Personalized Diagnostics and Targeted Therapies
The Philadelphia Chromosome provided the first evidence that genetic abnormalities were linked to cancer. This discovery at Penn more than 50 years ago ushered in the modern period of cytogenetics. Now, the Center for Personalized Diagnostics (CPD), founded in 2012, builds on this legacy and is set to pave the way for a new era of genomic and therapeutic pathology.
- A CAP/CLIA certified clinical laboratory for high throughput, next-generation DNA sequencing and other genomic analyses to provide diagnostic tests to clients within and beyond Penn Medicine
- A clinically oriented research group with a focus on developing new tools for personalized diagnostics, new methods for data analysis, particularly of the large volumes of data derived from massively parallel "-omics" technologies, and on collaborating to gather data correlating diagnostic information with patient outcomes
- A test development laboratory for generating additional clinical diagnostic tests that fall within the realm of personalized medicine in order to translate research into the clinical environment
- A clinical and translational education service for trainees as well as established pathologists and clinicians to guide them through this highly complex, rapidly evolving field and to aid in the understanding and implementation of genomic medicine
Current Test Panels
Cancer is fundamentally a disease of the genome. Genome-guided mutation detection can empower the medical oncologist to select cancer treatment therapies specific for tumors harboring these mutations. While a mutation may only be detected in a small subset of individual cancers, taken together, these mutations are not rare and specific molecular changes exist in all cancers.
The Center for Personalized Diagnostics currently offers two different cancer gene-sequencing panels:
- A custom hematologic malignancy panel, focused primarily on AML, MDS and CLL
- A more comprehensive solid tumor panel, containing 47 genes known to be mutated in a wide range of tumor types
Custom Hematologic Malignancy Panel
The primary focus of the first version of the hematologic malignancy panel is on acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). The AML, MDS, and CLL targets were chosen because of the extensive data in the literature on the molecular characterization of these tumors. Within this panel, there are genes that are:
- Predictive of outcome (for example, NPM1, IDH1 are good prognostic markers)
- Useful for chemotherapy decisions (for example, DNMT3A mutation detection can direct Daunorubicin dosage)
- Able to identify mutations linked to targeted therapies (ABL1 amplification and treatment with Imatinib, BRAF mutations and treatment with Vemurafenib)
- Not responsive to treatment (for example, ASXL1 is associated with a very poor outcome with conventional treatments). In such instances, tests may help determine if there are clinical trials that would be more useful
Taken together, the information provided by the sequencing of large panels has the potential to modify the diagnosis, with subclassification of the tumor or detection of secondary underlying malignancies, by yielding an oncologic profile based on the underlying genetic changes.
In turn, these characteristics will allow oncologists to integrate their knowledge of the patient with the disease, mutation profile and other laboratory testing to establish a personalized treatment plan for each individual patient.
Comprehensive Solid Tumor Panel
The vast majority of cancers are solid tumors, that is, non-hematological (blood or bone marrow) malignancies. Solid tumors typically present as a mass of cancer cells either within a specific organ or throughout the body as metastases.
Virtually every organ in the human body can develop cancer. Solid tumors can be difficult to treat if they are metastatic or inoperable. Because of this, the genetic characterization of tumors through personalized diagnostics can be extremely useful in determining the appropriate chemotherapy.
For example, lung cancer has revealed a wide range of genetic changes that have helped clinicians to treat subsets of their patients with targeted, individualized therapies.
First, mutations in the epidermal growth factor receptor (EGFR) were detected in approximately 15-20% of patients with adenocarcinoma of the lung. A targeted cancer therapy, Gefitinib or Erlotinib, can be selected by medical oncologists as a specific treatment option for patients with this mutation. More recently, chromosomal rearrangements of ALK and ROS1 in adenocarcinomas of the lung have been identified in small subgroups of patients, who can be treated with Crizotinib.
At the same time, there are many additional genetic mutations in lung cancer that occur in low percentages of individuals, but for which targeted therapies exist—including ERBB2 (Trastuzumab), BRAF (Vemurafenib), and PIK3CA (currently multiple inhibitors in clinical trials).
The ability to diagnose the underlying architecture of a tumor through massively parallel genome sequencing means that a single test can profile the tumor for all its known actionable and prognostic markers.
Translational Test Development
As the genomic revolution continues to uncover novel mutations in a variety of biological genes and pathways, the Center for Personalized Diagnostics (CPD) is actively engaged in new test development and is prepared to add new clinically useful markers to future versions of gene panels for both leukemias and solid tumors.
