Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

Indini, Alice; Rijavec, Erika; Grossi, Francesco

doi:10.3390/ijms22094774

Cited by 78 publications

(62 citation statements)

References 48 publications

(89 reference statements)

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“…Companion diagnostic criteria of HER2 expression in NSCLC is suggested as follows: (i) 0, HER2 expression negative; (ii) 1+, currently considered to be negative. With the increased application of ADC therapy and update of research evidence, 87 however, it needs to be confirmed whether 1 + should be considered to be HER2 expression negative or HER2 -low expression; (iii) 2+, 3+: HER2 expression positive.…”

Section: Recommendations For Her2 Alterations Test...mentioning

confidence: 99%

Consensus for HER2 alterations testing in non-small-cell lung cancer

et al. 2022

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Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Meanwhile, several HER2-targeted drugs, such as T-DXd, neratinib, afatinib, poziotinib and pyrotinib, have been evaluated in patients with advanced NSCLC, with several of them demonstrating clinical benefit. Therefore, identifying HER2 alterations is pivotal for NSCLC patients to benefit from these targeted therapies. Recent guidelines on HER2 testing were developed for breast and gastric cancer, however, and have not been fully established for NSCLC. The expert group here reached a consensus on HER2 alteration testing in NSCLC with the focus on clinicopathologic characteristics, therapies, detection methods and diagnostic criteria for HER2-altered NSCLC patients. We hope this consensus could improve the clinical management of NSCLC patients with HER2 alterations.

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Section: Recommendations For Her2 Alterations Test...mentioning

confidence: 99%

Consensus for HER2 alterations testing in non-small-cell lung cancer

et al. 2022

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“…Interestingly, the DrugBank analysis showed that the drug targeting GAA was Trastuzumab-deruxtecan. Trastuzumab-deruxtecan is primarily used for patients with human epidermal growth factor receptor 2 (HER2)-mutant tumours including non-SCLC and in the absence of SCLC (79)(80)(81). Upon binding to HER2, Trastuzumab-deruxtecan disrupts the HER2 signalling, undergoes internalisation and intracellular linker cleavage by lysosomal enzymes and ultimately causes DNA damage and apoptotic cell death (80).…”

Section: Discussionmentioning

confidence: 99%

“…Trastuzumab-deruxtecan is primarily used for patients with human epidermal growth factor receptor 2 (HER2)-mutant tumours including non-SCLC and in the absence of SCLC (79)(80)(81). Upon binding to HER2, Trastuzumab-deruxtecan disrupts the HER2 signalling, undergoes internalisation and intracellular linker cleavage by lysosomal enzymes and ultimately causes DNA damage and apoptotic cell death (80). In addition, Martinho et al found that the inhibitors of the HER family (mainly HER2) reduced cervical cancer aggressiveness by blocking glucose metabolism (82).…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates

Wang

Gao

et al. 2022

Front. Oncol.

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BackgroundThe competing endogenous RNA (ceRNA) network-mediated regulatory mechanisms in small cell lung cancer (SCLC) remain largely unknown. This study aimed to integrate multi-omics profiles, including the transcriptome, regulome, genome and pharmacogenome profiles, to elucidate prioritised ceRNA characteristics, pathways and drug candidates in SCLC.MethodWe determined the plasma messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) expression levels using whole-transcriptome sequencing technology in our SCLC plasma cohort. Significantly expressed plasma mRNAs were then overlapped with the Gene Expression Omnibus (GEO) tissue mRNA data (GSE 40275, SCLC tissue cohort). Next, we applied a multistep multi-omics (transcriptome, regulome, genome and pharmacogenome) integration analysis to first construct the network and then to identify the lncRNA/circRNA-miRNA-mRNA ceRNA characteristics, genomic alterations, pathways and drug candidates in SCLC.ResultsThe multi-omics integration-based prioritisation of SCLC ceRNA regulatory networks consisted of downregulated mRNAs (CSF3R/GAA), lncRNAs (AC005005.4-201/DLX6-AS1-201/NEAT1-203) and circRNAs (hsa_HLA-B_1/hsa_VEGFC_8) as well as upregulated miRNAs (hsa-miR-4525/hsa-miR-6747-3p). lncRNAs (lncRNA-AC005005.4-201 and NEAT1-203) and circRNAs (circRNA-hsa_HLA-B_1 and hsa_VEGFC_8) may regulate the inhibited effects of hsa-miR-6747-3p for CSF3R expression in SCLC, while lncRNA-DLX6-AS1-201 or circRNA-hsa_HLA-B_1 may neutralise the negative regulation of hsa-miR-4525 for GAA in SCLC. CSF3R and GAA were present in the genomic alteration, and further identified as targets of FavId and Trastuzumab deruxtecan, respectively. In the SCLC-associated pathway analysis, CSF3R was involved in the autophagy pathways, while GAA was involved in the glucose metabolism pathways.ConclusionsWe identified potential lncRNA/cirRNA-miRNA-mRNA ceRNA regulatory mechanisms, pathways and promising drug candidates in SCLC, providing novel potential diagnostics and therapeutic targets in SCLC.

