黏液性卵巢肿瘤的分子特征支持分层治疗方法，其中 19%的癌可针对 HER2 进行靶向治疗。

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

机构信息

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

出版信息

J Pathol. 2013 Jan;229(1):111-20. doi: 10.1002/path.4088.

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.

摘要

黏液性卵巢癌（MC）通常对当前的常规治疗没有反应。我们之前已经证明在 33 例黏液性卵巢癌（MC）中有 6 例（18.2%）HER2 扩增，并在一小部分 HER2 扩增（HER2+）MC 的女性中提供了 HER2 靶向治疗的轶事证据。在这里，我们在一个独立的 189 例 MC 和 199 例黏液性交界性卵巢肿瘤（MBOT）队列中探讨了 HER2 扩增和 KRAS 突变状态，并评估了其与临床病理特征的关系。HER2 状态通过免疫组化（IHC）、荧光原位杂交（FISH）和显色原位杂交（CISH）进行评估，并按照 ASCO/CAP 指南进行解释，在有全切片的情况下评估肿瘤内异质性。KRAS 突变检测采用 Sanger 测序。单变量和多变量分析均显示分期和分级与复发相关（p<0.001）。HER2 状态评估显示，在 154 例 MC 中有 29 例（18.8%）和在 176 例 MBOT 中有 11 例（6.2%）HER2 过度表达/扩增。HER2 状态的 IHC、FISH 和 CISH 评估之间具有极好的一致性（HER2 0 或 1+ IHC 与非扩增状态和 3+ IHC 与扩增状态完全一致）。在 71 例 MC 中有 31 例（43.6%）和在 33 例 MBOT 中有 26 例（78.8%）存在 KRAS 突变，并且几乎与 HER2 扩增相互排斥。在 189 例 MC 病例中，共观察到 54 例复发和 59 例死亡（53 例为进展性疾病）。在 MC 中，与既没有 HER2 扩增/过表达也没有 KRAS 突变的病例相比，HER2 扩增/过表达或 KRAS 突变与疾病复发（p=0.019）或死亡（p=0.0041）的可能性降低相关。在 26%的 HER2 过表达病例中观察到肿瘤内异质性。这些数据支持对 MC 进行新治疗方法的检测分层，HER2 靶向治疗是 HER2+晚期或复发性疾病的可行选择。需要进一步研究来描绘出既没有 HER2 扩增也没有 KRAS 突变的约 34%的 MC 病例的分子和临床特征。