Molecular Profiling Continues to Shape the Future of Cancer Care

Philadelphia and Fox Chase Cancer Center were at the center of the discovery in 1959 by David A. Hungerford and Peter C. Nowell of the tumor-specific genetic structure named “Philadelphia Chromosome.” This was the first consistent chromosomal abnormality associated with neoplasm - in this case, chronic myeloid leukemia (CML) - and paved the way for decades of discovery in molecular cancer profiling and targeted therapeutics. 

Today, Fox Chase continues to push the boundaries of molecular profiling by offering access to a wide spectrum of molecular profiling technologies, novel therapeutics, and the latest clinical trials. 

“The optimal diagnosis of cancer and subsequently, therapy, should be based on the biology of the malignant cells and on the pathogenesis of the disease,” said Mariusz A. Wasik, MD, Chair of the Department of Pathology at Fox Chase. “Both will gradually become highly specific for individual patients.” 

Dr. Wasik said that the paradigm shift that has occurred in the approach to managing cancer has led to a reinvention of medicine at the molecular level. 

The diagnosis and treatment of CML is the earliest and most well-known example of this reinvention. The discovery of the Philadelphia Chromosome led to the identification of the translocation involving chromosomes 9 and 22 and the novel fusion kinase BCR-ABL, which eventually led to a therapeutic inhibitor of BCR-ABL. 

Since then, many other powerful oncogenes have been identified and continue to be identified, any of which may alter the management of a malignancy. 

“In the last 10 to 15 years there have been significant changes in the ease of running these tests, in the cost of running the test, in the information that we get from it, and what we can do with that information,” said Efrat Dotan, MD, Chief of the Division of Gastrointestinal Medical Oncology at Fox Chase. “It has really changed how we think about treating patients.”

In gastrointestinal cancers, there is a battery of genes that clinicians must know the mutation status of - or the expression of those markers - to effectively recommend therapy. 

One of the most exciting areas of recent progress in gastrointestinal cancers has been the identification of actionable genetic alterations with fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements in patients with intrahepatic cholangiocarcinoma, Dr. Dotan said. The development of FGFR inhibitors has provided patients with a promising new class of agents to target the disease.

“About 10 percent to 15 percent of patients with intrahepatic cholangiocarcinoma have an FGFR2 fusion that can be treated with an FGFR inhibitor in a form of a pill. This drug was recently approved, providing patients with new treatment options and markedly improved outcomes,” Dr. Dotan said. 

In the diagnosis of lung cancers, molecular profiling has allowed clinicians to view entities like non-small cell lung cancer (NSCLC) as multiple diseases with various molecular markers. Within NSCLC, clinicians have eight or nine molecular targets with FDA-approved therapeutics. 

“The story in lung cancer is becoming even more interesting because up to just about a year and a half ago, we were offering molecular testing for everybody with metastatic disease,” said Hossein Borghaei, DO, MS, Chief of the Division of Thoracic Medical Oncology at Fox Chase. “Now, we have approval for a frontline treatment for the EGFR subtype, so molecular testing is moving to an even earlier stage of treatment.”

Lung cancer is also an important example of the use of re-biopsy and testing at the time of progression, which is completed in the majority of patients, Dr. Borghaei said. 

“This can be done with liquid biopsies using blood samples,” Dr. Borghaei said. “In the case of EGFR, for example, we re-biopsy because there is a slight chance of transformation to the more aggressive small cell lung cancer, or it could identify resistance mechanisms that can be targeted with a different targeted therapy.”

One exciting new area in lung cancer is the identification of the neuregulin-1 (NRG1) fusion protein, which is identified using RNA testing and points to the complexity of identifying relevant molecular alterations. 

“Even for something as rare as an RNA fusion panel target found in only one to two percent of patients, that percentage of patients can truly benefit from a targeted therapy,” Dr. Borghaei said. “We owe it to patients to do everything possible to identify these alterations to offer them the best possible treatment option.”

In a disease entity like gastrointestinal stromal tumor, where mutations in KIT or PDGFRA account for about 85% of cases, a next-generation sequencing analysis can provide important additional information.

“An easy test like immunohistochemistry will show you positivity for expression of KIT at the protein level, but that expression doesn’t tell you anything about the underlying mutation,” said Margaret von Mehren, MD, Chief of the Division of Sarcoma Medical Oncology at Fox Chase. “There can be other mutations like BRAF or SDH expression that might be targetable. In addition, for other soft tumor sarcomas, we often will do whole genome sequencing to see if we can identify something targetable that we might not have thought about that could make a patient eligible for a clinical trial.”

This type of thorough testing is one thing available at academic medical centers like Fox Chase that patients may not have access to at a community center. 

“These tests don’t just identify what patients are positive for, but also what they are negative for,” said Henry Chi Hang Fung, MD, FACP, FRCPE, Chair of the Department of Bone Marrow Transplant and Cellular Therapeutics. “The speed and quality of the tests are important, as is having a molecular pathologist able to interpret the results.”

This is true not only for patients who are already diagnosed with cancer but for those who may be at high risk for cancer being tested for germline mutations. 

“For patients who may be at high risk for cancer, we collect their normal DNA from lymphocytes through a blood draw, and we look for variability in particular cancer risk genes in their genome that has been associated with increased cancer risk,” said Michael J. Hall, MD, MS, Chair of the Department of Clinical Genetics. 

Fox Chase currently has a variety of programs designed to help screen people at high risk, including its Risk Assessment Program Registry, the Prostate Cancer Risk Assessment Program (PRAP), the Philadelphia Breast Cancer Family Registry, and research into chemoprevention for Lynch syndrome. 

“We will be one of four sites - and the only site in the Northeast - in a national/international clinical trial testing a frameshift vaccine developed for cancer prevention in Lynch syndrome,” Dr. Hall said. “Funded by the NCI, this study will recruit patients with Lynch syndrome to receive two doses of a frameshift vaccine developed to enhance the immune responses in Lynch syndrome patients to early cancers.”

Many patients can potentially benefit from targeted therapies chosen on the basis of the results of molecular profiling, Dr. Fung said. 

“These tests help not only with diagnosis, but risk stratification and specific treatments,” he said. “Fox Chase is working to continue to provide more information to our patients so that we can help get an accurate diagnosis and treatment, and improve outcomes.”