With the genomics revolution, scientists and physicians have increasingly been able to peer at the inner workings of tumor cells and pinpoint the specific genetic changes that transform them from their cells of origin into cancer.
For much of the history of cancer, tumors were characterized mainly by where they arose in the body. With the genomics revolution of recent years, scientists and physicians have increasingly been able to peer at the inner workings of tumor cells and pinpoint the specific genetic changes that transform them from their cells of origin into cancer.
This is the first part of a two-part story. The second part will examine the technology that makes it possible to perform genomic research on large numbers of tumor samples.
What these investigators are learning answers questions that have long puzzled oncologists: Why do some patients with a certain type of cancer do well with treatment, while others receiving the same treatment do poorly? Why does a drug shrink one patient’s tumor but not another’s? Even in the current era of targeted therapies, in which drugs are designed to exploit cancer cells’ specific weaknesses, some patients respond better than others.
“We’ve known for a while that every type of cancer is really a mix of different types,” says Leonard Saltz, Chief of Memorial Sloan Kettering’s Gastrointestinal Oncology Service. “We are getting smarter about starting to break down common cancers into more-specific subgroups so that we can figure out how to develop individualized treatments for patients.”
Advances have been made in collaborative studies, genetic testing, and clinical trials for certain types of lung cancer, colon cancer, melanoma, pancreas cancer, gastric cancer, soft tissue sarcoma, and acute myelogenous leukemia (AML), among others.
A Wealth of Information
Today a major focus of research is on looking for the molecular changes in patients’ tumors and drawing connections between mutations and clinical outcomes. This is possible due in large part to databases that record everything about patients’ treatment and the response to it and link those data anonymously to their tumor samples, which can then be genetically analyzed.
“The strength of the tissue samples that we use in these kinds of studies comes from being able to link them to our clinical databases,” says Murray F. Brennan, Vice President for International Programs at Memorial Sloan Kettering and former Chair of the Department of Surgery, who has dedicated much of his career to developing prospective databases that can be linked to patients’ tissue samples. “In addition to collecting tumor samples, several years ago we also began collecting normal tissue, including blood, from our patients. This allows us to look not only for genetic mutations in the tumors themselves but also for genetic markers in the normal tissue that might indicate that a cancer has an inherited component.”
Improving the genetic understanding of what causes cancer ultimately will lead to treatments tailored to individual tumors. However, “when you look at all the genetic changes in one patient’s tumor, you get so much data that it’s hard to tell which mutations are driving the cancer and which are passengers going along for the ride,” says Samuel Singer, Chief of the Gastric and Mixed Tumor Service. “What helps you sort it out is when you have groups of patients with the same cancer, and you can begin looking for patterns across all of them.”
Many Memorial Sloan Kettering investigators have research projects dedicated to teasing out these molecular differences in a variety of cancers — ranging from common types such as breast cancer and prostate cancer to rarer cancers, such as soft tissue sarcoma and a variety of pediatric tumors.Back to top
The Power of Collaborative Studies
Researchers from Memorial Sloan Kettering are active in several multicenter collaborations that seek to understand the molecular changes that characterize cancer. The largest of these is The Cancer Genome Atlas (TCGA), a project jointly funded by the National Cancer Institute and the National Human Genome Research Institute — both parts of the National Institutes of Health.
Memorial Sloan Kettering investigators have been involved in TCGA from its earliest stages, and Memorial Sloan Kettering currently houses one of TCGA’s Genome Data Analysis Centers, which is co-led by computational biologist Chris Sander and molecular pathologist Marc Ladanyi. Memorial Sloan Kettering researchers have been key participants in several TCGA projects, including detailed characterizations of glioblastoma (a type of brain cancer) and an in-depth analysis of ovarian cancer.
