Precision oncology — also known as genome-based oncology or personalized cancer medicine — is based on the idea that once we understand the genetic alterations that drive cancer cells to grow and spread, we can develop drugs to target them. Memorial Sloan Kettering has been a leader in the field by bringing together lab researchers and clinicians to focus on developing innovative ways to improve care for patients.
The concept seemed wildly futuristic as recently as two decades ago. Now, tens of thousands of people with cancer every year are benefiting from treatment with targeted therapies, which provide more-effective control of tumors while avoiding many harmful side effects common to more-traditional cancer treatments.
“Using precision oncology in cancer patients is an attractive strategy,” says Barry Taylor, Associate Director of MSK’s Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO). “But it’s difficult, and there are great challenges. We’re really only at the end of the beginning in this process.”
These challenges are twofold: They’re scientific, as the genetic complexities of cancer are not completely understood; and societal, as currently only a small percentage of cancer patients have access to genetic testing and clinical trials.
Dr. Taylor — along with MSK’s Physician-in-Chief José Baselga and Director of Developmental Therapeutics David Hyman — this week published an article in the journal Cell highlighting some of the many accomplishments in the field of precision oncology to date and acknowledging the barriers still to be overcome.
A State of the Union for Oncology
“This report is like a State of the Union for genome-based oncology,” Dr. Baselga explains. “It’s an in-depth description of where the field is today and where it’s going. MSK has been engaged in precision medicine for longer than most institutions, and we’re probably leading more clinical trials in this area than any other center.”
The CMO, which was established in 2014 and is just one reason that MSK is at the forefront in this field, aims to identify the functional significance of genetic alterations in tumors so that people with cancer can receive the most individualized treatments. MSK’s Human Oncology and Pathogenesis Program (HOPP), established eight years prior, brings together basic and clinical research, with the goal of bringing what happens in the lab into the clinic.
MSK’s researchers have also created a genetic sequencing test called MSK-IMPACT, which looks for mutations in more than 400 genes that are known to play a role in cancer. This test is currently offered to all patients with advanced cancers, and the findings from it can help shepherd patients into clinical trials for drugs that are based on the unique characteristics of their tumors. MSK currently has about 30 clinical trials under way that assign patients to targeted therapy based on the results from MSK-IMPACT.Back to top
Addressing the Challenges
Despite the value in identifying which mutations are responsible for a cancer’s growth and spread — an aspect of precision medicine that MSK and many other institutions are getting better and better at doing — this is only part of the battle. Just because we know what causes a tumor to grow doesn’t mean drugs are available to fix the problem.
Even for mutations that have effective drugs available, challenges remain. For one thing, tumor cells often evolve and develop resistance to the drugs that once worked against them, much like bacteria develop resistance to antibiotics. More research is needed to determine how this process occurs, and how new drugs can be developed to combat it.
Another aspect of tumor biology that makes precision medicine difficult to carry out is what is called tumor heterogeneity. This means that not all areas of a tumor have the same mutations; therefore drugs that are very effective at destroying one part of a tumor may have no effect on another part, which greatly reduces the chances that it can be completely eliminated.
Precision medicine is changing the way that many clinical trials are conducted.
MSK is already set up to address these challenges through “the integration of our scientific and clinical missions,” Dr. Taylor says. “We have an enormous multidisciplinary team and an institutional commitment to building the infrastructure that’s needed to move this work forward. We’ve already removed many of the barriers to moving new treatments into clinical trials and collecting as much data as we can on those patients so that others can benefit in the future.”
Because of the high volume of patients that MSK treats, both those with common cancers and those with rare ones, “we’re able to identify large populations of patients with specific mutations very rapidly,” Dr. Taylor says. “This is the first step in designing these kinds of studies in which you are targeting a particular mutation with a particular therapy.”Back to top
Focus on Clinical Trials
One aspect of precision medicine that MSK has been focused on is improving access to clinical trials. “We’ve opened up studies to patients at our MSK Cancer Alliance partners, and we’ve expanded our genetic sequencing out to those centers,” Dr. Hyman says. “This program is just starting, but the number is increasing.”
“If an MSK Cancer Alliance site does its own genetic testing, we will open our studies to them so that they can enroll their patients,” he adds. “If they don’t do their own testing, we can analyze patients’ samples for them.”
Another area in which MSK has been at the forefront is expanding precision medicine trials to pediatric patients.
“Pediatrics is an underserved patient population as far as trials, but we’ve been aggressive about lowering the age of eligibility so that younger patients can benefit from these new drugs sooner,” Dr. Hyman says. “In the past there have been ethical and safety concerns about conducting trials in children, but we think the best way to protect children is to give them access to the same drugs that our adult patients have.”
He notes that for drugs that don’t have available trials, pediatric patients may be able to get access to them through compassionate-use or expanded-access programs.
Overall, the way clinical trials are being conducted is changing. The traditional three-phase structure is less important in an era in which a drug’s activity and effectiveness can be determined right from the beginning. “Some drugs are going right from phase I or phase II to approval,” Dr. Hyman says.
Drug development is not going to be easy, Dr. Baselga says. “It’s not going to be one-size-fits-all. It’s going to be one gene at a time and one disease at a time. But more and more stories are coming out of these trials about patients whose cancer has been eliminated by some of these new drugs.”Back to top
Going Beyond Genetic Analysis of Tumors
Another area that MSK is also focused on is the analysis of mutations in the DNA code. “We need to go beyond genes and look at things on the epigenetic level,” Dr. Baselga says. (Epigenetic changes affect which genes are activated to make proteins, without changing the genes themselves.) Investigators are developing new ways to analyze proteins in tumors to look for these kinds of changes.
MSK researchers are also looking at new ways to obtain genetic material to study. One of these methods involves isolating cell-free tumor DNA, which is found in patients’ blood. This technology, sometimes called liquid biopsy, would enable doctors to monitor patients’ disease by analyzing their blood, rather than repeatedly having to conduct biopsies. It’s expected to provide new insight into how patients respond to targeted therapies, and how resistance develops.
One of the biggest challenges facing precision oncology and the cancer community is the sheer volume of data. Many efforts are now focusing on ways to aggregate findings from genetic studies and pooling the insights gained from clinical trials. One of these is AACR Project GENIE, a multicenter effort being coordinated by the American Association for Cancer Research, to which MSK has been the principal contributor.
Experts say that better data sharing will improve clinical decision-making and provide new information for diagnosis and treatment. Large compilations of data not only serve as a tool for cancer researchers around the world but also help to inform treatment decisions in community oncology centers.
“MSK has been an early adopter of many of the approaches to analyzing these kinds of data, and an important part of data-sharing initiatives,” Dr. Taylor says. “I firmly believe that these technologies should be democratized to all patients, and sharing our data and analysis is an important part of that.”Back to top