Our understanding of the pathogenesis or the optimal treatment of uterine serous papillary and clear cell EC is limited. The existing lack of prospective clinical trials assessing adjuvant therapy in these aggressive variants of EC and the absence of targeted treatment approaches reflects at least in part the low incidence of type II EC with the accompanying limited single institutional experiences. However, a reasonable estimate would predict that 3000–4000 women in the United States alone will be diagnosed with type II EC during 2008 and an estimated 55–65% will die, accounting for approximately 18–24% of all endometrial cancer-related deaths (Podratz and Mariani, 2003
). Thus the absence of randomised clinical trials for one of the most aggressive gynaecologic malignancies appears unacceptable.
Evidence for a role of HER2 and EGFR in the pathogenesis of various cancers has led to the rational design and development of agents that selectively target HER2 and EGFR. In unselected patients with endometrial cancer, HER2 amplification/overexpression represents a rare event. However, the findings of our study confirm and extend previous reports that indicate HER2 amplification/overexpression is seen more commonly in well-defined subtypes of EC such as uterine serous papillary cancer or clear cell cancer. Trastuzumab (Herceptin) a humanised anti-HER2 antibody has recently been approved for the adjuvant treatment of HER2-overexpressing (3+ IHC) or FISH-positive primary breast cancers based on a highly significant 52% reduction in the risk of recurrence in node-positive HER2-positive primary breast cancer (Romond et al, 2005
). More recent advances in biotechnology have led to the development of the oral dual tyrosine kinase inhibitor lapatinib, which has been shown to have significant activity in trastuzumab-refractory breast cancer (Geyer et al, 2006
). Encouraged by these clinical response data which were generated in breast cancer patients with HER2 amplification/overexpression, we comprehensively assessed the rate of HER2 gene amplification in a large consecutive series of patients with uterine serous papillary and clear cell endometrial cancers. These studies were intended to define a subset of type II EC patients who may benefit from a selective HER2 inhibitor or a dual kinase inhibitor, which targets both HER2 and EGFR. The aggressive nature of type II EC is confirmed in our study by the observation that two out of three patients diagnosed with uterine serous papillary and one of two diagnosed with clear cell cancer had extra-uterine disease at the time of primary surgery. HER2 gene amplification was found in 17 and 16% of the serous papillary and clear cell EC cases, respectively. Earlier studies have reported higher rates of HER2 gene amplification in uterine serous papillary EC. The most recent study conducted by Grushko et al
. detected HER2 gene amplification in 6 out of 28 (21%) patients with serous papillary and 3 out of 6 (50%) of clear cell EC (Grushko et al, 2008
). This study cohort of that report, however, differed considerably from the consecutive series in our study, as it included patients with measurable stage III, stage IV, or recurrent endometrial cancer that were enrolled in GOG study no. 177 evaluating the role of doxorubicin and cisplatin with or without paclitaxel in advanced endometrial cancer. Santin et al
. reported HER2 gene amplification in 14 out of 30 (47%) patients with uterine serous papillary cancer. Importantly, however, of the 30 patients included in his study, 12 were African-American patients of whom eight (67%) showed amplification by FISH compared with six (33%) of the remaining 18 Caucasian patients. Information on the patient's race was not collected in our current study, yet possible differences in patient populations may account for the reported discrepancy in the rate of HER2 gene amplification between both studies. Importantly, previous studies have reported a higher incidence of serous papillary endometrial cancer and a higher rate of HER2 gene amplification in African-American patients when compared with Caucasian patients (Maxwell and Risinger, 2006
; Morrison et al, 2006
). When combining the results of the aforementioned studies, which have all used FISH for assessment of HER2 status, HER2 gene amplification, at average, was detected in 54 out of 222 (24%) patients with serous papillary EC. In contrast to our low rate of HER2 gene amplification in type I EC, other groups have been able to demonstrate HER2 gene amplification in 9 out of 363 (4%) of unselected type I EC and in 5 out of 63 (8%) grade 3 endometrioid endometrial cancers (Morrison et al, 2006
). We may not have been able to confirm these rates possibly because of differences in the patient populations or because of the smaller sample size of type I ECs in our study. Previous data on the rate of HER2 gene amplification in clear cell EC (22–50%) are unquestionably limited by the small number of samples investigated so far. The actual rate of HER2 gene amplification in clear cell EC may thus be somewhat lower according to the findings of our study.
The clinical role of EGFR has not been studied well in EC, moreover this is the first study to evaluate the incidence and prognostic relevance of EGFR expression in type II EC. Importantly, EGFR may have a dual role in EC, such that high EGFR expression in type I EC was associated with low grade and favourable outcome. In contrast, EGFR expression in type II EC was associated with high grade and adverse clinical outcome. Therefore, EGFR expression did not appear to impact disease progression in well-differentiated endometrioid endometrial cancer, but did seem to affect disease progression in undifferentiated nonendometrioid endometrial cancer. To date EGFR inhibitors have not been clinically tested in type II EC. Importantly, the clinical benefit observed with anti-EGFR tyrosine kinase inhibitors (TKIs) across different disease entities has been variable. For example, EGFR TKIs are largely inactive in colorectal cancer and breast cancer (Tan et al, 2004
; Baselga and Arteaga, 2005
). Nevertheless, two of these drugs, gefitinib and erlotinib, have demonstrated clinical activity in non small cell lung cancer and responses have been observed in patients with advanced pancreatic cancer and in head-and-neck cancer (Baselga, 2006
). Preclinical data suggest that EGFR inhibitors may be clinically active in well-defined subgroups of endometrial cancer patients with HER2 gene amplification or high levels of EGFR expression (Konecny et al, 2008
). Importantly, however, EGFR receptor expression levels when assessed by IHC have not been able to predict a response to EGFR inhibitors in other tumour types. Earlier clinical studies in other disease entities show that potential markers of sensitivity to EGFR TKIs include the presence of EGFR gene amplification, mutations of the EGFR gene, and increased expression of EGFR ligands (Baselga and Arteaga, 2005
). Earlier studies have demonstrated significantly higher expression levels of the EGFR ligands TGF-α
and amphiregulin in EC compared with normal endometrium (Pfeiffer et al, 1997
; Ejskjaer et al, 2007
). The roles of EGFR gene amplification or mutations in EC, however, have not yet been studied.
Although HER2 gene amplification or EGFR expression each can only be detected in small subsets of patients with type II EC, collectively, 46% of the patients with type II EC demonstrated HER2 gene amplification and/or EGFR expression in our study. The pooling of national or global patient resources should allow the realisation of prospective clinical trials (that stratify for HER2 gene amplification or EGFR expression) for patients with type II EC that may involve HER2 and EGFR tyrosine kinase inhibitors in well-defined subsets with HER2 gene amplification or EGFR expression.