This summer, TCGA reported major analyses of colorectal cancer and squamous cell lung cancer, which makes up about 30 percent of all non-small cell lung cancers. “The colorectal study is the most comprehensive characterization of colorectal cancer to date,” says physician-scientist Timothy A. Chan, who was a key member of Memorial Sloan Kettering’s team on this TCGA project. “This study highlights the benefits that can be afforded by the cancer genomics revolution, allowing us to dissect the molecular foundations of cancers and identify new targets for therapy that were not previously apparent.”
For patients with some types of cancer, genetic testing is already a standard part of treatment. For example, in patients with metastatic colorectal cancer the tumors are routinely tested for mutations in the gene KRAS. Treatment for this advanced form of the disease can include either the drug cetuximab (Erbitux®) or panitumumab (Vectibix®), both of which are antibodies that target mutations in the gene EGFR. However, researchers learned several years ago that for patients who have certain KRAS mutations in their tumors, these drugs are not effective. Testing helps ensure that the drugs are only given to those patients who are likely to benefit, sparing others unnecessary treatment and side effects.
Similarly, the most-frequent mutations in lung adenocarcinoma — another type of non-small cell lung cancer — are in EGFR and KRAS. Patients with tumors that have the EGFR mutation usually respond well to treatment with the targeted therapy erlotinib (Tarceva®). But adenocarcinomas with KRAS mutations are resistant to erlotinib, and patients with tumors that have this mutation are not given the drug.
In gastric cancers (cancers of the stomach and esophagus), researchers have found that some patients’ tumors have multiple extra copies of the gene HER2, a genetic abnormality that is also seen in many breast cancers. Data have shown that the drug trastuzumab (Herceptin®), part of the standard treatment for breast cancer patients whose cancers are found to carry the extra copies of HER2, is effective against this subset of gastric cancers as well. Based on these findings, trastuzumab is now a standard part of treatment for certain patients with gastric cancer.Back to top
Linking Genomics Discoveries to Clinical Trials
Genetic testing in lung cancer is conducted as part of the Lung Cancer Mutation Analysis Project (LC-MAP), which Memorial Sloan Kettering Cancer Center launched in 2009 to look for all known mutations in lung adenocarcinoma tumors. Patients whose tumors have non-EGFR mutations may be offered participation in one of several clinical trials investigating new medicines that target these specific genetic defects.
“As additional mutations are discovered, they can be quickly included in the routine molecular analyses used at Memorial Sloan Kettering,” says Mark G. Kris, Chief of the Thoracic Oncology Service. “At the same time, our investigators continue to probe specimens in which no known mutations were found to look for additional targets.”
Recently, Memorial Sloan Kettering expanded its genetic testing to include tumors from patients with squamous cell lung carcinoma. This testing, which looks for an array of mutations, comes as part of the Squamous Cell Lung Cancer Mutation Analysis Program (SQ-MAP). The project, launched in October 2011, is modeled after the LC-MAP.
This summer, Memorial Sloan Kettering researchers reported that at least one of three cancer-causing mutations is detected in the tumors of more than half of patients with squamous cell lung cancer. Memorial Sloan Kettering patients with tumors carrying one of these specific genetic aberrations are eligible for enrollment in clinical trials to test therapeutic agents. Two trials are already enrolling patients and the third is expected to start soon.
“In just one year, we’ve gone from having zero clinical trials of targeted therapies for our squamous cell lung cancer patients to now being able to offer trials to more than half of them,” says Paul K. Paik, a medical oncologist on Memorial Sloan Kettering’s Thoracic Oncology Service and lead investigator of SQ-MAP.
Dr. Paik says the tumor testing will include more genetic mutations as they are identified, with SQ-MAP using these discoveries to sort patients into clinical trials. Dr. Paik was the key clinical member of Memorial Sloan Kettering’s team in TCGA’s efforts to define molecular changes in squamous cell lung cancer.
Dr. Ladanyi, who worked with Dr. Paik to implement SQ-MAP, explains that the program’s purpose is to ensure that the vast amounts of genetic information generated by TCGA and other research efforts provide real-world benefits for patients. “We don’t want to be telling patients, ‘You have this very interesting mutation, but there’s nothing we can do about it,’” he says. “We want to make sure the genotyping is for mutations that can help oncologists choose the best available therapies for patients, even if some of these new drugs are available only in our clinical trials.”
