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

doi:10.21203/rs.3.rs-1406019/v1

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

https://doi.org/10.21203/rs.3.rs-1406019/v1

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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.

Urothelial carcinoma

HER2

Immunohistochemistry

Targeted therapy

Urothelial carcinoma (UC) is a common malignancy worldwide. UC accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. According to GLOBOCAN 2018, bladder cancer is the 10th most common form of cancer worldwide, with an estimated 549,000 new cases and 200,000 deaths[1]. At the time point of diagnosis of bladder cancer, approximately 70%-75% of patients present with non-muscle-invasive bladder cancer (NMIBC), while the remaining 25%-30% show muscle-invasive bladder cancer (MIBC) or even distant metastases[2]. Despite all the advances in medical oncology in recent years, patients with advanced or metastatic UC have been unfortunate, their prognosis remains very poor, with a median overall survival (OS) of about 15 months once diagnosed[3]. The current first-line therapy is cisplatin-based chemotherapy, although cisplatin has a high response rate, only a small percentage of patients (10%-15%) achieve long-term remission, up to 50% of patients are intolerant of cisplatin due to side effects, often including impaired kidney function, cardiovascular disease, neuropathy, and poor functional status[4]. Although the emergence of immune checkpoint inhibitors offers a glimmer of hope for patients with metastatic UC, the treatment of these patients remains challenging and the prognosis is generally poor[5]. Therefore, it is urgent to find new targets to change the treatment status of UC.

Erbb-2, a member of the receptor tyrosine kinases EGFR family, is also known as HER2[6]. HER2 is a type I transmembrane tyrosine kinase receptor with a molecular weight of 185 kDa, and its encoding gene is located on chromosome 17q21[7]. HER2 exists on various types of cell membranes and is usually an inactive monomer form. However, with the overexpression of HER2, the ligands of its corresponding EGFR family members will be activated, resulting in homoor heterodimerization. Finally, the autophosphorylation of tyrosine residues occurs in the cytoplasm of heterodimer, and a variety of signal pathways are started[8]. HER2 can activate a variety of cellular signaling pathways, and then affect cell survival, differentiation, proliferation, invasion and migration, which are exactly the indispensable factors for tumor occurrence and progression[9].The study of HER2 was first launched in breast cancer for more than 30 years[10], the detection of HER2 mainly relies on immunohistochemistry(IHC) and fluorescence in-situ hybridisation, HER2 positivity accounts for about 15–20% of breast cancers[11]. Nowadays, the recommended first-line therapy for HER2-positive metastatic breast cancer consists of the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab given with a taxane[12].

In this study, we focused on the entire urothelial system, evaluated the expression of HER2 in whole UC, including upper tract urothelial carcinoma (UTUC), urothelial bladder carcinoma (UBC) and urethral carcinoma, and analyzed the correlation between HER2 overexpression and multiple clinicopathological factors in order to find new therapeutic target for UC and enable better selection of UC cases for anti-HER2 therapy in the future.

Ethical approval

This study was approved by the Ethics Committee of Lanzhou University Second Hospital (IRB number, 2022A-016) and was performed in accordance with the principles of the Declaration of Helsinki. Signed informed consent form was obtained from all eligible participants.

Patients

One hundred and seventy UC patients who underwent surgery at the Department of Urology of Lanzhou University Second Hospital from January 2021 to December 2021 were included in this study. Clinicopathological information was obtained by reviewing medical records. Clinicopathological factors evaluated in this study were sex, age, tumor size, tumor location, invasiveness, histologic grade, T stage, N stage, M stage, multiple, and recurrence. Histologic slides were reviewed according to the WHO classifcation of tumors of the urinary system and male genital organs[13]. The 8th edition of the Union for International Cancer Control Staging System was referenced to classify the TNM stage of UC patients[14, 15].

