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Single center, single arm, prospective and open clinical study of pyrroltinib maleate tablets and trastuzumab combined with FOLFOX6 regimen in the preoperative treatment of HER-2 positive colorectal cancer

ABSTRACT: Interventions: HER-2 positive colorectal cancer:pyrroltinib maleate tablets and trastuzumab combined with FOLFOX6 regimen Primary outcome(s): pCR Study Design: Single arm

DISEASE(S): Her-2 Positive Colorectal Cancer

PROVIDER: 2698207 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: 48 patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: 8 of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). 5 (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% vs 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen. harri-00137 Assay Type: Gene Expression Provider: Affymetrix Array Designs: HG-U133_Plus_2 Organism: Homo sapiens (ncbitax)

Project description:Background: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs (tDRs), a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tDRs and trastuzumab resistance is still unknown. Methods: We detected the levels of tDRs expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed tDRs in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tDRs. Progression-free survival (PFS) was analyzed using Cox-regression. Furthermore, Gene Ontology (GO) and pathway analyses indicated the potential mechanism underlying tDR-mediated trastuzumab resistance. Results: Our sequence results showed that tDRs were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tDR-1960 and tDR-1969 were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tDR-1960 and tDR-1969 were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tDR-1960 and tDR-1969 expression were associated with signiﬁcantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Additionally, the GO analysis indicated that tDR-1960 and tDR-1969 were mainly involved in the cellular response to drug, which may partially explain the molecular mechanism underlying trastuzumab resistance in HER-2 positive breast cancer. Conclusion: we comprehensively analyzed tDRs in trastuzumab-sensitive and -resistant breast cancer. Our results suggest that tDR-1960 and tDR-1969 play important roles in trastuzumab resistance. Patients with high levels of tDR-1960 and tDR-1969 expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these tDRs. tDR-1960 and tDR-1969 may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

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Single center, single arm, prospective and open clinical study of pyrroltinib maleate tablets and trastuzumab combined with FOLFOX6 regimen in the preoperative treatment of HER-2 positive colorectal cancer

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