Genetic testing of patients’ tumor samples can lead to participation in clinical trials for other types of cancer as well. In colon cancer, about 5 percent of patients’ tumors have mutations in the BRAF gene — a mutation also seen in about half of melanoma patients. The drug vemurafenib (Zelboraf®), which Memorial Sloan Kettering played a lead role in developing, was approved by the US Food and Drug Administration last year to treat melanoma patients with BRAF mutations.
While an initial trial of this agent in colon cancer did not work, based on recent findings about BRAF in colorectal cancer, gastrointestinal medical oncologist and scientist Rona Yaeger is developing a clinical trial to evaluate the use of vemurafenib plus panitumumab in colorectal cancer patients with BRAF mutations. Dr. Kris and the thoracic team are also using vemurafenib to treat people with lung cancers that contain the same BRAF mutation.
In two ongoing studies, medical oncologist Eileen M. O’Reilly is testing a class of drugs called PARP inhibitors in certain patients with pancreas cancer. Investigators have noted that some pancreas cancers are associated with alterations in the BRCA and PALB2 genes, inherited mutations that are implicated in some breast and ovarian cancers. PARP inhibitors have already shown promise for treating those cancers, and Dr. O’Reilly’s trials are based on the idea that they could be effective against BRCA- and PALB2-related pancreas cancers as well.
Medical oncologist Yelena Y. Janjigian is evaluating the effectiveness of another experimental drug, called PU-H171, against gastric cancers that are characterized by amplification of the HER2 gene. PU-H171 was developed by Memorial Sloan Kettering chemist Gabriella Chiosis and has been shown in the laboratory to block HER2 and induce cell death (apoptosis). Dr. Janjigian is looking for additional molecular markers beyond HER2 that will help determine which patients are most likely to benefit from the drug before beginning clinical trials.
For soft tissue sarcomas — rare cancers that arise in tissues such as fat, muscles, nerves, tendons, and blood and lymph vessels — Dr. Singer is systematically finding mutations and other changes in tumors. He is also creating cell lines from many tumor samples, which allow him to screen for new drugs that potentially may be effective against subsets of this cancer. “If you have a drug that targets a mutation found in 10 percent or 25 percent of patients, then you can begin to plan clinical trials,” he says.
Several trials are already under way based on the molecular understanding of sarcomas. One tests an investigational drug that blocks a factor called CDK4, which is known to be overactive in liposarcoma, one of the most common types of sarcoma.
Another trial is being planned for the subset of liposarcoma patients who have certain changes in a gene called CEBP-alpha. The gene produces CEBP-alpha, a factor that controls how cells become more specialized, and when deficient it can lead to the development of extremely aggressive tumors. Investigators have found in the laboratory that for cancers with CEBP-alpha deficiency — about 25 percent of one subtype of liposarcoma — a class of drugs called HDAC inhibitors can be effective.
Genomic research is being done not only in solid tumors but also in leukemias. In March 2012, Memorial Sloan Kettering researchers, led by medical oncologist and scientist Ross L. Levine, published a study that identified a set of genetic abnormalities that can be used to more accurately make prognoses in people with acute myelogenous leukemia (AML).
The finding could enable more than two-thirds of AML patients to be stratified into newly defined prognostic groups. This in turn helps clinicians know which subset of patients will actually benefit from intensive therapies such as a higher chemotherapy dose or a bone marrow transplant, and which patients will do well with standard care.
“We are very focused on developing new drugs, but there’s another important area that may grow out of genomics, and that is better methods for prognosis,” Dr. Brennan concludes. “It will be wonderful when we are able to identify patients whose cancers will not recur after surgery and allow them to avoid any unnecessary treatments, as well as the side effects that those treatments can cause.”Back to top