HER2 Status in Molecular Subtypes of Urothelial Carcinoma of the Renal Pelvis and Ureter

Yorozu, Tomoko; Sato, Shun; Kimura, Takahiro; Iwatani, Kosuke; Onuma, Hajime; Yanagisawa, Takafumi; Miki, Jun; Egawa, Shin; Ikegami, Machiko; Takahashi, Hiroyuki

doi:10.1016/j.clgc.2019.12.003

Cited by 15 publications

(13 citation statements)

References 21 publications

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“…In the present study, 75% of HER2 positive cases (9/12) were of luminal subtype and the remaining 3 HER2 + ve cases (25%) were of basal type. This was in agreement with Yorozu et al [20] who reported that HER2 protein overexpression and gene amplification were specifically detected in the luminal subtype of urothelial carcinoma of renal pelvis and ureter (UCRPU), suggesting that these patients may benefit from HER2-targeted therapies like trastuzumab. Also Kiss et al [45] studied HER2 alterations in MIBC and concluded that HER2 alterations were higher in the luminal subtype compared to basal.…”

Section: Discussionsupporting

confidence: 92%

“…However, they found no effect on OS of patients. On the other hand Yorozou et al [20] concluded in their study of UCRPU that the OS of patients with HER2 positive was significantly shorter than those with HER2 negative tumors. Because of limited number of patients in the present study which included a relatively high number of censored cases, the difference in survival among HER2 positive "luminal", HER2 positive "basal", HER2 negative "luminal" and HER2 negative "basal" subtypes of MIBC remains inconclusive.…”

Section: Discussionmentioning

confidence: 96%

“…Cases were classified according to the immunostaining profile into luminal, basal or p53-wild subtype following the Choi et al stratification strategy [19]. Tumors positive for CK5/6 and negative for GATA3 were considered basal; tumors negative for CK5/6 and positive for GATA3 were considered luminal [20]. P53 subtype of cases was assigned according to immunostaining pattern for p53 antibody.…”

Section: Identification Of the Molecular Subtypementioning

confidence: 99%

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Immunohistochemical based molecular subtypes of muscle-invasive bladder cancer: association with HER2 and EGFR alterations, neoadjuvant chemotherapy response and survival

et al. 2023

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Muscle-invasive bladder cancers (MIBCs) is a group of molecularly heterogonous diseases that could be stratified into subtypes with distinct clinical courses and sensitivities to chemotherapy. Clinical application of molecular subtypes could help in prediction of neoadjuvant chemotherapy (NAC) responders. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 5/6, and p53 are associated with these subtypes and are widely available. Human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) are mutated in multiple cancers including MIBC and are potential therapeutic targets. HER2/EGFR status of MIBC subtypes has not been investigated. Tissue microarrays (TMAs) were constructed from transurethral resection of the bladder tumor (TURB) specimens and stained with GATA3,CK5/6,p53 and HER2 in addition to Quantitative Reverse Transcription PCR for detection of EGFR gene. Of the total cases, 45% were luminal, 36.7% basal and 18.3% p53 wild subtype (p53-WT). Univariate analysis showed that overall survival (OS) and disease-free progression survival (DFS) were significantly longer for luminal subtype. In multivariate analysis, molecular subtype, HER2 status and LV invasion were independent prognostic factors for DFS and OS. Basal subtype showed a significantly better response to NAC. HER2 expression was significantly higher in luminal while EGFR expression was significantly higher in basal subtype. Kaplan-Meier survival curves revealed a significant longer OS and DFS for HER2 negative than positive cases. MIBC can be stratified using a simple IHC panel [GATA3,CK5/6,P53] into clinically relevant prognostic molecular subtypes. Basal tumors are aggressive and respond well to NAC while luminal have better OS. P53-WT tumors are chemoresistant and require further treatments. HER2 and EGFR are potential therapeutic targets for molecular subtypes of MIBC where luminal tumors are more likely to benefit from HER2 and basal from EGFR directed therapies.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Identification Of the Molecular Subtypementioning

confidence: 99%

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Immunohistochemical based molecular subtypes of muscle-invasive bladder cancer: association with HER2 and EGFR alterations, neoadjuvant chemotherapy response and survival

et al. 2023

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“…However, the overexpression rate of HER2 in MIBC was only 18.8%-41.8% in previous reports, which is much lower than our study, and its signi cance was controversial [23][24][25][26]. Previous studies have reported that the overexpression rate of HER2 in UTUC was 14.0%-35.7%, which is similar to our results, and HER2 overexpression was signi cantly correlated with histologic grade, stage, and poor prognosis [27][28][29]. However, we have not seen relevant reports of HER2 in urethral cancer so far, which may be due to the rarity of urethral cancer.…”

Section: Discussionsupporting

confidence: 82%

HER2 Overexpression In Urothelial Carcinoma Is Closely Associated With Disease Progression: A Single-Center Retrospective Study

et al. 2022

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Background: Urothelial carcinoma especially metastatic UC, is still challenging to treat and associated poor outcomes remain. It is urgent to find new targets to change the treatment status of UC. As an important target of breast cancer, HER2 has been found to be closely related to other tumors in recent years.Methods: We performed immunohistochemical staining of HER2 in 170 human UC tissue sections, assessed the positive rate of HER2 in UC and analyzed the correlation between HER2 positivity and clinicopathological datas of the patients.Results: HER2 positivity exists in the whole UC, including UBC, UTUC and urethral carcinoma, the positive rate of HER2 in whole UC was 51.2%, and in UBC, UTUC, urethral carcinoma were 56.4%, 31.4%, 50%, respectively. In UBC, the positive rate of HER2 in NMIBC was 53.1%, while in MIBC was 65.7%. In addition, HER2 positivity was significantly correlated with multiple, histologic grade, invasiveness, T stage and location of the tumors.Conclusions: The positive rate of HER2 in UC especially in UBC was significantly higher than that in breast cancer reported by others, HER2 positivity is closely associated with tumor progression, HER2 may be an important target of UC, and HER2-positive UC patients may also benefit from HER2-targeted therapy in the future.

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“…Following BC and GC, the third tumor type that HER2+ is UC, while the expression level of HER2 in patients was 48% with overexpression and approximately 20% with low expression (Fleischmann et al., 2011 ; Yorozu et al., 2020 ).…”

Section: Therapeutic Efficacy Of Rc-48 Adc In the Clinical Studymentioning

confidence: 99%

Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy

et al. 2022

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Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

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HER2 Status in Molecular Subtypes of Urothelial Carcinoma of the Renal Pelvis and Ureter

Cited by 15 publications

References 21 publications

Immunohistochemical based molecular subtypes of muscle-invasive bladder cancer: association with HER2 and EGFR alterations, neoadjuvant chemotherapy response and survival

Immunohistochemical based molecular subtypes of muscle-invasive bladder cancer: association with HER2 and EGFR alterations, neoadjuvant chemotherapy response and survival

HER2 Overexpression In Urothelial Carcinoma Is Closely Associated With Disease Progression: A Single-Center Retrospective Study

Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy

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