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“…The ERBB2 gene encodes the human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK), a member of the epidermal growth factor receptor (EGFR)related family of RTKs, and ligand-independent activation of HER2 can result from HER2 overexpression or ERBB2 amplification (ERBB2amp). [1][2][3][4] HER2-targeted therapy revolutionized cancer care by providing one of the first demonstrations of clinical utility of biomarker-selected approaches and led to the approval of anti-HER2 therapies in breast cancers with HER2 overexpression. [5][6][7] The anti-HER2 therapy trastuzumab is also approved in advanced gastroesophageal adenocarcinoma (advGEA) in combination with first-line chemotherapy on the basis of results from the Trastuzumab for Gastric Cancer trial, 8 and investigational use of anti-HER2 therapies is being explored in other tumor types including colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

ERBB2 Copy Number as a Quantitative Biomarker for Real-World Outcomes to Anti–Human Epidermal Growth Factor Receptor 2 Therapy in Advanced Gastroesophageal Adenocarcinoma

Zhang

Hamdani

Gjoerup

et al. 2022

JCO Precision Oncology

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PURPOSE Human epidermal growth factor receptor 2 (HER2) overexpression or amplification ( ERBB2amp) are biomarkers for approved anti-HER2 therapies. ERBB2amp may better predict response compared with immunohistochemistry or in situ hybridization, and quantitative copy number (CN) may further stratify patients. We characterized ERBB2amp in advanced gastroesophageal adenocarcinomas (GEA) and hypothesized that increased CN was associated with better outcome to trastuzumab. METHODS Comprehensive genomic profiling, including assessment of ERBB2amp, was performed for 12,905 GEA tissue cases. Clinical outcomes were assessed using a clinicogenomic database linking deidentified electronic health record–derived clinical data to genomic data. Multivariable Cox proportional hazard models were used for real-world progression-free survival (rwPFS) comparisons. RESULTS ERBB2amp (CN ≥ 5) was detected in 15% (1,934 of 12,905) of GEA; median CN 22 (interquartile range 9-73). Median ERBB2 amplicon size was 0.27 megabase (interquartile range 0.13-0.95), and smaller amplicons were associated with higher CN ( P < .001). In the clinicogenomic database, of 101 evaluable first-line trastuzumab-treated patients, ERBB2 CN was a significant predictor of rwPFS as a continuous variable (adjusted hazard ratio = 0.73; 95% CI, 0.60 to 0.89; P = .002), whereas ERBB2 CN was not predictive of rwPFS on chemotherapy (adjusted hazard ratio = 0.93; 95% CI, 0.73 to 1.20; P = .59). Among trastuzumab-treated patients, no significant associations with ERBB2 CN were observed for disease site, age, stage at advanced diagnosis, or most selected coalterations. CONCLUSION ERBB2amp was detected in 15% of GEA tissue samples, with significant diversity in ERBB2 CN and amplicon focality. ERBB2 CN was predictive of rwPFS as a continuous variable for patients treated with trastuzumab. Further studies exploring the clinical utility of quantitative ERBB2 CN, particularly in the setting of the evolving anti-HER2 landscape and combination therapies, are warranted.

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Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

Cited by 78 publications

References 48 publications

Consensus for HER2 alterations testing in non-small-cell lung cancer

Consensus for HER2 alterations testing in non-small-cell lung cancer

Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates

ERBB2 Copy Number as a Quantitative Biomarker for Real-World Outcomes to Anti–Human Epidermal Growth Factor Receptor 2 Therapy in Advanced Gastroesophageal Adenocarcinoma

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