HER2 amplification significantly increases death risk in micropapillary bladder cancer

Micropapillary urothelial carcinoma is a unique type of bladder cancer affecting approximately 2,000 to 3,000 people each year in the United States. It has a distinctive histology and is associated with rapid spread, a high rate of locally advanced disease and increased mortality. Because micropapillary bladder cancer is known to metastasize with little invasion of the bladder muscle wall, early radical surgery is usually recommended.

Now, Mayo Clinic researchers have shown that amplification of human epidermal growth factor receptor 2 (HER2) and overexpression of its protein product occur more often in micropapillary bladder cancer than in typical urothelial carcinoma and that amplification in micropapillary cancer patients is associated with a significantly increased risk of cancer death. The findings appeared in the November 2013 advanced online issue of Modern Pathology.

"HER2 gene amplification was previously identified in bladder cancer and was associated with poorer outcomes, but not with the aggressive outcomes we saw in micropapillary urothelial carcinoma," says Mayo Clinic pathologist and lead investigator John C. Cheville, M.D.

For the study, Dr. Cheville's group reviewed pathologic material and data from patients undergoing cystectomy at Mayo Clinic from 1980 to 2008. Using fluorescence in situ hybridization (FISH), they identified HER2 amplification in 15 percent of patients with micropapillary urothelial carcinoma compared with 9 percent of those with typical bladder cancer.

HER2-amplified micropapillary tumors were more aggressive and increased the risk of bladder cancer death nearly threefold — a risk that remained elevated on multivariate analysis. No correlation was seen between HER2 amplification and cancer-specific survival in patients with typical bladder cancer or between survival and HER2 protein expression assessed by immunohistochemistry.

"These findings show that it is critical for pathologists to recognize this type of bladder cancer and for providers to order the appropriate tests," Dr. Cheville says. "When HER2 was first implicated in breast cancer, it was associated with a poorer prognosis. Now, treatment with the anti-HER2 antibody trastuzumab has led to better outcomes for patients who have HER2-amplified tumors than for those who don't. The hope is that trastuzumab may be as beneficial for HER2-positive bladder tumors as it is for breast and gastric cancers. But appropriate testing in the correct group of patients is essential in any clinical trial examining the drug's effectiveness."

One unexplained finding of the current study was that some tumors with high protein overexpression did not show HER2 amplification (39 of 142 nonamplified tumors) and that elevated HER2 protein level was not necessarily associated with aggressive tumor behavior, casting doubt on the prognostic value of HER2 protein expression detected by immunohistochemistry.

"Clinical trials using therapies targeted to HER2 for treatment of HER2-amplified bladder cancers are ongoing. It's important that these trials use central pathology review to correctly diagnose the different types of bladder cancer and that there is a standardized assessment of HER2 tumor status by FISH and not just immunohistochemistry," Dr. Cheville says.

He adds, "We're trying to identify prognostic and therapeutic biomarkers and ultimately match the most effective drug to the tumor. My concern is that the effect of novel therapies on these less common types of bladder cancers will be overlooked if the pathology of bladder cancer is not considered."

For more information

Schneider SA, et al. Outcome of patients with macropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Modern Pathology. In press.