'All action no talk': the role of HER2/neu in adjuvant therapy choice for gastric cancer.

HER2 protein is a transmembrane tyrosine kinase receptor belonging to the HER family. HER2 is known to be involved in the pathogenesis of several human cancers and its overexpression and/or amplification, in the last three decades, has been robustly associated with poor prognosis in breast cancer, leading to the use of trastuzumab and other anti-HER2 targeted agents as the backbone of HER2-positive patients’ treatment [1]. The interest in studying the role of HER2 in gastric cancers has developed differently. The pivotal work [2] demonstrating the prognostic value of the HER2 gene in gastric cancer was published at the beginning of 1990s, but for the following 20 years, a large variation in the rate of HER2 positivity (ranging from 44 to 53.4%) across different studies [3] was found. This lack of consistency can be partly attributed to the differences in study populations, but especially to the use of non-standardized methodology (mainly based on IHC) and different scoring criteria. Things changed when the majority of researchers adopted the scoring criteria developed by Hofmann et al. for the ToGA trial [4], which reduced the variation to a range of 9.4%– 15.7% [5–9]. However, it is not surprising that the potential prognostic role of HER2 in gastric cancer is still under debate [10, 11]. Although most of the authors have found significant correlation between HER2positive status and poor outcomes, others have not demonstrated any association between HER2 expression and prognosis [3]. The results from the ToGA [5] trial further complicated this issue as the study showed a longer than expected (historical controls) overall survival of patients who received chemotherapy alone, leading the authors to take into account a possible role of HER2 overexpression in conferring a better prognosis. Therefore, the authors concluded that further studies were needed to obtain a definitive answer about the prognostic role of HER2 in gastric cancer. Although trastuzumab is, so far, the only targeted therapy that has demonstrated in a randomized trial a modest but clinically significant improvement in survival when combined with chemotherapy as first-line treatment in metastatic gastric cancer, further research aiming to elucidate the actual biological and prognostic role of HER2 overexpression in this disease would seem to be mandatory. The contribution provided by Gordon et al. [12] interestingly describes the role of HER2 status in an unexplored landscape of the chemo-radiation adjuvant setting. In particular, the authors investigated the potential prognostic and/or predictive role of HER2 amplification/overexpression using the population of the SWOG9008/INT-0116 trial. In this phase III trial 582 patients with resected stage IB-IV(M0) gastric and gastroesophageal (GE) junction cancer were randomly assigned to postoperative adjuvant therapy with 5-fluorouracil (5-FU)/leucovorin plus external beam radiation versus observation. After a median follow-up of 10 years, a survival advantage was observed in all subsets of patients treated with postoperative chemoradiation (except for cases with diffuse histology) and HER2 positivity status was able to independently predict a lack of benefit from adjuvant chemo-radiation, especially considering that none of the 28 HER2-positive cancers had diffuse histology [13]. These data are in accordance with previously reported preclinical evidence suggesting a possible role of HER2-mediated PI3K/ AKT pathway activation in reducing cytotoxicity of 5-FU and radiation in breast cell lines [14–17] and with the reported reduction in resistance of HER2 overexpressing gastric cancer cell lines treated with trastuzumab [18]. Therefore, this study could represent a step forward in understanding the clinical utility of HER2 assessment in gastric cancer patients as it elucidates for the first time in the literature a predictive role in the adjuvant setting in a phase III prospective trial. Furthermore, despite not being able to reach a conclusion regarding the prognostic role of HER2 status in the postoperative setting, given the low number of HER2-positive cases, these results support the rationale to further consider this biological marker as one of the possible parameters to guide clinical decisions regarding adjuvant treatment. To note, despite the paper by Gordon et al. having a robust methodology, some factors should be taken into consideration in order to better understand the global value of this analysis. The first concern is related to the molecular analysis which was done retrospectively and was not planned in this clinical trial: <50% (258 of 559) of the enrolled patients had pathological specimens available and this could reflect a selection bias. Second, the balance of the main clinical and pathological characteristics between the two arms has not been analysed in the HER2/neu-positive patients. Third, the number of HER2-amplified cases is lower than the findings in previous reports [10]. This result is particularly relevant if we take into account that GE junction cancers. It is well documented that GE junction cancers show a higher rate of HER2 amplification, in contradistinction to the results reported by Gordon et al. Finally, it is also worth pointing out that the level of concordance between in situ hybridization methods (FISH and SISH) and IHC positivity seems to be considerably lower compared with the ones in ‘post ToGa era’ studies. One explanation for this weak correlation could be related to the IHC scoring criteria used for the study. As mentioned by the authors, the common breast cancer scoring system (BCSS) [19] has been applied to carry out the work instead of using the ed ito ria ls editorials Annals of Oncology 24: 1715–1717, 2013 doi:10.1093/annonc/mdt172 Published online 12 May 2013