HER-2/neuoverexpression and amplification in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and fluorescencein situhybridization

Abstract

Uterine serous papillary carcinoma (USPC) is a rare and highly malignant form of endometrial cancer (EC) characterized by early metastasis, chemoresistance, and high mortality rate. Little is known about USPC tumorigenesis even if recently a HER-2/neu role has been suggested in its development and progression. The aim of the present study was to evaluate HER-2 expression by immunohistochemistry (IHC) in 12 USPC formalin-fixed, paraffin-embedded (FFPE) samples. Moreover, we looked at the correlation between HER-2 protein expression and HER-2/neu gene amplification by fluorescence in situ hybridization (FISH), other than HER-2/neu messenger RNA expression by quantitative real-time reverse transcription (RT)-polymerase chain reaction (PCR). Finally, these results have been compared with commonly evaluated clinical features in EC patients, in order to define the potential prognostic value of HER-2/neu overexpression in USPCs. A high expression of HER-2 protein by IHC was noted in 2 of 12 patients (16.6%), and the same cases showed specific HER-2/neu gene amplification by FISH. All the samples investigated displayed a perfect concordance between IHC and FISH data. Five (41.6%) of 12 tumors demonstrated polysomy of chromosome 17 and, focusing on the 2 USPCs that showed HER-2/neu overexpression, one of them (50%) was polysomic for chromosome 17. All the other USPC cases (58.4%) showed to be disomic for chromosome 17. Quantitative RT real-time PCR performed on complementary DNA obtained from all FFPE USPC samples showed a complete correlation with FISH and IHC data. Moreover, HER-2/neu overexpression was associated with a poorer overall survival and a very low relapse-free survival time, thus being considered a candidate marker of worse overall prognosis in USPC. The use of trastuzumab (Herceptin), a monoclonal antibody directed against HER-2/neu, for the therapy of patients with HER-2/neu-positive USPCs should be further investigated in clinical trials.

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

“…[14][15][16]34,35 Several previous studies used non-FDA-approved HER2 antibodies, ie, c-erbB-2 clone A0485 (DAKO), 24,35,36 c-erbB-2/ Her-2/neu Ab17 (monoclonal antibodies e2-4001 and 3B5; Neomarkers) 8 and clone TAB250 (Zymed). 16,35 Although most studies used the FDA scoring criteria for HER2 immunohistochemistry, 8,9,[13][14][15]18,22,24,30,35,36 many of them considered both the 2 þ and 3 þ immunohistochemical scores positive for HER2 overexpression. 8,13,15,30,35,36 Others used selfdeveloped semiquantitative immunohistochemical scoring systems, not currently approved for any other tumor types.…”

“…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.…”

“…[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).…”

The Role of ErbB Receptors in Endometrial Cancer

“…Overexpression of ErbB-2 is frequent in head, neck, breast, lung, pancreatic, esophageal, liver, colorectal, prostate, bladder, ovarian, endometrial and cervical cancer [Odicino et al;Ross & Fletcher, 1998;Yarden & Sliwkowski, 2001b;Uberall et al, 2008]. It is an indicator of a more aggressive clinical behavior [Ross & Fletcher, 1998;Yarden & Sliwkowski, 2001b;Odicino et al, 2008]. Overexpression of ErbB-3 is frequent in head, neck, breast, gastric, liver, colorectal, prostate and ovarian cancer [Yarden & Sliwkowski, 2001b;Uberall et al, 2008].…”

“…They associated with higher grade, disease progression, poor survival and resistance to radiotherapy and chemotherapy [Yarden & Sliwkowski, 2001b;Lurje & Lenz, 2009]. Overexpression of ErbB-2 is frequent in head, neck, breast, lung, pancreatic, esophageal, liver, colorectal, prostate, bladder, ovarian, endometrial and cervical cancer [Odicino et al;Ross & Fletcher, 1998;Yarden & Sliwkowski, 2001b;Uberall et al, 2008]. It is an indicator of a more aggressive clinical behavior [Ross & Fletcher, 1998;Yarden & Sliwkowski, 2001b;Odicino et al, 2008].…”