Blood-based cancer tests reveal complex genomic landscape of non-small cell lung cancers.

A new UC San Francisco-led study challenges the dogma in oncology that most cancers are caused by one dominant “driver” mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world’s most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.

These findings, published online on November 6, 2017, in the journal Nature Genetics, strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising.

“Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best—sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.

The new UCSF-led study—which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City, Calif.-based Guardant Health—is the first to extensively profile the genetic landscape of advanced-stage non-small cell (NSC) lung cancer, the most common form of the disease.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment,” said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”

The single-driver view of lung cancer has been buttressed by influential genomic studies, such as The Cancer Genome Atlas (TCGA). However, these studies have so far focused on genomic alterations in early, stage 1 tumors, which are usually treatable with surgery and chemotherapy, rather than the more deadly advanced-stage tumors that challenge clinical oncologists.

“Until recently, our field has relied on genomic data from early-stage cancers, but most of the patients we are treating have stage 4 disease,” Bivona said. “This study is the first in-depth look at the complex genomics of advanced NSC lung cancer, where it turns out that the genetic landscape is wildly different.”

To begin to map out the genetic landscape of stage 4 lung cancer, Bivona’s team collaborated with Guardant Health, whose clinically validated Guardant360® cell-free DNA platform finely analyzes patient blood samples to check for any mutations in 73 genes known to contribute to cancer. The researchers analyzed this so-called “liquid biopsy” data from 1,122 patients in Guardant Health’s database whose tumors contained a mutated EGFR gene—considered the dominant genetic driver of about 15% of cases of NSC lung cancer—as well as 944 patients whose tumors did not have this mutation.

This analysis revealed that the 92.9% of tumors from patients with advanced-stage lung cancer harbored multiple changes in cancer-related genes