palovarotene In addition to lifestyle factors
In addition to lifestyle factors, genetic factors may also influence the efficacy of antineoplastic drugs in breast cancer patients.16, 17 The HER2 gene contains several single nucleotide polymorphisms (SNPs). Two of the most investigated HER2 SNPs are Ile655Val (rs1136201) and Ala1170Pro (rs1058808).19, 20 The Ile655Val polymorphism leads to the substitution of isoleucine for valine. A preclinical study reported that the Val substitution might increase tumorigenic potential of breast cancer palovarotene because it predisposes the HER2 receptor to assume an active conformation, leading to enhanced activity of the tyrosine kinase domain. The Ala1170Pro polymorphism results in the substitution of alanine for proline. The biologic relevance of this polymorphism, however, remains undefined. To date, only 2 studies have investigated the association between HER2 Ile655Val SNP and the response to trastuzumab.23, 24 Whereas Beauclair et al did not observe an association between HER2 genotype and response to trastuzumab in a cohort of 61 patients with advanced HER2-positive breast cancer, Han et al found that Ile655Val SNP was associated with better DFS among 212 HER2-positive breast cancer patients who received adjuvant trastuzumab treatment.
Thus, we hypothesized that the risk of recurrence among trastuzumab-treated HER2-positive breast cancer patients is increased by tobacco and alcohol consumption and is affected by HER2 polymorphisms. The goal of our study was to evaluate the association of tobacco and alcohol consumption and HER2 polymorphisms with the risk of recurrence in a cohort of nonmetastatic HER2-positive breast cancer patients treated with trastuzumab.
Patients and Methods
Results Over a median follow-up period of 7.4 years, 66 (28.0%) of 236 patients experienced disease recurrence. Baseline characteristics of the study population are presented in Table 1. Approximately 35.0% of patients were younger than 50 years, and 55.1% had a body mass index higher than 25 kg/m2. Almost two-thirds (63.1%) of patients had grade III tumors, 53.4% had positive lymph node status, and 29.7% had stage III tumors. Positive ER and progesterone receptor status was observed in 66.1% and 47.0% of patients, respectively. Most of the patients received radiotherapy (85.2%), and 63.6% of patients received adjuvant endocrine therapy. At the time of diagnosis, 16% of patients were current smokers and 58% consumed alcohol. Association between tobacco use and DFS is presented in Table 2. Compared to nonsmokers, the adjusted HR for DFS was 2.63 (95% CI, 1.48-4.68, P = .001) for patients who smoked before breast cancer diagnosis. Average number of cigarettes smoked per day and number of years spent smoking before breast cancer diagnosis were associated with breast cancer recurrence, but only in the extreme category (HR, 3.65, 95% CI, 1.35-9.89, P = .01 for > 20 cigarettes per day, and HR, 3.19, 95% CI, 1.55-6.56, P = .002 for > 20 years spent smoking, respectively). For the 131 patients for whom we had information about smoking status during trastuzumab treatment, smoking during trastuzumab treatment was not significantly associated with breast cancer recurrence (HR, 2.15, 95% CI, 0.92-5.04, P = .08). When stratified according to ER status, an increased risk of recurrence was observed in the ER-negative subgroup (Table 3). Among patients with ER-negative tumors, the adjusted hazard ratio for DFS was 3.73 (95% CI, 1.56-8.89, P = .003) for patients who smoked before breast cancer diagnosis and 4.49 (95% CI, 1.26-16.00, P = .02) for patients who smoked during trastuzumab treatment compared to nonsmokers. In the ER-positive subgroup, neither smoking before breast cancer diagnosis nor smoking during trastuzumab treatment was associated with DFS (HR, 1.91; 95% CI, 0.84-4.31, P = .12, and HR, 1.33; 95% CI, 0.27-6.47, P = .72, respectively). Association between alcohol consumption and DFS is presented in Table 4. Compared to nondrinkers, the adjusted hazard ratio for DFS was 0.56 (95% CI, 0.33-0.94, P = .03) for patients who consumed alcohol before breast cancer diagnosis. Further analyses by type of alcohol consumed revealed Operon wine consumption before breast cancer diagnosis was associated with reduced risk of breast cancer recurrence compared to non–wine drinkers (adjusted HR, 0.42; 95% CI, 0.18-0.95, P = .04). However, beer consumption before breast cancer diagnosis was not significantly associated with a higher risk of breast cancer recurrence compared to non–beer drinkers (adjusted HR, 1.60; 95% CI, 0.47-5.47, P = .46). For the 128 patients for whom we had information about alcohol use during trastuzumab treatment, we did not observe a significant association between DFS and consumption of alcohol (adjusted HR, 0.68, 95% CI, 0.30-1.56, P = .36), wine (HR, 0.55; 95% CI, 0.23-1.33, P = .18) or beer (HR, 1.98; 95% CI, 0.53-7.33, P = .31). We could not generate results regarding the association between spirit consumption—neither before breast cancer diagnostic nor during trastuzumab treatment—and risk of cancer recurrence because only a few women consumed spirits. Moreover, there are no data on the association between alcohol consumption and DFS according to ER status as a result of an insufficient number of patients.