Reply to P. Bohanes et al
Authors: Maria D. Begnami
Journal: Journal of Clinical Oncology (2011)

With this background, Begnami et al 7 recently published their retrospective evaluation of the prognostic role of the HER-family protein and gene amplification in patients with stages I to IV operated gastric cancer.The authors concluded that HER2 and HER3 expressions are significant predictors of poor survival.However, before agreeing with their conclusion, several points should be considered.In contrast to the recent literature, HER1 protein overexpression in the study of Begnami et al 7 was unexpectedly low, despite using the scoring system recommended by the EGFR pharm Dx (Dako Denmark, Glostrup, Denmark) kit that recognizes epidermal growth factor receptor positivity as any immunohistochemistry staining of the tumor cell membrane.With only three HER1-positive tumors, the authors were most likely unable to evaluate the prognostic role of HER1 protein expression.The authors 7 reported that HER2 amplification, but not HER2 protein expression, was associated with poorer outcome.However, this positive result was not challenged in a multivariate analysis, as recommended by the criteria of reporting recommendations for tumor marker prognostic studies. 8Instead, the multivariate model presented accounted only for tumor stage, surgical margins, and age, which resulted in limited application and usefulness.Although there has been a large amount of data that evaluated the use of HER2 as a prognostic marker, the results have been contradictory and failed to provide support for a definitive conclusion. 6The lack of consistency in the results is likely related to the heterogeneity of patients, samples, and methods used.It has been proven that a specific molecular alteration can be prognostic in the metastatic setting but not in early-stage disease (ie, BRAF mutation in colorectal cancer).With this fact taken into account, it is important for the authors to provide comment on the adopted classification scheme (sixth versus seventh edition of American Joint Committee on Cancer staging classification) and the extent of disease of the included patients with stage IV gastric cancer because these patients constituted 28% of the entire sample population.This discussion may provide additional insight, especially considering a recently presented international collaborative analysis of HER2 status in 338 patients with advanced gastric cancer who were included in six prospective first-line therapeutic trials.This study failed to find any significant association with HER2 gene amplification or HER2 protein expression in an extensive multivariate analysis. 9ith respect to HER3, the authors 7 reported that HER3 protein expression correlated with decreased survival but only when nuclear staining was considered.However, the authors 7 failed to provide any information to support that such an association is independent from recognized prognostic factors.In the hypothetical case that this intriguing finding remains significant in the multivariate model, this unplanned subgroup analysis should still be seen as explorative and in need of additional validation in another large data set.Finally, while awaiting complementary information from the authors, 7 clinicians trying to put these data into perspective should take into consideration that patients included in the study were treated with surgery alone, which is no longer the standard of care.Most patients would now been given selected perioperative therapy, the result of which is speculation that these evaluated markers would remain significant when given postoperative chemoradiotherapy or perioperative chemotherapy.In summary, although we would like to complement the authors 7 for evaluating an important molecular pathway in gastric cancer, we cannot agree with their generic conclusion that HER2 and HER3 are significant predictors of survival in gastric cancer.It is critical to have clear, solid, and reproducible data before "falling in love" with a putative biomarker, as suggested by the song referred to in