Personalized treatments for lung cancer and the diagnostic tests that make it possible

Lung x-ray © iStockphoto
The emerging field of pharmacogenoics aims to tailor lung cancer drug regimens to the genetic profiles of patients and tumors. 

Bay Area physician, patient chooses UC Davis care

Posted May 12, 2010

Fred Marcus knew exactly what to do when he was diagnosed with lung cancer.

That's because the 62-year-old physician had been treating patients with the disease in his Silicon Valley practice for nearly 30 years.

"It was a surreal experience," says Marcus, who lives in the town of Nipomo, about 25 miles south of San Luis Obispo. "I never smoked, and I had never been sick."

First, Marcus had his tumor analyzed at the genetic level. Then he turned to UC Davis Cancer Center's David Gandara for treatment.

"I have known David Gandara professionally for many years," says Marcus, who was diagnosed in 2006. "He's also the best lung cancer doctor in our area."

Gandara is associate director of clinical research and director of the center's Thoracic Oncology Program, and an international leader in the treatment of lung cancer.

Marcus knew that Gandara and his colleagues could provide personalized treatment for lung cancer, care he could find only at a National Cancer Institute-designated cancer center like UC Davis.

Dr. Fred Marcus © UC Regents"There is no question in my mind that this personalized approach is the answer."
— Fred Marcus

In treating all of his patients, Gandara takes into account a host of factors such as age, gender and stage of disease, which oncologists have relied upon for years. But he also evaluates the patient's genetic makeup to select chemotherapy drugs that will have the fewest side effects. And he conducts genetic tests of the tumor to determine which therapies most likely will kill the cancer.

This integrated approach has worked for Marcus, who continues to benefit from Gandara's efforts to optimize his treatment regimen. "There is no question in my mind that this personalized approach is the answer," Marcus says.

Gandara agrees. "Personalized medicine is having a profound impact on the way physicians approach making the best treatment choices for their patients with lung cancer," says Gandara, who also is a UC Davis professor of medicine.

Gandara likes to use a shopping analogy to describe how personalized cancer therapy will work. "It is becoming increasingly apparent that one size does not fit all when it comes to cancer therapy. Instead of buying your new clothes off the rack, the tailor — the oncologist — will be able to custom-fit your selection."

Even before his treatment, Marcus encouraged colleagues in his practice and in the oncology community to use the personalized approach. "I was doing the cutting-edge genomic testing before it was very popular," he recalls.

Mack and Gandara © UC Regents
Left to right: Phil Mack and David Gandara

Gandara says Marcus is an exception among lung cancer physicians, many of whom do not realize how important genetic differences are in how our bodies handle drugs. "We don't treat on the basis of these individual differences," he says. "For some of these cancer drugs, we may need to do that."

Gandara is on a mission to educate fellow physicians about the importance of personalized treatment for lung cancer and the availability of diagnostic tests that make it possible. As incoming president for the International Association for the Study of Lung Cancer, he works toward that goal, including serving as co-chair of the association's 13th World Conference on Lung Cancer in San Francisco, which was held in July 2009.

"Physicians need to know that we can already use predictive biomarkers to choose lung cancer treatments," Gandara says. Tests for those markers are covered by Medicare and by most insurance companies, he adds.

In addition to caring for patients and educating physicians, Gandara is conducting clinical trials research in the emerging field of pharmacogenomics. This area of science aims to tailor drug regimens to patients' genetic profiles.

Gandara notes that he is on the board of directors of Response Genetics Inc., a Los Angeles-based company that offers genetic testing for lung and colon cancer patients.

In May, Gandara and a team of United States and Japanese researchers published a groundbreaking pharmacogenomics study that used a new model, called the common-arm clinical trial, to look at the differences in effectiveness of cancer therapies between ethnic groups.

In a common-arm study, clinical trials conducted in different countries use a standardized design that included similar study designs, eligibility criteria and treatment regimens. "We're the only ones taking this approach to cancer therapy," Gandara says.

Gandara is a member of the Southwest Oncology Group (SWOG), the largest federally funded U.S. cancer trials network. The common-arm study was a huge undertaking that took years of collaboration between SWOG and the Japanese equivalent of the U.S. Food and Drug Administration.

