HER2 Overexpression Linked to GATA3, PPARG in Urothelial Carcinoma

The overexpression of human epidermal growth factor receptor 2 (HER2) in patients with urothelial carcinoma (UC) is linked to more aggressive disease and poor outcomes, but the genetic basis of HER2 overexpression other than ERBB2 amplification in UC is not well understood.

To resolve this knowledge gap, a research team led by Xiaolin Zhu, MD, PhD, retrospectively analyzed 172 tumor samples from 162 patients with upper tract and muscle invasive UC using immunohistochemistry (IHC) and next-generation sequencing.

Of the 162 patients, 87 (53.7%) developed metastatic disease, 32 (19.8%) had primary upper tract tumors, 116 (71.6%) underwent definitive surgery, and 9 (5.6%) received definitive chemoradiation. Patients with metastatic disease received a median of 2 lines of systemic therapy in the metastatic setting.

HER2 IHC scores of 0, 1+, 2+, and 3+ were found in 30.2%, 20.3%, 32.0%, and 17.4% of tumor samples, respectively. A higher rate of IHC 3+ was seen in metastatic versus primary tumors (29.8% vs 11.3%; P=.005).

GATA3 and PPARG copy number gains were found to individually predict HER2 protein expression independently of ERBB2 amplification; these findings were validated by the Memorial Sloan Kettering/The Cancer Genome Atlas dataset.

HER2 and key transcription factors GATA3 and PPARG are potentially linked, and an increase in the copy numbers of GATA3 and PPARG is independently associated with higher ERBB2 expression in UC tumor samples.

These study results provide a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification, as well as a way to identify these tumors for HER2-targeted therapies.