HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies

Abstract

HER2 or ErbB2 is a member of the epidermal growth factor family and is overexpressed in subsets of breast, ovarian, gastric, colorectal, pancreatic and endometrial cancers. HER2 regulates signaling through several pathways (Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol-3 kinase/protein kinase-B/mammalian target of rapamycin pathways) associated with cell survival and proliferation. HER2 overexpressed and/or gene amplified tumors are generally regarded as biologically aggressive neoplasms. In breast, cervical, endometrial and ovarian cancer, there have been several studies linking the amplification of the c-erbB2 gene with chemo-resistance and overall poor survival. Tyrosine kinase inhibitors and immunotherapy with monoclonal antibodies targeting HER2 holds promise for patients harboring these aggressive neoplasms. Trastuzumab combined with cytotoxic chemotherapy agents or conjugated with radioactive isotopes is currently being investigated in clinical trials of several tumor types.

PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas

“…In GOG-177, 234 specimens representing advanced or recurrent endometrial cancer were available for immunohistochemistry (IHC) and 182 for fluorescence in situ hybridisation. Of these, 11% of grade 3 endometrioid and 21% of serous tumours demonstrated HER2 gene amplification by FISH (English et al, 2013c). The proportion of overexpression by IHC was significantly higher in serous vs nonserous histologies (61% vs 41%, P ¼ 0.03).…”

“…Many previous studies have investigated HER2 overexpression and/or gene amplification in endometrial cancer patients. In GOG181B, in which 286 advanced or recurrent endometrial carcinomas were screened for HER2 overexpression, only 7% of endometrioid tumours were HER2-amplified, compared with 28% of serous cancers (English et al, 2013c). In GOG-177, 234 specimens representing advanced or recurrent endometrial cancer were available for immunohistochemistry (IHC) and 182 for fluorescence in situ hybridisation.…”

“…Accordingly, in vitro studies have identified phosphatidylinositol 3-kinase (PI3K) expression, low PTEN expression, AKT phosphorylation and S6K phosphorylation as potential mediators of primary trastuzumab resistance in breast cancer cell lines (Kataoka et al, 2010;O'Brien et al, 2010). In this regard, while in normal cells the PIK3CA/AKT/ mTOR pathway is tightly controlled, a large number of human cancers including endometrial tumours may harbour PIK3CA mutations which result in the deregulated activation of the pathway and the ability of tumours to metastasise and invade normal tissues, continue to grow under conditions of low nutrients or low oxygen, and resist radiation and chemotherapy treatment (Brachmann et al, 2009;English et al, 2013c).…”

“…HER2/neu is located upstream to the PIK3CA/AKT/mTOR pathway (English et al, 2013c). HER2/neu and the PIK3CA/AKT/ mTOR pathway can be constitutively activated secondary to gene amplifications (i.e., HER2/neu) or activating mutations in the PIK3CA/AKT genes (She et al, 2008;Brachmann et al, 2009).…”

Expresión y amplificación del gen HER2 en el cáncer gástrico avanzado

“…En el cáncer gástrico avanzado se ha incorporado al tratamiento la quimioterapia estándar y la terapia con anticuerpos monoclonales como el trastuzumab en aquellos casos que presentan sobreexpresión o amplificación del gen HER2 [12][13][14] . Esto ha permitido abrir expectativas con terapias dirigidas a blancos moleculares tal y como se está empleando en otros cánceres como el cáncer de mama, colon y pulmón 15,16 . Entre los cánceres gástricos de origen epitelial, se reconocen dos grandes grupos histológicos: los de tipo intestinal (tumores mejores diferenciados) y los difusos (con menor diferenciación), como lo señalado en la original clasificación de Lauren en 1965 17,18 .…”