cancer genomics and genomics research

AACR cancer progress report.
Nikhil Wagle, MD
Instructor in Medicine at the Dana-Farber Cancer Institute, Boston, and Associate Member of the Broad Institute, Cambridge, Massachusetts.



There's been a revolution in cancer genomics and genomics research over the past decade, thanks to the plummeting cost of sequencing and the development of new technologies. As a result, we understand much more about the molecular underpinnings of cancer biology, and this is beginning to influence clinical decision making. Further developing this base of knowledge is really the key to better implementing precision medicine.

In recent years, there has been a shift in the treatment of cancer patients from less targeted, traditional therapies toward the use of molecularly targeted therapies. This approach to treatment is known as precision medicine. It is a direct result of genomic analyses in the research laboratory being used to inform molecularly targeted drug development. As our understanding of the molecular dependencies of tumors grows, so, too, will the number of molecularly targeted drugs.

We are now witnessing great advances as genomic analyses are increasingly being applied to the clinical research setting. For example, we are using genomics to understand the molecular features of a tumor that can influence treatment decisions, tell us about the likelihood of response or resistance to certain therapies, help with diagnosis, and give clues about prognosis.

Although genomic analysis doesn’t help all patients, there is an increasing number of patients for whom it has impacted clinical decision making. For example, whole-exome sequencing of the tumor from one patient with advanced lung cancer revealed three potentially clinically relevant genetic alterations that hadn’t been detected by standard testing. As a result of our analysis, the treating physician enrolled the patient in a clinical trial that stabilized his disease for many months, which was the best response he had had to date. When that trial ended, another clinical trial was identified from which he might benefit, based on our prior genome analysis, and as a result, he continues to do well.

The use of genomics clinically has become increasingly important for understanding why there is diversity in the response of patients to anticancer therapies. We have always known that some patients respond to certain therapies and others do not, but in most cases we don’t know why these differences occur. Over the past few years, we have seen that studying “exceptional responders”—rare patients with exquisite sensitivity or unexpected long durations of response to therapies—is a good way to shed light on this issue.

We have found that in several exceptional responders, we are able to identify the mutation, or combination of mutations, that makes these patient’s tumors extraordinarily responsive to the treatments. The next step is to look for the same or similar mutations in other patients and enroll them in clinical trials to see if they, too, might respond well to the therapy. In fact, analysis of exceptional responders has seeded a number of so-called “basket” trials, in which patients are enrolled based primarily on the genetic alterations of their tumors as opposed to an anatomical basis or specific clinical features.

Genomic analysis is also key to understanding how tumors become resistant to molecularly targeted therapies. What we’ve learned is allowing us to begin to predict which patients will likely have a tumor that is resistant to a certain therapy and to identify combinations of therapies that will overcome resistance.

We are beginning to see genomic analysis move from the research setting to standard of care, but there are still challenges that must be overcome if this trend is to increase dramatically in the next few years. The key challenge is assembling enough data to support meaningful analysis. Frankly, we need data from sequencing of hundreds of thousands of tumors, submitted to large, centralized, shared databases. Moreover, the data have to be interpreted and annotated, and then communicated so that both patients and physicians can understand how to use this information in making the best treatment decisions.

The ultimate goal is for genomic analysis to be part of the routine battery of pathological and diagnostic tests run on tumor tissue from all cancer patients in order to determine the optimal care for each individual.