Researchers launched the study in hopes of explaining why clinical trials conducted in different countries involving two commonly used chemotherapy agents, paclitaxel and carboplatin, resulted in different outcomes for patients with nonsmall- cell lung cancer.

Fred Marcus © UC Regents
Fred Marcus continues to benefit from Gandara's efforts to optimize his treatment regimen.

The results confirmed those of previous studies, explains molecular biologist Philip Mack, a UC Davis Cancer Center researcher, one of the study authors and also a member of SWOG. "The Japanese experienced more toxicity, but a better one-year survival rate," Mack says.

The researchers also looked at single-nucleotide polymorphisms, or SNPs (pronounced snips), in six genes associated with drug metabolism. SNPs are portions of genes in which the DNA sequence varies by a single nucleotide — A, T, C or G.

They found differences in genetic variation for four of the genes between the two groups. "We were able to determine that there are significant differences in distributions of these SNPs," says Mack, who also is a UC Davis associate adjunct professor of medicine.

Gandara says the results of the study support the idea that genetics matter when it comes to treating lung cancer. "SNPs account for the differences in how our bodies handle drugs. We don't typically treat on the basis of these individual differences. For some of these cancer drugs, we may need to do that."

He explains that this kind of common-arm study is part of a growing trend toward the globalization of clinical trials. Gandara plans to collaborate with researchers conducting similar studies in the future, including ones from Latin America now planning common-arm clinical trials with SWOG.

Gandara and Mack also are working to personalize lung cancer treatment based on tumor genetics. Mack's lab is responsible for identifying oncogenes in tumor samples of cancer center patients. An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancerous one.

"Two people with the same diagnosis may have radically different compilations of oncogenes that contribute to their disease," Mack explains. The latest cancer therapies target cellular signaling pathways that are abnormally activated by these oncogenes. "We can do a better job of using these tools if we can understand the specific genetic profile of each individual's tumor."

These treatments are more likely to work in the growing number of lung cancer patients who have never smoked, Mack says. That's because non-smokers have fewer oncogenes than smokers do, making it easier to predict which targeted molecular therapy will work. "In the next two years, we should be able to assign never-smokers to optimal initial therapy in 30 to 50 percent of cases," Mack predicts.

More about UC Davis cancer research and programs

Cover of Winter 2009 Synthesis © UC Regents

"A custom fit for lung cancer treatment"  also appears in Synthesis, the biannual magazine of UC Davis Cancer Center. The most recent issue explores cancer stem cells, cancer treatment during pregnancy and an exciting new collaboration that will bolster the assault on breast cancer.

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On the other hand, personalizing treatment for smokers based on tumor genetics will take longer. "The tumors of smokers often have rampant mutations, and therefore the tumors are generally less responsive to molecular therapies," Mack says.

In both non-smoker and smoker cases, the genetic profiles needed to individualize therapy are sometimes hard to come by. That's because lung cancer tumors are diagnosed from very tiny biopsies, and often there is not enough tissue left over from pathology tests to use to perform molecular analysis. So, recently, Mack and his colleagues instead have begun to look at harvesting tumor cells and DNA from patient plasma.

"Tumor material is shed into the blood, and we can investigate that for the presence of key mutations. It's forensic-type research," Mack explains. "We're looking for small amounts of tumor DNA in the blood."

According to Mack, both pharmacogenomics and tumor genetics are revolutionizing cancer therapy. "We're still in the information-gathering stage, but we can already refine a patient's therapeutic course so that they are more likely to receive a drug that will be successful," he says.

Gandara concurs. Thanks to this two-pronged, personalized approach, cancer treatment is evolving from empirical selection of therapies — choosing drugs based on a person's age, stage of disease and other general factors — to what Gandara calls "molecular selection."

Marcus, however, points out that patients like him still can't access specific drugs for every type of tumor, since drug development has yet to catch up with what's being learned about genomics and tumor biology. But he's hopeful. "Even in the last three years there have been great advances in tailoring therapy to individual needs," he says. "It's the promise of personalized medicine, and it's really coming to fruition."