Monday, May 8, 2017
Memorial Sloan Kettering (MSK) has reached a major milestone in bringing personalized treatments to more cancer patients. Michael Berger, PhD, Ahmet Zehir, PhD, and colleagues have reported an in-depth analysis of the first 10,336 patients whose tumors were submitted for clinical genomic sequencing by MSK-IMPACT™, a powerful diagnostic test developed at MSK to provide detailed genetic information about a patient’s cancer. Their landmark work, published in Nature Medicine, analyzes the central findings in one of the only studies that has evaluated the clinical impact of real-time large-scale tumor sequencing in patients with metastatic cancer.
Building on MSK’s rich history of innovation, a team of nearly 100 MSK researchers reported the results for the first 10,945 tumors that underwent clinical genomic sequencing through MSK-IMPACT™. MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets) detects gene mutations and other critical genetic aberrations in both rare and common cancers. The study found that nearly 37 percent of patients who had their tumors sequenced through MSK-IMPACT™ had at least one actionable mutation, meaning that drugs to target these mutations were available either in a clinical trial or as part of the standard of care. Additional patients harbored mutation profiles suggesting they were more likely to respond to immunotherapy treatment. In addition, the breadth and depth of MSK-IMPACT™ allowed the researchers to detect important genomic alterations that would have been missed by other approaches.
“This study represents the culmination of a major effort and investment in implementing large-scale clinical sequencing of patients at MSK,” says Dr. Berger, Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and senior author of the study. “Now that we have sequenced more than 10,000 patients, we have assembled a data set with enormous opportunities for data mining and discovery. The first 10,000 patients were a big milestone for us, and this paper describes how the tumor sequencing data contributed to these patients’ care.”
Implications for Patients
Based on the study results, 11 percent of patients were able to participate in clinical trials of treatments that directly targeted the genetic alterations in their tumors. MSK-IMPACT™ has helped doctors accelerate the entry of patients into cancer clinical trials, which are crucial to test new therapies.
Collaboration and Data Sharing with Colleagues
All of the data collected through MSK-IMPACT™ testing is being made available to the larger scientific community through a database developed at MSK called the cBioPortal. Patients’ identifying information is removed, but basic clinical data are included, allowing researchers at MSK and beyond to study the connections between particular genomic alterations and the patients’ responses to therapy and their eventual outcomes. In addition to having a leading role in data-sharing initiatives, such as the American Association for Cancer Research’s Project GENIE, MSK has created a number of its own initiatives aimed at increasing DNA sequencing in minority populations and for patients around the world.
MSK also launched the MSK Cancer Alliance in 2014, aimed at improving the quality of care and outcomes for people with cancer in community settings. These are just a few examples of the work being done to break down the silos, increase collaboration and information exchange, and ultimately expand accessibility to new precision treatments. MSK’s exceptionally powerful and seamless integration of clinical and scientific teams makes it uniquely situated to help design the future of precision oncology.
Enrolling Patients in Genomically Informed Clinical Trials
MSK patients increasingly have the opportunity to participate in clinical trials — including basket trials, which target the mutations that drive tumors regardless of where the cancer originated in the body. By sequencing patients’ tumors with MSK-IMPACT™, doctors can accelerate the accrual of patients, which allows for faster enrollment in clinical trials and faster analysis of the results and potentially leads to earlier approval of new therapies.
As evidenced by the establishment of the CMO and the vision of MSK’s Physician-in-Chief, José Baselga, MD, PhD, MSK leadership saw the promise of precision oncology early on and committed to realizing its ability to create better treatment options for all people with cancer. With more than 800 clinical trials currently open, MSK has a strong clinical trial infrastructure. After launching a comprehensive survey and determining that only 4 percent of all patients enroll in clinical trials for cancer each year, the MSK community is actively working to expand enrollment in clinical trials.
“Genomic sequencing is allowing scientists to glean new insights into why some patients respond very well to drugs while others do not. By focusing on so-called exceptional responders, it’s possible to uncover new insights connecting particular gene mutations to drug responses,” says Dr. Baselga, also a study author. “Less than 5 percent of adults with cancer in the United States enroll in clinical trials. This means that many trials take longer to perform due to slow patient accrual, which in turn means it takes longer to test a drug’s efficacy. MSK-IMPACT™ is designed to address this problem.”
The MSK-IMPACT™ Team
MSK-IMPACT™ sequencing has been approved by the New York State Department of Health as a clinical test and is performed in the clinical laboratories of the MSK Molecular Diagnostics Service, led by Marc Ladanyi, MD, who played a key role in implementing MSK-IMPACT™ sequencing clinically and who oversees this effort together with Maria Arcila, MD. In MSK-IMPACT™, both the tumor sample and a normal sample from the same patient are sequenced in each case.
This is done to identify genetic differences between the two in order to pinpoint the cancer-causing mutations, but it also provides valuable information about inherited mutations that may increase the risk for cancer development. Detecting inherited mutations can allow doctors to more closely monitor the organs in which cancer may arise, and it offers the opportunity for the patient’s family to be tested for the mutation and screened for earlier cancer detection if they also carry the same mutation.
The MSK-IMPACT™ team includes molecular pathologists, clinical bioinformaticians, genomic technology scientists, genomic variant curators, and highly specialized clinical technologists working together to ensure that the most accurate and clinically useful information is obtained through this clinical tumor sequencing program, possibly the largest of its kind anywhere.
“As we pass this important MSK-IMPACT™ milestone, I think we are well on our way to establishing a new paradigm for cancer care,” says Dr. Ladanyi, also a study author. “As part of the standard initial assessment of cancer patients, we can now not only identify the exact type of cancer and how far it has spread but also determine the mutations that drive the cancer cells to divide. Knowing the genetic makeup of the patient’s cancer now helps us select the drugs most likely to be effective in that patient.”