Genome-Forward Medicine in Lung Cancer

Caroline Helwick

August 2011, Vol 2, No 5 - ASCO Annual Meeting

Chicago, IL—Whole genome sequencing was the topic of a session at the 2011 ASCO annual meeting in which specialists discussed the implications of “genome-forward medicine” in lung cancer.

This entails “how to get to the nature of tumors and their heterogeneity,” said Elaine Mardis, PhD, Codirector of the Genome Institute at Washington University, St Louis, MO. Next-generation sequencing, she said, will eventually guide treatment decisions.

“Cancer is well known to be a disease of the genome,” Dr Mardis stated. “This is not limited to point mutations on genes but to the full spectrum of somatic alterations.”

According to Dr Mardis, the genomic discovery methods used by researchers are being applied to endstage and difficult-to-diagnose patients to shape genome-guided treatment decisions. Currently, the patient population is small, “but this is actively happening today at somemedical centers,” she explained.

The next step is to make the process user-friendly in the clinic. “We have to compress the process into a time frame that is meaningful and appropriate for the patient, which is the time between diagnosis and decisions about treatment— about 4weeks,” she pointed out.

The stage is also being set, she said, for moving genome-forward medicine into clinical trials, to test expensive targeted agents in more enriched patient subsets.

Targeted Agents Work in NSCLC

Ramaswamy Govindan, MD, also of the Genome Institute, emphasized that “targeted therapies in targeted patients work. With mutation-targeted agents such as the epidermal growth factor receptor [EGFR] inhibitors in non– small-cell lung cancer [NSCLC], responses can be durable.”

The challenge now is to identify all the other targets in lung cancer. Most targets that can be treated with drugs have been identified for adenocarcinoma; fewer have been established for squamous-cell carcinoma.

“No one believes that EGFR is the only player. Large populations ofmutations are virtually unknown,” he noted.

Researchers at the International Cancer Genome Consortium Cancer Genome Projects and the Cancer Genome Atlas Research Network are sequencing thousands of genes in an intelligent fashion. They will prospectively collect fresh tumor samples from primary, recurrent, and metastatic tumors, to be optimized for genomic analysis of genetic mutations, as well as other cancer processes. “By the end of this year we will see important papers coming from this research,” Dr Govindan predicted.

The clinical implications of genetic analysis in NSCLC are the identification of new targets that can be treated with drugs; discovery of mechanisms of tumor resistance to treatment; subcategorization of the disease that will dictate treatment approaches; and prediction, through genetic profiling, of persons at risk for lung cancer.

“One thing has become obvious so far: lung cancer is a more complex disease than we once thought,” he pointed out. “Compared to childhood malignancies, for example, the mutation rates are much higher.” An example of the complexity is the “stunning difference” in the number of mutations observed in tumors that come from nonsmokers versus smokers. Smokers’ tumors have multiple mutations in DNA repair pathways that are completely absent in tumors of nonsmokers.

“We must get used to the notion that cancer is heterogeneous. We are unlikely to find common mutations in more than about 5% of patients,” Dr Govindan stated.