In our substudy patients carrying the Ile Val

In our substudy, patients carrying the Ile/Val or Val/Val genotypes had significantly worse DFS compared to patients carrying the Ile/Ile genotype, after adjustment for potential confounders. Two previous studies examining the association between HER2 Ile655Val polymorphism and trastuzumab response in HER2-positive breast cancer patients reported conflicting results.23, 24 Beauclair et al showed that Ile655Val polymorphism measured in blood was not associated with trastuzumab treatment response among 61 patients with advanced HER2-positive breast cancer patients. On the other hand, Han et al observed, in their study of 212 trastuzumab-treated HER2-positive breast cancer patients, that patients carrying the Ile/Val or Val/Val genotypes, as measured in blood, showed significantly better DFS compared to those carrying the Ile/Ile genotype. Several elements could explain the discrepancies between our results and those reported in these 2 studies. These include the tissue type used for genotype determination (formalin-fixed, paraffin-embedded breast cancer tissues [our study], vs. blood23, 24), the characteristics of the study population (early [our study] vs. advanced breast cancer patients), and the analyses performed (multivariate [our study] vs. univariate models23, 24). In our opinion, our results are concordant with HER2 biology. It can be argued that because Val substitution leads to enhanced activity of the tyrosine kinase domain, and because trastuzumab does not block dimerization with other HER family members,35, 36 HER2-positive breast cancer Glucagon (19-29), human carrying the Val allele might be more prone to developing trastuzumab resistance in the presence of alternative signaling pathways. Our study adds knowledge to the few others that have examined the association of tobacco consumption and HER2 polymorphisms with trastuzumab response, in addition to providing information on the effects of alcohol use on treatment response. However, our study has some weaknesses, including the small sample size and its retrospective design. Moreover, although we performed multivariate analysis, we cannot completely exclude the possibility of residual confounding. In addition, it is well known that self-reported tobacco and alcohol exposure is subject to error, but if any, it would result in nondifferential misclassification and would have underestimated the true associations. Furthermore, categorization of alcohol intake may have affected results, given that patients who consumed alcohol in modest amounts were classified as nondrinkers in the analysis examining alcohol consumption and breast cancer recurrence during trastuzumab treatment. This might have underestimated the true association.
Conclusion Lifestyle factors such as tobacco and alcohol consumption and genetic factors like HER2 polymorphism could influence efficacy of trastuzumab treatment in HER2-positive breast cancer patients. These results need to be confirmed in a larger cohort, using detailed questionnaires about tobacco use and type of alcohol consumed at several times after a diagnosis of breast cancer. The findings in our study, if confirmed, might contribute to developing lifestyle habit recommendations for trastuzumab-treated HER2-positive breast cancer patients. Another important aspect that still needs to be evaluated is the relative predictive importance of tobacco and alcohol consumption regarding response to trastuzumab. This new knowledge will help physicians provide better recommendations to their breast cancer patients on which lifestyle habits they should preferentially modify in order to maximize their response to targeted anti-HER2 treatment.
Disclosure
Acknowledgments
Introduction Targeted therapies against lung cancer harboring EGFR mutations, ALK or ROS1 fusions and BRAF mutation using respective tyrosine kinase inhibitors (TKI) comprise the standard of care [1]. The list of these driver genes of NSCLC is continuously expanding, and the human epidermal growth factor receptor 2 (ERBB2/HER2) mutation is one of these emerging driver mutations that were originally shown in 2004 to be present in NSCLC patients [2].