Additionally, validation is underway to expand sequencing to the entire coding region of the genome (exome) in order to identify truly personal mutations that may be affecting key biological pathways.
The CPD will also serve as a cancer research center to detect clinical correlations for treatment and outcome, with the goal to identify prognostic markers for future diagnostic and treatment options. Interested researchers should contact the CPD technical director.
The CPD Team
The concept of cancer as a genomic disease has been clear since 1960, when Peter Nowell, from the University of Pennsylvania, and his graduate student David Hungerford identified an abnormal chromosome (the Philadelphia chromosome) associated with chronic myelogenous leukemia (CML). Amazingly, the first targeted therapy for cancer, Imatinib, was later developed around the Philadelphia chromosome and its targeted fusion gene product BCR-ABL1 as well.
Targeted therapy can be categorized into small molecules and monoclonal antibodies. Small molecules are chemicals that block the growth of cancer cells, often by mimicking a substrate, which blocks the active site in the molecule. Some examples of small molecules in cancer include imatinib mesylate (Imatinib), commonly used for CML, gastrointestinal stromal tumors, as well as some other tumors and erlotinib and gefitinib, which are targeted against EGFR mutations in lung and pancreatic adenocarcinomas.
There are also monoclonal antibodies that target specific genetic changes in tumor cells. An example of a monoclonal antibody that has altered disease outcome is trastuzumab, which targets ERBB2 (also known as her2/neu) that is expressed in some breast cancers and some lung adenocarcinomas. The promise of trastuzumab as a targeted therapy that can both treat advanced cancer and prevent its development or reoccurrence traces its origins to the pioneering contributions of Dr. Mark Greene, now a University of Pennsylvania faculty member in the Department of Pathology and Laboratory Medicine. The Center for Personalized Diagnostics at the University of Pennsylvania builds on this legacy of personalized medicine.
David B. Roth, MD, PhD, FCAP
Acting Director, Center for Personalized Diagnostics
Dr. Roth is the Simon Flexner Professor and Chair, Department of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, and Acting Director of the Center for Personalized Diagnostics. Previously he was the Irene Diamond Professor of Immunology and Chair of the Department of Pathology at NYU Langone Medical Center.
Dr. Roth earned both his MD and PhD degrees at Baylor College of Medicine in Houston before he became an HHMI post-doctoral research fellow at the National Institutes of Health. He has held faculty positions at Baylor and the NYU Skirball Institute of Biomolecular Medicine. A frequent recipient of support from the NIH, Dr. Roth's research and clinical interests are genome instability in cancer and whole genome sequencing of lymphomas.
Jennifer Morrissette, PhD
Clinical Director, Center for Personalized Diagnostics
Dr. Morrissette is a dually board certified clinical molecular geneticist and clinical cytogeneticist through the American Board of Medical Genetics (ABMG) and the Scientific Director of the Clinical Cancer Cytogenetics Laboratory in the Department of Pathology and Laboratory Medicine of the Perelman School of Medicine at the University of Pennsylvania.
She received her PhD in Molecular Genetics from the State University of New York at Buffalo and completed a Postdoctoral Fellowship in Molecular Genetics at Harvard Medical School and a Fellowship in Clinical Cytogenetics at The Children's Hospital of Philadelphia.
CPD Staff Members
- Alan Fox, Technologist
- Barnett Li, Technologist
- David Lieberman, Genetic Counselor
- Shrey Sukhadia, Data Analyst
CPD Resources and Selected Publications
- Zhang L, Znoyko I, Costa LJ, Conlin LK, Daber RD, Self SE, Wolff DJ. Clonal diversity analysis using SNP microarray: a new prognostic tool for chronic lymphocytic leukemia. Cancer Genet. 2011 Dec;204(12):654-6. doi: 10.1016/j.cancergen.2011.10.012
- Segal JP, Aikawa V, Daber R, Morrissette JJ. Array Cytogenomics as a Diagnostic Aid for Acute Myeloid Leukemia: A Comparison of Four Different Platforms. Association for Molecular Pathology, Annual Meeting Abstracts. J Mol Diagn. 2011 Nov;13(6):730. doi: 10.1016/S1525-1578(11)00254-6
- Download AMP Meeting Abstract (PDF)
- Wertheim GB, Daber R, Bagg A. Molecular Diagnostics of Acute Myeloid Leukemia: It's a (Next) Generational Thing. J Mol Diagn. 2013 Jan;15(1):27-30. doi: 10.1016/j.jmoldx.2012.08.002