Boris J. ; Kalloger, Steve E. ; Senz, Janine ; Yang, Winnie ; Steed, Helen ; Allo, Ghassan ; Ferguson, Sarah ; Shaw, Patricia ; Teoman, Attila ; Garcia, Joaquin J. ; Schoolmeester, J. Kenneth ; Bakkum-Gamez, Jamie N ; Tinker, Anna V. ; Bowtell, David D. ; Huntsman, David G. ; Gilks, C. Blake ; McAlpine, Jessica N. / Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. In: Journal of Pathology. 2013 ; Vol. 229, No. 1. pp. 111-120.
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T1 - Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas

AU - Anglesio, Michael S.

AU - Kommoss, Stefan

AU - Tolcher, Mary C.

AU - Clarke, Blaise

AU - Galletta, Laura

AU - Porter, Henry

AU - Damaraju, Sambasivarao

AU - Fereday, Sian

AU - Winterhoff, Boris J.

AU - Kalloger, Steve E.

AU - Senz, Janine

AU - Yang, Winnie

AU - Steed, Helen

AU - Allo, Ghassan

AU - Ferguson, Sarah

AU - Shaw, Patricia

AU - Teoman, Attila

AU - Garcia, Joaquin J.

AU - Schoolmeester, J. Kenneth

AU - Bakkum-Gamez, Jamie N

AU - Tinker, Anna V.

AU - Bowtell, David D.

AU - Huntsman, David G.

AU - Gilks, C. Blake

AU - McAlpine, Jessica N.

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N2 - 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 ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

AB - 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 ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

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