Researchers have discovered that nearly 25% of muscle-invasive bladder cancers fall into a “basal-like” subgroup that overexpresses EGFR and other proteins in the same pathway. EGFR inhibitors like erlotinib and cetuximab are effective against basal-like cell lines and tumors implanted into mice, arguing for clinical trials of the drugs for patients with this cancer subtype.

Muscle-invasive bladder cancer (MIBC) is aggressive, hard to treat, and lethal. Researchers now report they've discovered a subtype of the cancer that is vulnerable to EGFR inhibitors.

Although it accounts for about 30% of cases, MIBC causes most bladder cancer deaths. Even after bladder removal, about half of patients die within 5 years. No new treatments for this form of cancer have reached the clinic in more than 20 years, and the heterogeneity of MIBC has posed an obstacle for researchers.

To sort through this diversity, a team led by François Radvanyi, PhD, of the Institut Curie in Paris, France, analyzed gene expression data from 383 MIBC tumors. The researchers found that about a quarter of the tumors fell into a cohesive group that resembled the basal subtype discovered in breast cancer. Clinical data from the patients showed that these “basal-like” MIBC tumors were more deadly than other MIBC tumors.

The basal-like MIBC tumors also revealed a potential vulnerability: They overexpressed genes in the EGFR pathway, including EGFR itself. As the researchers reported in July, the EGFR inhibitor erlotinib (Tarceva) diminished cell proliferation in 9 of 11 MIBC basal-like cell lines, but in only 1 of 11 non–basal-like lines (Sci Transl Med 2014;6:244ra91). The EGFR-targeting antibody cetuximab (Erbitux) also proved effective, particularly in 2 basal-like cell lines where it reduced cell numbers by around 75%.

To test whether erlotinib works in vivo, Radvanyi and colleagues implanted MIBC tumors into mice. Erlotinib curbed the growth of basal-like tumors, but the non–basal-like tumors didn't respond. The researchers also tested a chemically induced mouse model whose tumors resemble the basal-like growths. Treatment with erlotinib delayed the appearance of the tumors and increased the animals' survival.

Although previous clinical trials in MIBC patients found that EGFR inhibitors had little effect, Radvanyi notes that these studies included patients with non–basal-like tumors who were unlikely to benefit, which might explain the negative results. The team's findings also suggest excluding patients with RAS-activating mutations, which render tumors insensitive to the drugs. MIBC “can't be treated as one disease anymore,” says Radvanyi. “It will be several diseases that are treated separately.”

What makes the result compelling is that “it was comprehensive across all three types of tumor models,” says James McKiernan, MD, of the Columbia University College of Physicians and Surgeons in New York, NY, who wasn't connected to the study.

If further studies confirm the existence of the basal-like subtype, “it is reasonable … to take it to the clinic and see if it works,” says Mark Soloway, MD, of Memorial Regional Hospital in Hollywood, FL.

EGFR tyrosine kinase domain with erlotinib.

EGFR tyrosine kinase domain with erlotinib.

Close modal

McKiernan agrees. A clinical trial “is a no-brainer,” he says.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.