1999P - Expression heterogeneity of ADC-related targets between primary tumors and metastatic lymph nodes in advanced urothelial cancers

Background

Antibody‒drug conjugates (ADCs) have dramatically improved clinical outcomes in urothelial cancers as a novel, effective and low-toxicity therapeutic approach recently. However, previous studies ignored the expression heterogeneity of ADCs-relative genes in metastatic tissues of pN+ patients, which are the crucial populations to improve overall outcomes. Here, we aimed to explore HER2, HER3, Nectin4 and Trop2 expression in advanced urothelial cancers between primary tumors and metastatic lymph nodes (mLN) in pairs.

Methods

306 pN+ urothelial cancer patients including 65 renal pelvis, 38 ureter, 179 bladder and 24 urethral cancer from SYSUCC were included. The IHC scores of 2/3+ were defined as HER2 high expression. HER3, Nectin4 and Trop2 were evaluated by H-scores (range 0-300, rank 0 to 3+) which multiplied by the extent and intensity of the staining, and H-scores >15 were considered positive.

Results

HER2 positive expression (1-3+) was detected in 74.8% advanced urothelial cancers and 49.4% patients were HER2 high expression (2/3+). HER2 high expression rate of renal pelvis, ureter, bladder and urethral primary tumors were 33.8%, 42.2%, 56.5% and 50%, while 30.1%, 41.7%, 51.9% and 50% in mLN respectively. The concordance rate of HER2 expression between primary and mLNs was 71.9%. Meanwhile, 27.7%, 42.1%, 52%, and 66.7% primary tumors of renal pelvis, ureter, bladder and urethral cancer patients had HER3 positive expression (71.9% in consistency with mLN); 72.3%, 89.5%, 77.7%, 87.5% positive expression rate for Nectin4 (50.7% in consistency); 89.2%, 94.7%, 83.2%, 95.8% positive expression rate for Trop2 (65.3% in consistency). Furthermore, survival analysis showed that HER2, HER3 and Trop2 overexpression were associated with poor OS (p<0.05), and only HER2 overepxression in mLNs was independent unfavourable prognostic factor.

Conclusions

We first investigated the expression heterogeneity of ADC-related targets in primary urothelial tumors and mLNs in a large cohort, especially in pN+ patients. Therapy targeting HER2-ADCs might show better homogeneity in advanced disease, but it is more recommended to detect IHC staining both in primary and metastatic tissues to guide subsequent treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Natural Science Foundation of Guangdong Province, China, No. 2022A1515012318.

Disclosure

All authors have declared no conflicts of interest.