Immunohistochemical staining and scoring

HER2 IHC was performed using the HercepTest (Dako, Glostrup, Denmark) according to the manufacturer’s recommendations. The IHC staining was scored according to recommendations of the American Society of Clinical Oncology/College of American Pathologists 2018 HER2 test guideline established for breast cancer[16]. the IHC scoring criteria are as follows: score 0, no staining observed or membrane stating that is incomplete and faint/barely perceptible and within 10% or less of tumor cells; score 1, incomplete membrane staining that is faint/barely perceptible and within more than 10% of tumor cells; score 2, weak to moderate complete membrane staining in more than 10% of tumor cells or complete membrane staining that is intense but within 10% or less of tumor cells; and score 3, complete membrane staining that is intense and more than 10% of tumor cells (readily appreciated using a low-power objective and observed within a homogeneous and contiguous population of invasive tumor cells). All cases were scored for HER2 IHC status by a single pathologist (XLS). Immunohistochemical images of some cases are shown in Figure 1, we considered 2+ and 3+ staining as HER2 overexpression or positivity[1].

Statistical analysis

Chi-square categorical variables were used to compare the differences in demographic, clinical, and pathological characteristics between HER2-positive and enrolled patients. Logistic regression analysis and Lasso regression were used to screen out the risk factors influencing HER2 positivity. R software was used for statistical analysis in this study. Logistic regression analysis was performed in R using GLM (generalized linear model) functions and fitted to LASSO regression models using GLMNET. P < 0.05 on both sides was considered statistically significant.

All clinicopathological information is presented in Table 1, The mean patient age was 64.8 years (range: 24-91 years). There was a male predominance, with a male: female ratio of 129:41. HER2 overexpression was identified in 87/170 (51.2%) cases. Among the 170 cases, 133 cases were diagnosed with UBC of which 75/133(56.4%) cases were HER2 positivity, 35 cases were diagnosed with UTUC of which 11/35(31.4%) cases were HER2 positivity, and 2 cases were diagnosed with urethral carcinoma of which 1/2(50%) cases were HER2 positivity. In UBC, 98 cases were diagnosed with NMIBC of which 52/98(53.1%) cases were HER2 positivity, and 35 cases were diagnosed with MIBC of which 23/35(65.7%) cases were HER2 positivity. The clinicopathological stages were as follows: Ta (51/170, 30%), T1 (54/170, 31.7%), T2 (23/170, 13.5%), T3 (30/170, 17.6%), T4 (12/170, 7.0%), N0 (144/170, 84.7%), N1+N2(26/170, 15.2%), M0(164/170, 96.4%), M1(6/170, 3.5%), it is worth mentioning that HER2 was positive in all M1 cases.

Single-factor Logistic analysis of her2-positive correlation was performed on 170 patients included in the study, and the results showed that multiple, histologic grade, invasiveness, T stage and location were correlated with HER2 positive of patients (all P < 0.05) (Table 2). Lasso regression screening variables (Figure 2) and

cross-validation results (Figure 3) showed that the best factors (taking a standard error) were multiple, invasiveness, and location. Further Logistic multivariate regression analysis showed that invasiveness and location were correlated with HER2 positivity of patients (all P < 0.05), invasiveness (No vs Yes: OR [Hazard Ratio], 17.383, P < 0.001) was most correlated with HER2 positivity (Table2).

UC includes UBC, UTUC and urethral carcinoma, of which UBC is the majority. UBC is more likely to recur than any other solid tumor, which is an important clinical feature of UBC. Once diagnosed, more than 70% of patients will have a recurrence during the first 2 years, and the tumor grade and/or stage are higher after recurrence, which results in a poor prognosis for the patient[17]. UTUC, which accounts for about 5%-10% of all UC, is relatively rare, but this tumor is generally more aggressive and has a worse prognosis than UBC[18]. In contrast, urethral cancer is much rarer and has been poorly studied[19].

Our study found that HER2 overexpression exists in the whole UC, including UBC, UTUC and urethral carcinoma, the overexpression rate of HER2 in whole UC was 51.2%, and in UBC, UTUC, urethral carcinoma were 56.4%, 31.4%, 50%, respectively. In addition, we found that HER2 overexpression was significantly correlated with multiple, histologic grade, invasiveness, T stage and location, but not with gender, age, tumor size, recurrence, N stage and M stage. Interestingly, we have not seen the related reports of HER2 in whole UC so far, but only in UBC and UTUC respectively.

