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Under the Microscope: Targeted Therapies for Mutation-Linked Lung Cancer

Despite declining smoking rates, lung cancer remains the leading cause of cancer deaths in the United States and worldwide. While smoking is considered to cause the majority of lung cancer cases, lung cancer can occur even in people who haven’t smoked a day in their lives. In fact, lung cancers not related to smoking are on the rise.

The V Foundation has invested nearly $20 million in lung cancer research grants. Some of the most innovative work involves understanding the causes, and possible treatments, of lung cancer in nonsmokers.

The influence of ancestry

In 2004, scientists discovered mutations in a gene called epidermal growth factor receptor (EGFR) in some patients with nonsmoking lung cancer. In normal cells, EGFR instructs the cells when to grow and divide. Mutations that occur during lung cancer development can cause EGFR to get stuck in the “on” position, creating cancer cells that continue to grow and divide without the normal checks and balances.

With V Foundation funding, Matthew Meyerson, MD, PhD, a researcher at Harvard University’s Dana Farber Cancer Institute, is looking closely at EGFR to understand the risk factors associated with these mutations.

“In our research, we saw that the mutation was much more common in East Asian patients than in American patients or others of European descent,” said Meyerson. “We wanted to know, why are East Asians more likely to develop this mutation than people of European descent?”

One clue came from a study of lung cancer patients from Latin America. Meyerson and his collaborators—Oscar Arrieta in Mexico, Andres Cardona in Colombia and researchers in other Latin American countries—found that the prevalence of EGFR mutations in the study group varied by country. For example, EGFR mutations appeared in only 10 percent of lung cancer patients from Argentina but in 50 percent of patients from Peru, with intermediate levels of around 30 percent in Mexico and Colombia.

The differences, said Meyerson, could be related to ancestry. Argentina’s population includes much more European ancestry while Peru includes a large Native American population, leading the researchers to believe there could be an inherited factor, more prevalent in East Asians and Native Americans, that makes EGFR mutations more likely to occur during the development of cancer.

Looking forward, Meyerson’s team is focused on finding out which factors might increase the susceptibility to cancer and how. “We want to know if there are inherited factors that make this mutation more likely in certain populations during the development of lung cancer,” he said.

 

From one patient to a system for testing and treatment

As scientists and clinicians began to study the relationship between lung cancer and EGFR mutations, they found a silver lining: several drugs already approved by the FDA have delivered great results in treating EGFR-related lung cancers. Even better, these drugs, including afatinib, gefitinib and erlotinib, can all be administered as pills, saving patients from the stress and side effects of traditional chemotherapy.

These findings were a major step forward in precision medicine—medical treatment tailored to account for variability in patients’ genetics, environments and lifestyles. The anti-EGFR drugs worked in lung cancer patients whose tumors had certain EGFR mutations, but not for lung cancers with other causes.

Unfortunately, mutation testing is not always straightforward. Such was the case for a 33-year-old nonsmoking man diagnosed with stage IV lung cancer at Vanderbilt University’s Vanderbilt-Ingram Cancer Center. His tumor did not have the “normal” EGFR mutations but showed a previously unknown EGFR mutation. As a result, he was not eligible for treatment with anti-EGFR drugs.

Christine Lovly, MD, PhD, an assistant professor of medicine at Vanderbilt University whose work is funded in part by the V Foundation, studied this new EGFR variant in her laboratory. She showed that the new EGFR variant was found in several patients’ tumors and that it could be effectively treated with afatinib.

“Now that we can do genetic testing of tumors, we are able to discover variants that we know, but also many that we don’t know,” she said. To build on their work, Lovly’s team is creating an experimental pipeline that starts with genetic testing, proceeds to study of the specific mutation, and then matches the mutation to a drug with a good chance of treating the cancer.

“When a patient shows an usual EGFR mutation that has never been reported before, you can’t simply start pill therapy because there is no evidence to support it,” said Lovly. “We want to develop a process to take those test results, bring them to the lab and design experiments that can help patients.”