All authors have read and approved all versions of the manuscript, its content, and its submission

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All authors have read and approved all versions of the manuscript, its content, and its submission. Abbreviations CEP17Centromeric probe 17FISHFluorescence in situ hybridizationHER2Human epidermal growth factor receptor 2Homo-HER2 positiveHomogeneously HER2 positiveHetero-HER2 positiveHeterogeneously HER2 positiveIHCImmunohistochemistryPFSProgression-free survivalORRObjective response ratesOSOverall survivalRTKReceptor tyrosine kinase Notes Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures followed were in accordance with the Ethical Standards of the Responsible Committee on Human Experimentation (Institutional and National) and with the Helsinki Declaration of 1964 and later versions. group were significantly longer than those in the Hetero-HER2-positive group (PFS; 20.0?months [95% CI 17.8C22.2] vs. 6.0?months [95% CI 2.3C9.7]; HR 0.11; 95% CI 0.03C0.41; value was less than 0.05 in univariate analysis. Patient characteristics and response rates were evaluated by Fishers exact test. Depth of response was compared using MannCWhitney test. The level of significance was set to valuesheterogeneously HER2 positive, homogeneously HER2 positive, gastroesophageal junction, Eastern Cooperative Oncology Group Performance Status, fluorescence in situ hybridisation, immunohistochemistry, carcinoembryonic antigen, carbohydrate antigen 19-9 Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy The median follow-up period was 17.9?months for all patients and 33.0?months for the censored patients, respectively. The median PFS and OS were 11.0?months (95% CI 7.1C14.9) and 24.0?months (95% CI 4.6C43.4), respectively. Twenty-five patients (89.3%) discontinued the trastuzumab-based chemotherapy due to disease progression, whereas three patients were still on treatment. These three patients belonged to the Homo-HER2-positive group. The median number of cycles of trastuzumab therapy was 23.7 (range 2C62) in the Homo-HER2-positive group and 9.3 (range 1C18) in the Hetero-HER2-positive group, respectively. Fifteen patients (53.6%) died at the data cutoff. Second-line chemotherapy after disease progression was given to all patients (11/11) in the Homo-HER2-positive group. Meanwhile, in the Hetero-HER2-positive dBET57 group, 11 of 14 (78.6%) patients received second-line chemotherapy. Taxans as monotherapy or weekly paclitaxel with ramucirumab were mainly dBET57 initiated as post-discontinuation therapy dBET57 in the both groups. Survival is shown in Fig.?2. The median PFS in the Homo-HER2-positive group was significantly longer than that in the Hetero-HER2-positive group (20.0?months [95% CI 17.8C22.2] vs. 6.0?months [95% CI 2.3C9.7]; HR 0.11; 95% CI 0.03C0.41; valuesvaluesgastroesophageal junction cancer, Eastern Cooperative Oncology Group Performance Status, hazard ratio, 95% confidential interval, median dBET57 progression-free survival, median overall survival, not applicable, not reached, carcinoembryonic antigen, carbohydrate antigen 19-9 Table?3 Survival outcomes by multivariate analysis valuesvalueshazard ratio, 95% confidential interval, progression-free survival, overall survival Because our data showed shorter survival of Hetero-HER2-positive group, it is unclear whether patients with Hetero-HER2-positive gastric cancer benefit from additional trastuzumab. Next, we compared survival of the Hetero-HER2-positive group and those of HER2-negative gastric cancer who received cisplatin and capecitabine. Eighteen patients with HER2-negative gastric cancer received cisplatin and capecitabine in the same period. The median PFS and OS were 5.7?months (95% CI 0.0C11.4) and 14.1?months (95% CI 6.6C21.6), respectively. No dBET57 statistical difference was PLCG2 found between the Hetero-HER2-positive and HER2-negative group (HR 1.21; 95% CI 0.59C2.50; valuescomplete response, partial response, stable disease, progression disease, objective response rate, heterogeneously HER2 positive, homogeneously HER2 positive Open in a separate window Fig.?3 Best change from baseline in size of target lesion. Water-fall plot shows that patients in the Homo-HER2-positive group obtain deeper tumor shrinkage compared with the Hetero-HER2-positive group (a). Scatter plot shows statistically significant difference in tumor shrinkage between two groups (amplification level was associated with favorable trastuzumab efficacy [25, 26]. These reports are compatible with our survival results. Moreover, comprehensive genomic alternation and protein overexpression analysis revealed that cases with high-level receptor tyrosine kinase (RTK) amplification showed simple tumor biology such as corresponding protein overexpression and, rarely, other gene amplification [27]. Therefore, homogeneous HER2-positive gastric cancer may link to simple tumor biology, which means that almost all tumor cells depend on the HER2-driven pathway and these patients are probably the optimal population for anti-HER2 agent treatment. On the other hand, patients in the Hetero-HER2-positive group did not obtain enough survival benefit from trastuzumab. Previous data demonstrated that HER2 heterogeneity was involved in co-amplification or co-overexpression of other RTKs such as EGFR, cMET, and FGFR2 [27C30]. These molecular diversities may result in trastuzumab resistance, suggesting the requirement of new treatment strategy. Multikinase inhibitors or combination treatment corresponding to molecular alternations possibly overcome molecular diversity in gastric cancer [31, 32]. The mechanism of HER2 heterogeneity remains unclear. Lee et al. examined HER2 heterogeneity individually by IHC and FISH in the same area, and they revealed a strong correlation between HER2 protein over-expression and gene amplification. These data suggest that genetic heterogeneity is underling in HER2 heterogeneity [17]. In addition, several data showed that HER2 heterogeneity was associated with diffuse histology. Recent data from the cancer genome atlas proposed that gastric cancer was classified into four subtypes: EpsteinCBarr virus positive, microsatellite unstable, chromosomal instability, and genomically stable tumor. Genomically stable tumors were enriched for diffuse histology and were associated with less frequency of RTKs amplification [30]. Because gastric cancer commonly showed histological heterogeneity, this histological.