Oncology Central

The Rare Tumor Initiative in the National Cancer Institute: Harnessing expertise and existing resources to better develop therapies for rare tumors



Rare cancers in the United States have been defined as those cancers for which the incidence rate is less than 15 cases per 100,000 population or fewer than 40,000 new cases per year [1]. While the incidence of any one rare cancer may be small, they collectively account for 27% of neoplasms diagnosed each year, and are responsible for 25% of cancer-related deaths in the United States [1].

Rapid technological advances have allowed cancer characterization to move beyond histology to detailed mutational analysis at the molecular level. The rapidly changing diagnostic landscape will likely increase the numbers of cancers considered to be ‘rare’ as mutational analyses identify rare molecular subtypes of ‘common’ cancers. This is already happening in common cancers such as non-small-cell lung cancer, with approximately 2–7% of these cancers found to be harboring mutations in the ALK gene [2]. With the Surveillance, Epidemiology, and End Results Program reporting an overall non-small-cell lung cancer incidence rate of approximately 41 in 100,000 individuals, the incidence rate of ALK-mutated non-small-cell lung cancers qualifies these as rare cancers [2, 3]. Although therapies targeted to ALK-mutated non-small-cell lung cancer are showing promise [3], treatments for many rare cancers are sorely needed. We review here the difficulties in developing treatments for rare cancers and describe a new Rare Tumor Initiative (RTI) in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI).

Clinical and basic research challenges in rare tumor research

Rare diseases present several challenges to researchers working to develop therapies.

Establishing clinical disease expertise:

Even large academic centers may not see enough patients with exceedingly rare tumors to establish broad expertise in the pathogenesis, clinical presentation, natural history, diagnosis, and best management of very rare tumors. Without an understanding of how the disease progresses it is difficult to counsel patients and their families, as well as to determine the most robust endpoints in clinical trials.

Understanding the basic biology and identification of targets for therapy:

An in-depth basic understanding of rare tumors requires access to tumor samples and other biologic specimens from as many patients as possible to study molecular and genomic alterations. Because patient samples come from heterogeneous genetic backgrounds, it is difficult to identify tumor drivers without studying sufficient samples for statistical analyses. Inability to collect sufficient high-quality samples can negatively impact progress in learning about the basic biology of rare tumors.

Developing robust models for drug screening:

Patient samples are also needed to establish cultured cell lines or patient-derived xenografts for testing potential therapeutics. Candidate molecular drivers can be harnessed to develop genetically engineered mouse models to further study tumor biology and test candidate therapies. Without patient samples and knowledge of molecular drivers of tumorigenesis, preclinical testing of therapies becomes severely limited, if not impossible.

The development and conduct of clinical trials for very rare tumors:

The development, timely enrollment, and completion of clinical trials for very rare tumors is challenging due to the need for participation by multiple national and potentially international sites, which may be associated with logistical difficulties and specific regulatory requirements. Robust clinical endpoints are needed to allow results to be analyzed from small numbers of patients.

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