Tackling the 'Common Disease, Rare Mutation' Problem

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Recent cancer research has led to an increased understanding that there are gene changes in cancers that could be the key to effectively killing the tumor.

Such strategies have provided significant gains in several tumor types, as exemplified by chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). In these tumors, the gene mutations are present in almost all of the patients' tumors and use of targeted chemotherapy treatments have provided meaningful benefits. 


Kopetz2.jpg In contrast to these "rare disease, common mutation" examples, results presented at this year's ASCO meeting addressed the similar problem in more common tumor types such as breast, lung and colon cancers.

In lung cancer, treatment with a new drug was very successful in the small percent of patients with a particular genetic change in their tumor (awkwardly denoted the "ELM4-ALK trans-location"). In contrast to the uniform genetic change seen in almost all CML patients, this ELM4-ALK trans-location is only present in less than 5% of lung cancer patients. Similarly, mutations in the BRAF gene in colon cancer (in 5% of tumors) is associated with some sensitivity to a novel BRAF inhibitor, according to the research I presented at the meeting. 

Also at ASCO, MD Anderson investigators reported on mutations in a gene called PIK3CA (present in 2% to 20% of patients), which appears to identify patients sensitive to experimental inhibitors of this pathway. 


While the treatment results in these patients are impressive, the requirement to screen 20 patients to identify one patient who may benefit is a significant logistical challenge. Such efforts require the development of new tests and validation steps to make sure that these molecular changes are accurately identified in patients' tumors. In addition, there are unique problems that arise in this "common disease, rare mutation" scenario. 

Patients are commonly choosing between immediate treatment with standard chemotherapy or waiting several weeks without therapy to see if their tumor is one of the rare ones that may benefit from these novel therapies. At other times, there may not be a sufficient amount of tumor available for testing, requiring patients to undergo additional biopsies to obtain enough material for these increasingly important tests.

In addition, the state of oncology commonly changes faster than insurance companies can keep up. As these molecular tests become part of routine cancer care, reimbursement problems can occur. Even small, preliminary clinical trials require coordination between multiple institutions to successfully identify enough patients. 

At MD Anderson, these challenges are being met through a new Institute of Personalized Medicine, which is developing these new tools necessary for the "common disease, rare mutation" research, and working to minimize these roadblocks to implementation. The goal of such Herculean efforts is to have patients' tumors undergoing screening for many of these genetic changes prior to determining therapies. It is hoped that as such testing becomes commonplace for clinical care, many of these barriers will be reduced.

Ultimately, we believe that surmounting the "common tumor, rare mutation" problems will be the best path forward for improving the collective outcomes of cancer patients.

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