The Next Step in Personalized Medicine

Lung. Breast. Colon. Pancreas. For as long as people have studied cancers, they have been categorized primarily by the part of the body where they appear to have originated.

More recently, genetic sequencing has allowed us to peer into the inner workings of cancer cells; we’ve since learned that while two cancers that arise from the same organ may look exactly the same under a pathologist’s microscope, their underlying biology can be completely different. Similarly, we now know that two cancers that arise from different organs can be driven by the same underlying biology.

For decades, scientists around the world, including those at Genentech, have been unraveling the genetics of different tumors with the goal of discovering new medicines that target specific mutations that drive their uncontrolled growth. If successful, they could develop medicines with the ability to treat tumors based on their underlying mutations, regardless of where they originate in the body.

But discovering a mutation that drives a specific cancer only gets us halfway there. We also need to develop diagnostic tests to recognize those mutations across cancer types, which would enable us to deliver targeted, personalized treatments to more people living with cancer. Sound too good to be true?

It’s not.

What, not Where

I’ve spent a large part of my career working on personalized cancer medicines—treatments designed to target the genetic abnormalities driving a person’s cancer. These types of medicines have fundamentally changed the way we treat a wide range of cancers. But these medicines were typically developed to address the effects of a specific mutation in one of these specific cancer types (such as lung or breast cancer). By taking a tumor-agnostic approach, that is, looking at the biology of the tumor and not simply where it arose in the body, in some cases we can extend the reach of personalized treatments to target a specific genetic mutation regardless of the type of cancer a person has.

This has been made possible by research revealing common genetic mutations across different types of cancer. One example is the discovery of the Neurotrophic Tyrosine Receptor Kinase (NTRK) family of genes. In some tumors, genetic rearrangements of NTRK genes can result in gene fusions that drive the growth and proliferation of cancer.

Tumor-agnostic medicines are designed to target a specific genetic mutation shared across different types of cancers regardless of where they originated in the body.

NTRK gene fusions have been identified in a range of cancers including lung, colorectal, thyroid, brain and others. Studies have shown that these types of fusions can vary in incidence among tumor types, from 0.5 percent in colorectal cancer to up to 40 percent in certain rare pediatric brain cancers.

This means that the option of targeting specific genetic mutations, like NTRK, can mean different things for different patient groups. In a disease like lung cancer, where a number of genetic mutations can drive tumor growth, there are dozens of smaller patient subgroups, each of which may respond to a type of targeted therapy tailored to their disease. For rarer cancers, identifying genetic mutations responsible for the disease could reveal new treatment options where there are currently few. But how would you sort it all out?

Needle in a Haystack

This is where a new type of diagnostic technique—called next generation sequencing (NGS)—comes into play. Rather than using individual genetic tests to search for mutations one at a time, NGS can identify a wide range of cancer-causing mutations across the entire genome of a tumor using only a small sample. This powerful approach offers a molecular snapshot of each person’s tumor and helps to identify potentially rare gene mutations or fusions like those that can occur in NTRK across multiple tumor types.

Our scientists are at the forefront of this personalized approach to cancer care. We have a long history of developing personalized medicines and have an established and evolving set of tools to continue researching tailored treatments. This approach extends to basic science research conducted in our labs, where we continue to dissect cancer at the molecular level in hopes of identifying new personalized therapies.

In conjunction with companies like Foundation Medicine and Flatiron Health, we have also expanded our capabilities in NGS-based cancer diagnostics and advanced data analytics. With access to large amounts of clinical data, combined with advanced analytic techniques, we now have the ability to understand which patients might benefit from new tumor-agnostic therapies and how to best identify those individuals. It’s also important to remember that these types of advances don’t happen in a vacuum. Collaboration with health authorities, clinical investigators, physicians and patient groups is critical to making more personalized options a reality.

Treatment decisions in cancer have traditionally been made based on the tissue or organ where a cancer originated in the body and have been treated non-specifically. In certain cases, tumor-agnostic medicines could offer a more personalized treatment approach by targeting a specific genetic mutation regardless of where the cancer originated.

The Right Trials

There’s one more challenge, however. As we identify groups of patients with these genetic abnormalities, we’ve needed to change how we design clinical trials. Traditionally, new medicines are evaluated in large randomized studies that include patients with a single cancer type.

But now we can identify specific people who are more likely to benefit from an experimental medicine across multiple types of cancer based on the genetics of their tumors. That means we have needed to rethink the way we design clinical studies, especially for extremely rare mutations or alterations where traditional large, randomized clinical trials aren’t practical.

For example, tumor agnostic medicines targeting NTRK genetic mutations are being evaluated in trials that use a basket study design, which enrolls participants with different types of cancer that all share a common genetic mutation. Ultimately, adapting clinical studies to personalize treatments makes research more efficient and a better proposition for participants.

Next Step

In my 15 years at Genentech, I’ve had the privilege of working on a number of personalized cancer medicines that each addressed a specific gene alteration in lung, breast or skin cancer. The commonalities between these experiences in different types of cancer have opened my eyes to the power of combining scientific knowledge with advanced diagnostics to truly target the genetic cause of a person’s disease, regardless of where it originated. At the same time, we need innovative clinical trial designs that can bring these new treatment options to patients faster than would have previously been possible.

By going beyond a particular organ or tissue to address the genetic underpinnings of a person’s disease, tumor-agnostic therapies have the potential to offer people with different types of cancer, including those with rare tumor types, a more personalized option. It’s a dramatic evolution that’s helping to redefine the level of personalized care we can bring to people with cancer.