In UBC, we also found that the overexpression rate of HER2 in NMIBC was 53.1%, while in MIBC was 65.7%, these overexpression rate was relatively high. Previous studies have reported that the overexpression rate of HER2 in NMIBC was 18.3%-49.0%, and HER2 overexpression was significantly correlated with tumor size, histological grade, stage, overall recurrence and progression rates[20-22]. 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 significance was controversial[23-26]. 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 significantly correlated with histologic grade, stage, and poor prognosis[27-29]. However, we have not seen relevant reports of HER2 in urethral cancer so far, which may be due to the rarity of urethral cancer.

It is worth mentioning that trastuzumab, an anti-HER2 drug, has greatly improved the prognosis of patients with HER2-positive breast cancer since its introduction in the 1990s[30]. With the in-depth study of HER2, people found that HER2 positivity in cancer is associated with poor prognosis in various cancers, and anti-HER2 therapy is well established for HER2 overexpressing breast cancers and gastric cancers at present[31]. But the FDA has not approved anti-HER2 drugs for the treatment of UC so far. Considering that HER2 is an important target for breast cancer and gastric cancer, and that HER2 has such a high positive rate in UC, we have reason to believe that HER2 may also be an important target for UC in the future. Of course, more studies are needed to prove this.

Our study also has some clear limitations, A major limitation is that the datas were from a single center and the number of cases was relatively small, therefore, large numbers of datas from multiple centers may be needed to further clarify the positive rate of HER2 in UC and its relationship with various clinicopathological factors. In addition, our study suggests that HER2 may be a carcinogenic target of UC, but the underlying mechanism is still unclear, future studies should determine the molecular mechanisms underlying the role of HER2 in UC. Furthermore, our follow-up time for patients is relatively short, so that we do not have a long-term prognosis datas of patients.

In conclusion, Our study found that HER2 overexpression exists in the whole UC and HER2 overexpression was significantly correlated with multiple, histologic grade, invasiveness, T stage and location, The positive rate of HER2 in UC especially in UBC was significantly higher than that in breast cancer reported by others, with the advent of the era of precision medicine, we believe that HER2 may be an important target of UC, and HER2-positive UC patients may also benefit from HER2-targeted therapy in the future.

UC:Urothelial carcinoma; UTUC:upper tract urothelial carcinoma; UBC:urothelial bladder carcinoma; NMIBC:non-muscle-invasive bladder cancer; MIBC:muscle-invasive bladder cancer;IHC:immunohistochemistry; 95% CI: 95% Confdence interval.

Acknowledgements

The biospecimens and data used in this study were provided by the Department of Pathology, Lanzhou University Second Hospital. All samples were obtained with informed consent under institutional review board-approved protocols.

Authors’ contributions

QCL, HBW, ZLD were participated in the conception and initial design. QCL, SYC, ZLD performed the clinical treatment of the urothelial carcinoma, QCL, XLS, WBX, LLQ, YJY, JRW were participate in articles search, review, data extract, statistical analysis. QCL, XLS were participate in immunohistochemical staining and scoring. QCL, WBX, ZLD were participate in manuscript writing and revising. All authors have read and approved the manuscript.

Funding

The present study was supported by National Natural Science Foundation of China (no.82160148). Funds were used for purchasing the materials and had no role in the design, collection, analysis, or interpretation of data or writing of this manuscript.

Availability of data and materials

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Lanzhou University Second Hospital (IRB number, 2022A-016) and was performed according to the Declaration of Helsinki. Each eligible participant signed an informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

1 Department of Urology, Lanzhou University Second Hospital. 2 Institute of Urology, Lanzhou University Second Hospital. 3 Gansu Province Key Laboratory of Urological Diseases. 4 Department of Pathology, Lanzhou University Second Hospital.

