Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance

Abstract

Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients. A total of 115 AGC patients, including 56 of histopathologic HER2 (hHER2) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2 patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy. A fluctuated positive HER2 phenotype on CTCs (cHER2) was revealed, showing cHER2 at different time intervals during treatment. Acquisition of the cHER2 phenotype in 91.0% of hHER2 and 76.2% hHER2 patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2 patients and chemotherapy alone for hHER2 patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2 phenotype, which provides a growth advantage to HER2 CTCs against therapeutic pressure, leading to the development of therapeutic resistance. Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2 on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. .

Aneuploid circulating tumor endothelial cells (CTECs) affect the detection of CTC, but they are fundamentally different

“…3A. The clinical relevance of different types of aneuploid CTCs has been demonstrated, for example, highploid CTCs has been shown to be associated with tumor resistance and relapse [9,10]. However, the clinical significance of aneuploid CTECs are still unclear.…”

“…Current reports on CTC ploidy tend to combine tetraploid and pentaploid into a subgroup, collectively referred to as polyploid. Compared to triploids, polyploids do find some clinical significance, such as related to metastasis, recurrence and drug resistance [9]. Therefore, we also tried to combine triploid and tetraploid into a subclass, namely, polyploid, and then compare the significance of this new subclass in the diagnosis of tumor staging.…”

Research and application of single-cell sequencing in tumor heterogeneity and drug resistance of circulating tumor cells

“…Therefore, increasing studies are conducted on tumor resistance through CTC. Scholars study choriocarcinoma [ 22 ], colorectal cancer [ 23 – 26 ], liver cancer [ 27 ], lung cancer [ 28 , 29 ], breast cancer [ 30 , 31 ], lymphoma [ 32 ], gastric cancer [ 33 ] and other malignant tumors through CTC to explore the drug resistance of tumor cells. However, most current CTC analyses are based on CTC epithelial biomarkers, and epithelial biomarkers may not be expressed in several tumor types [ 34 ].…”

Circulating Tumour Cells (CTCs) as Potential Biomarkers of Clinicopathological and Prognostic Significance in Gastric Cancer Patients: A Systematic Review and Meta-Analysis

“…Eighteen of the remaining 21 articles [16, 20, 21, 23, 24, 26, 29, 30, 32-34, 38, 40, 42, 48, 50-52] with 21 arms provided HRs for OS. Nine articles [12,16,20,21,23,24,29,30,40] with 11 arms provided HRs for PFS, and 3 articles [37,39,52] provided HRs for DFS.…”