Next-Generation Sequencing Propelling Forward Cancer Knowledge, Therapy

Wayne Kuznar

November 2015, Vol 6, No 10 - AVBCC 2015 5th Annual Conference


The impressive progress in cancer care is partly attributable to the advent of next-generation sequencing (NGS). To take full benefit of advances made possible by NGS, more American patients with cancer must be involved in clinical trials, said Raju Kucherlapati, PhD, Professor of Genetics, Harvard Medical School, at the Fifth Annual Conference of the Association for Value-Based Cancer Care.

Dr Kucherlapati discussed novel clinical trial methodologies that facilitate the enrollment of patients receiving care in community cancer centers.

Cancer often involves a genetic component. Germline mutations in BRCA1 and BRCA2 are 2 of the most well-known mutations to confer a risk for breast or ovarian cancer before age 50 years.

“If a cancer is a genetic disease, it would be wonderful to be able to try to generate a comprehensive understanding about what those changes are,” said Dr Kucherlapati. “This really became possible through our ability to sequence the human genome.”

As of January 2015, the cost of sequencing the genes of an individual has been reduced to approximately $2500. “There is nothing in our human enterprise where the cost has gone down this much in such a short period,” Dr Kucherlapati said. “It really has remarkably changed, and the fact that we can sequence the DNA for this low cost, and it is still going down, is driving our ability to be able to understand what is happening.”

NGS can replace immunohistochemistry, fluorescence in situ hybridization, and microarray analysis with a single sample. The Cancer Genome Atlas reveals that cancer is heterogeneous and can be divided into subtypes based on the genetic changes present in the tumor, such as in non–small-cell lung cancer (NSCLC; Figure).

Figure

NSCLC is now classified into those with EGFR mutation (approximately 12%), KRAS mutation (approximately 30%), and BRAF mutation (7%). Targeted therapies for these are either approved or are in development.

In addition to single-point mutations, noted Dr Kucherlapati, structural rearrangements and translocations are also involved in cancer. In the case of NSCLC, EML4-ALK is an “actionable” translocation targeted by the ALK inhibitor crizotinib (Xalkori).

“What is really remarkable, it turns out, is that the same drug is also very effective in those patients who have translocations involving RET and ROS,” he said. “Currently, clinical trials are under way to test the effectiveness of the same drug on these.”

Advances in Pancreatic Cancer

Another example is pancreatic cancer, which involves a substantial number of mutated genes. Some of these genes are involved in a process known as double-strand break repair, in which BRCA1 and BRCA2 are implicated. “It is important, because just earlier this year, a new drug was approved for patients with ovarian cancer whose tumors have mutations in this pathway,” Dr Kucherlapati said. “We understand the molecular basis for that recommendation, and this immediately suggests that all of these patients with pancreatic cancer may be able to benefit from such a treatment.”

Many genetic changes in pancreatic cancer increase the mutation frequency inside the tumor, and tumors that contain very high levels of mutations are the ones that are most likely to respond to immunotherapies, noted Dr Kucherlapati.

More than 90% of pancreatic tumors contain a mutation in KRAS, and several drugs are already approved for other cancers with KRAS mutation. “I anticipate that in the next few years, we are going to see a revolution of the availability of different types of drugs and therapies to be able to treat pancreatic cancer,” Dr Kucherlapati predicted.

New Clinical Trial Paradigm

The many targets in different cancers require clinical trials to prove the effectiveness of targeted agents, but participation in clinical trials in the United States is low, Dr Kucherlapati said. The reason is that most patients with cancer in the United States receive treatment in community centers, and the costly infrastructure and inadequate reimbursement for clinical trial participation in this setting are barriers. A new clinical trial paradigm is therefore needed.

Basket and umbrella clinical trials involve 1 drug that is tested against a particular genetic mutation across several cancer types. An example of this type of trial is the US-based 500-site Lung Cancer Master Protocol, an ongoing phase 2/3 registration trial that is testing 7 distinct therapies for NSCLC, which are selected based on results from NGS (Table).

Table

Another is the NCI-MATCH trial at the National Cancer Institute, in which more than 20 drugs are being tested in more than 3000 patients, using actionable mutations that have been identified through NGS.