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Table 1 Clinicopathologic variables and the expression of HER2 in urothelial carcinomas

Variables	Total	HER2-	HER2+	P value
N	170	83 (48.8% )	87 ( 51.2%)
Age, year （mean:64.8, range:24-91）				0.767
24-65	82	41 (50% )	41 (50% )
66-91	88	42 ( 47.7%)	46 (52.3% )
Sex				0.074
Male	129	58 ( 45%)	71 (55% )
Female	41	25 (61% )	16 ( 39%)
Tumor Size ≥ 3 cm				0.100
Yes	66	27 ( 40.9%)	39 ( 59.1%)
No	104	56 (53.8% )	48 ( 46.2%)
Multiple				<0.001
Yes	66	17 (25.8% )	49 (74.2% )
No	104	66 ( 63.5%)	38 ( 36.5%)
Recurrence				0.680
First	135	67 ( 49.6%)	68 ( 50.4%)
Recurrence	35	16 ( 45.7%)	19 (54.3% )
Histologic Grade				<0.001
Low	44	33 (75% )	11 ( 25%)
High	126	50 (39.7% )	76 (60.3% )
Invasiveness				<0.001
Noninvasive	51	44 (86.3% )	7 (13.7% )
Invasive	119	39 (32.8 )	80 (67.2 )
T				<0.001
Ta	51	44 ( 86.3%)	7 ( 13.7%)
T1	54	8 ( 14.8%)	46 ( 85.2%)
T2	23	11 ( 47.8)	12 ( 52.2%)
T3	30	17 (56.7 )	13 (43.3% )
T4	12	3 (25% )	9 (75% )
N				0.679
NO	144	72 ( 50%)	72 ( 50%)
N1+2	26	11 ( 42.3%)	15 (57.7% )
M				0.015
M0	164	83 (50.6 )	81 ( 49.4%)
M1	6	0 ( 0%)	6 ( 100%)
Location				0.032
UTUC	35	24 ( 68.6%)	11 ( 31.4%)
Bladder NMIBC MIBC	133 98 35	58 (43.6% ) 46(46.9%) 12(34.3%)	75 (56.4% ) 52(53.1%) 23(65.7%)
Urethra	2	1 (50% )	1 (50% )

Table 2 Uni- and Multivariate Logistic regression model analysis of HER2 in urothelial carcinomas

Variables	Univariate			Multivariate
Variables	OR	95% CI	P value	OR	95% CI		P value
Age, year			0.767					-
<65	Reference			-
≥65	1.095	0.600-2.003	0.767	-		-		-
Sex			0.076					-
Male	Reference			-
Female	0.523	0.251-1.062	0.076	-		-		-
Tumor Size			0.101					-
<3CM	Reference			-
≥3CM	1.685	0.906-3.167	0.101	-		-
Multiple			*<0.001*					*0.070*
Single	Reference			Reference
Multiple	5.006	2.575-10.104	<0.001	2.302		0.928-5.704
Recurrence			0.680					-
No	Reference			-
Yes	1.170	0.555-2.490	0.680	-		-		-
Histologic Grade			*<0.001*			-		-
Low	Reference			-
High	4.560	2.167-10.226	<0.001	-		-		-
Invasiveness			*<0.001*					-
No	Reference			Reference				*<0.001*
Yes	12.894	5.622-33.713	<0.001	17.383		6.914-49.281		<0.001
T stage			*<0.001*					-
Ta	Reference			-
T1	36.143	12.889-117.155	<0.001	-		-		-
T2	6.857	2.253-22.624	<0.001	-		-		-
T3	4.807	1.683-14.805	0.004	-		-		-
T4	18.857	4.484-102.824	<0.001	-		-		-
N stage			0.471					-
N0	Reference			-
N1+2	1.364	0.590- 3.240	0.471	-		-		-
M stage			0.986					-
M0	Reference			-				-
M1	∞	∞		-		-
Location			*0.015*	-		-		*0.013*
UTUC	Reference			Reference
Bladder	2.821	1.305-6.435	0.010	4.332		1.613-12.356		0.004
Urethra	2.182	0.081-58.688	0.593	1.849		0.069-49.898		0.674

CI = confidence interval; OR = odds ratio; UTUC = upper tract urothelial carcinoma.

No competing interests reported.

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

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