on Friday, May 1, 2009
Using genetic tests to provide a prognosis and tailor treatment is becoming the standard of care for patients with a few forms of cancer.
Using genetic tests to provide a prognosis and tailor treatment is becoming the standard of care for patients with a few forms of cancer. But for most cancer types, personalized medicine is not yet a reality because there is not enough known about the genetic aspects of the disease.
Memorial Sloan Kettering Cancer Center’s Geoffrey Beene Translational Oncology Core Facility was established in 2007 to increase understanding of the genes involved in cancer by taking advantage of the Center’s wealth of tumor samples collected from patients. The samples are anonymously linked to patients’ clinical records, which contain data about whether a tumor responded to certain treatments, whether the cancer recurred or spread, and, ultimately, how long a patient survived. The lab makes it possible to characterize the genomic features of tumors — looking for variations that might be linked to certain clinical responses.
“The Beene core came about because it was becoming abundantly clear that genomic information obtained from tumors held the key for tumor prognosis and predicting the response to treatment,” said Charles L. Sawyers, Chair of Memorial Sloan Kettering Cancer Center’s Human Oncology and Pathogenesis Program (HOPP). Dr. Sawyers was involved in the creation of the facility, along with Adriana Heguy, who runs its operations.
Dr. Heguy collaborates with clinical investigators on their research projects, from the planning stages to the interpretation of data. The facility’s primary function is to extract DNA from tumor samples and amplify it so that it can be sequenced. Robotics and automated equipment make it possible to study hundreds of tumor samples at the same time and look for both common and rare genetic changes. Biostatisticians and bioinformatics experts are also important collaborators.
One challenge the lab has addressed is obtaining good-quality DNA from tumor samples, which are usually fixed with formalin and sealed in paraffin. “Fixing agents degrade the DNA and cut it into small pieces, making it much harder to sequence,” Dr. Heguy explained. Some newer tumor samples are also frozen, which better preserves the DNA, but storage exclusively in paraffin blocks is still considered standard practice at most institutions.
For these fixed DNA samples, a specialized type of mutation detection is needed, using an instrument called a MALDI-TOF mass spectrometer, located in the laboratory of HOPP member Marc Ladanyi. The instrument is operated by Genomics Project Manager Laetitia Borsu. The technique compares the masses of DNA molecules and is used to detect known mutations. For frozen samples with higher-quality DNA, however, genetic sequencing is outsourced to a company using a different technology, which can detect both known and previously undiscovered mutations.
David B. Solit, a medical oncologist and member of HOPP, has collaborated with the Beene core facility on studies of colon cancer, bladder cancer, and melanoma. His research is focused on how mutations in several genes, including Ras and B-Raf, are related to cancer. “We’re finding that the role of Ras mutations in these cancers has been underappreciated,” Dr. Solit explained, “because it had been very difficult to sequence for mutations. The core has allowed us to do a much broader survey than we were able to do in the past. It’s also much less expensive and faster.”
Mary Ellen Moynahan, a researcher and medical oncologist, is studying 590 tumor samples to determine the role that mutations in the PIK3CA gene play in breast cancer. Several studies have indicated that the gene is mutated in 25 to 35 percent of breast tumors, but it is not known whether the mutations are associated with a better or worse outcome for patients.
“Because patients with hormone-receptor-positive breast cancers can experience a recurrence ten or more years after diagnosis, it was important to use tumor specimens linked to longer patient histories. Our paraffin-embedded samples were collected in the 1990s,” Dr. Moynahan explained. “These new methods allow us to ask clinically important questions with small quantities of tumor from older samples.”
“There’s no question that the core has been an unbelievable success,” Dr. Solit said. “In the age of genomic oncology, you have to be able to determine the mutational status of tumors.”
“For people who don’t have their own labs, the core allows them to ask translational questions,” Dr. Moynahan added. “Clinicians understand the potential impact that these studies will have on patient care, and now they have the help and the resources to be able to do this kind of research.”
The Beene core facility is part of the Geoffrey Beene Cancer Research Center at Memorial Sloan Kettering, which was established with a gift from the estate of Geoffrey Beene, the fashion designer and philanthropist. In addition to the core facility, the center provides funding support for several other facilities and programs at Memorial Sloan Kettering.