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To evaluate human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridisation (FISH) in urothelial non-muscle-invasive bladder carcinoma (NMIBC), as HER2 is a potential therapeutic target in muscle-invasive bladder carcinoma (MIBC) and HER2 expression and gene amplification in low/high-grade and pTa/pT1 NMIBC is not clear. The study included 93 bladder cancers; 25 MIBC and 68 NMIBC (37 low- and 31 high-grade). All HER2 positive (3+) and equivocal (2+) cases were subjected to FISH using a HER2/CEN 17 dual-colour probe kit. IHC and FISH were scored as per the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 Guidelines for breast cancers. Based on the number of signals/nuclei, amplification was categorised as low (≥6–10) and high-level (≥10). HER2 2–3+ expression was seen in 29% of NMIBCs (10.8% low- and 51.6% high-grade). HER2 3+ expression was seen in high-grade NMIBC (nine of 31; 29%) and MIBC (nine of 25; 36%). In all, 87% of high-grade NMIBCs were lamina invasive (pT1). Gene amplification was found in 45% (eight of 18) of 3+ tumours. None of the HER2 2+ tumours showed gene amplification. IHC and FISH results were in closest agreement when ≥50% of tumour cells showed 3+ expressions. High-level amplification correlated with increased gene expression on reverse transcriptase-polymerase chain reaction. On multivariate analysis, lower stage, grade, and HER2 expression significantly correlated with progression-free survival. HER2 3+ expression in NMIBC correlated significantly with time to recurrence and progression. Our present results show that HER2 FISH should not be performed for HER2 2 + and low-grade NMIBC. This contrasts with breast cancers where it is recommended for equivocal 2+ tumours. About 50% of HER2 3+ MIBC and high-grade NMIBC show HER2 gene amplification and can be potential candidates for HER2-targeted therapy. ASCO/CAP: American Society of Clinical Oncology/College of American Pathologists; DAB: 3,3ʹ-diaminobenzidine; FISH: fluorescent in situ hybridisation; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry;(N)MIBC: (non-) muscle-invasive bladder carcinoma; MPUC: micropapillary variant of urothelial bladder cancer; PFS: progression-free survival; TURBT: transurethral resection of bladder tumour [ABSTRACT FROM AUTHOR]

The oncogene HER2 is an important molecular target in oncology because it is associated with aggressive disease and the worst prognosis. The development of non-invasive imaging techniques and target therapies using monoclonal antibodies is a rapidly developing field. Thus, this work proposes the study of the radioimmunotheranostic pair, [111In]In-DTPA-trastuzumab and [177Lu]Lu-DOTA-trastuzumab, evaluating the influence of the chelating agents and radionuclides on the biological properties of the radioimmunoconjugates (RICs). The trastuzumab was immunoconjugated with the chelators DTPA and DOTA and radiolabeled with [111In]InCl3 and [177Lu]LuCl3, respectively. The stability of the RICs was evaluated in serum, and the immunoreactive and internalization fractions were determined in SK-BR-3 breast cancer cells. The in vivo pharmacokinetics and dosimetry quantification and the ex vivo biodistribution were performed in normal and SK-BR-3 tumor-bearing mice. The data showed that there was no influence of the chelating agents and radionuclides on the immunoreactive and internalization fractions of RICs. In contrast, they influenced the stability of RICs in serum, as well as the pharmacokinetics, dosimetry and biodistribution profiles. Therefore, the results showed that the nature of the chelating agent and radionuclide could influence the biological properties of the radioimmunotheranostic pair.

The oncogene HER2 is an important molecular target in oncology because it is associated with aggressive disease and the worst prognosis. The development of non-invasive imaging techniques and target therapies using monoclonal antibodies is a rapidly developing field. Thus, this work proposes the study of the radioimmunotheranostic pair, [111In]In-DTPA-trastuzumab and [177Lu]Lu-DOTA-trastuzumab, evaluating the influence of the chelating agents and radionuclides on the biological properties of the radioimmunoconjugates (RICs). The trastuzumab was immunoconjugated with the chelators DTPA and DOTA and radiolabeled with [111In]InCl3 and [177Lu]LuCl3, respectively. The stability of the RICs was evaluated in serum, and the immunoreactive and internalization fractions were determined in SK-BR-3 breast cancer cells. The in vivo pharmacokinetics and dosimetry quantification and the ex vivo biodistribution were performed in normal and SK-BR-3 tumor-bearing mice. The data showed that there was no influence of the chelating agents and radionuclides on the immunoreactive and internalization fractions of RICs. In contrast, they influenced the stability of RICs in serum, as well as the pharmacokinetics, dosimetry and biodistribution profiles. Therefore, the results showed that the nature of the chelating agent and radionuclide could influence the biological properties of the radioimmunotheranostic pair. [ABSTRACT FROM AUTHOR]