Clinical significance of Her-2/neu overexpression in uterine serous carcinoma

Díaz-Montes, Teresa; Ji, Hongxiu; Sehdev, Ann E. Smith; Zahurak, Mariana L.; Kurman, Robert J.; Armstrong, Deborah K.; Bristow, Robert E.

doi:10.1016/j.ygyno.2005.08.017

Cited by 53 publications

(37 citation statements)

References 27 publications

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“…These findings, which have been recently confirmed by other groups (Diaz-Montes et al, 2006), as well as those in cooperative multicentric studies reported by the Gynecologic Oncology Group (Grushko et al, 2008), have highlighted the potential of targeting HER2/neu as a new therapeutic marker in patients harbouring aggressive type II carcinomas such as USPC. Similar to the great promise for treatment of metastatic breast cancer in patients harbouring tumours with proven amplification or strong (i.e., 3 þ by IHC) HER2/neu overexpression, endometrial cancer patients with disease refractory to standard treatment modalities may potentially benefit from HER2/neu-targeted therapy.…”

Section: Discussionsupporting

confidence: 72%

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

et al. 2009

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BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1 þ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complementcontaining plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P ¼ 0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.

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Section: Discussionsupporting

confidence: 72%

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

et al. 2009

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“…Overexpression of Her-2/neu was seen in 50.0% (11/22) of UPSC patients with advanced disease, compared to 14.3% (2/14) of patients with early disease. Similar findings were reported by Slomovitz, Santin, and Díaz-Montes et al, in which overexpression of Her-2/neu in patients with advanced disease were 24%~81.8%, compared to 8%~28.6% of patients with early disease [19, 20, 30]. Díaz-Montes et al also demonstrated that overexpression of Her-2/neu was associated with higher Ki-67 index, larger tumor sizes, and worse survival outcome.…”

Section: Discussionsupporting

confidence: 80%

Clinicopathological Characteristics and Her-2/neu Status in Chinese Patients with Uterine Papillary Serous Carcinoma

Ren

Wang

Zhou

et al. 2011

ISRN Obstetrics and Gynecology

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Objective. To analyze clinico-pathological features of Chinese patients with UPSC, and investigate roles of Her-2/neu protein expression and gene amplification in UPSC prognosis. Methods. Thirty-six patients with UPSC treated in Cancer Hospital of Fudan University from 1996 to 2006 were analysed retrospectively. Chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) were performed to evaluate Her-2/neu gene amplification and protein expression respectively. Results. The median age was 63 years, and 61% (22/36) were late stages (stage III/IV). The 1-year, 3-year, and 5-year overall survival (OS) was 73.1%, 51.9% and 43.9%, respectively. Advanced stages (P = .0006) and deep myometrial invasion (P = .0138) were significantly associtated with a shorter OS. In 36 cases, 27.8% (10/36) showed 2+ staining and 8.3% (3/36) showed 3+ by IHC. Amplification of the Her-2/neu gene was observed in 11.1% (4/36) cases. The 5-year overall survival rate in Her-2/neu IHC 2 + ∼3+ and 0 ~ 1+ cases was 12.9% and 68.6% respectively. Her-2/neu protein expression 2 + ∼3+ was significantly associated with advanced surgical stage and worse overall survival (P = .03 and P = .0023, resp.). Conclusion. Chinese patients with UPSC showed characteristics of deep myometrial invasion, advanced stages and poor overall survival. Her-2/neu protein overexpression is associated with advanced stage and poor survival outcome.

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“…Previous studies evaluating the HER2 status in endometrial carcinomas suffered from several limitations, including inappropriate case selection and lack of standardized HER2 testing and scoring criteria, leading to a wide range-14-80%-of reported HER2 positivity in endometrial serous carcinoma [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] (Buza et al, in press). One of the largest studies-a phase II clinical trial of singleagent trastuzumab in advanced or recurrent endometrial carcinoma-for example, has been previously criticized for including a large number of type I and mixed endometrial carcinomas, and the histological subtype was not specified in nearly half of the cases.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7] Although HER2/neu has been studied in endometrial cancer for over 15 years, standard testing methods or scoring guidelines are yet to be developed. The reported rates of HER2 overexpression in endometrial serous carcinoma range between 14 and 80%, due to-at least in part-the significant variation in the HER2 testing methods, interpretation and scoring criteria used [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] (Buza et al, in press).…”

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confidence: 99%

Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice

et al. 2013

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HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely-at least in part-resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases-85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component-were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients' medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended, due to the significant heterogeneity of HER2 protein expression. Keywords: endometrial serous carcinoma; fluorescent in situ hybridization; HER2 testing; heterogeneity; immunohistochemistry The significance of human epidermal growth factor receptor 2 (HER2/Neu, ERBB2) amplification and HER2 protein overexpression has been well established in the pathogenesis and targeted therapy of breast cancer and more recently in gastric and gastroesophageal junction carcinomas. 1-3 Tumorspecific HER2 testing guidelines have been developed to reflect the unique biological features of each of these tumor types and to predict the clinical response to HER2-targeted therapy. [4][5][6][7] Although HER2/neu has been studied in endometrial cancer for over 15 years, standard testing methods or scoring guidelines are yet to be developed. The reported rates of HER2 overexpression in endometrial serous carcinoma range between 14 and 80%, due to-at least in part-the significant ...

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Clinical significance of Her-2/neu overexpression in uterine serous carcinoma

Cited by 53 publications

References 27 publications

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

Clinicopathological Characteristics and Her-2/neu Status in Chinese Patients with Uterine Papillary Serous Carcinoma

Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice

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