Outliers Join the Research Fold: Technological Advances Spark Initiatives to Study Exceptional Responders

Jane de Lartigue, PhD
Published: Thursday, Nov 20, 2014
MicroscopeDespite numerous reports of “miracle cures” for a select few patients treated with a variety of different anticancer therapies, drugs that failed to show improvement for a large number of patients have historically been considered failures and have been shelved.

Now, major advancements in our ability to more readily and affordably perform genome sequencing on biopsied tumor samples are leading researchers to revisit the idea of exceptional responses and uncover the molecular mechanisms underlying them.

In September, the National Cancer Institute (NCI) launched an initiative to gather and analyze tissue and clinical data about exceptional responders from patients treated during studies of experimental therapies, in standard therapy settings including community practice, and from pharmaceutical industry studies.

“The increasing ability of molecular technologies to stratify tumor types by prognosis or response to treatment will result in many common cancers being separated into specific subtypes that may respond to drugs in very different ways,” Barbara A. Conley, MD, of the NCI’s Division of Cancer Treatment and Diagnosis and co-lead investigator for the study, said when the agency announced the project.

At the very least, these analyses will broaden our understanding of the complex biology underlying tumor development and evolution. Many are hoping that it may prove to be a source of novel therapies and even serve as a revival for failed therapies in tumor types in which they had previously been written off.

Technology Spurs Interest

According to the current paradigm of cancer drug development, successful therapies are those that are broadly active, helping the largest number of patients, and clinical trials accordingly focus on seeking out the best responses. Yet, time and again, oncology clinical trials are peppered with reports of anomalous patients who staged a spectacular recovery.

In fact, it’s estimated that between 1% and 10% of patients are so-called exceptional responders, a subpopulation for which the NCI has developed a specific definition (Figure 1). Such patients are often heavily pretreated individuals who demonstrate remarkable and, in many instances, durable control of their cancer. With no way to decipher the molecular meaning behind these responses, researchers discounted these individuals as statistical outliers and there was little interest, particularly for pharmaceutical companies, in pursuing these anecdotal outcomes further.

Defining an Exceptional Responder


In recent years, the oncology field has come to appreciate the significant heterogeneity among tumors, even between those that are morphologically indistinguishable, and to recognize that a spectrum of therapeutic responses is to be expected. Understanding this variability may present a unique opportunity to unravel novel molecular mechanisms of sensitivity to anticancer therapies and improve our understanding of the biology of cancer to provide better therapies and diagnostics.

Early Cases Indicate Potential

Among the first to pursue the sequencing of exceptional responders were researchers at Memorial Sloan Kettering Cancer Center (MSK). In an overall negative phase II trial of the mammalian target of rapamycin (mTOR) inhibitor in metastatic bladder cancer, everolimus (Afinitor), there was one patient with an exceptional response— a complete disappearance of her cancer within 3 months and a continued response after 4 years of treatment.

The researchers at MSK performed whole-genome sequencing on her tumor biopsy and discovered more than 17,000 genetic aberrations that were not present in her normal cells. Among them were mutations in the tuberous sclerosis 1 (TSC1) and neurofibromin 2 (NF2) genes. Both of these mutations lead to activation of the mTORC1 component of the mTOR protein complex, which is the target of everolimus. Thus, researchers hypothesized that these mutations made the cancer cells dependent on the mTOR pathway and sensitized the tumor to mTOR inhibition.

Studying exceptional responders can be particularly helpful in identifying potential novel therapies for patients with tumors that are more rare and harder to characterize.

Vivek Subbiah, MD, an assistant professor at The University of Texas MD Anderson Cancer Center, described a striking response that one of his patients experienced after receiving sorafenib-based therapy for a difficult-to-characterize tumor that was being treated like a conventional sarcoma.

Using next-generation sequencing (NGS), the researchers were able to identify a unique fusion protein, as well as loss of the tumor suppressor protein phosphatase and tensin homolog (PTEN).

“This was the first report of a patient with that kind of tumor responding to sorafenib-based therapy,” Subbiah said in an interview with OncologyLive. “This may be extremely rare, this may be an ‘N of 1’ study, but for the next patient with a similar aberration we can probably offer the same targeted agents.”


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