A complex interplay of molecular alterations was associated with exceptional responses to anticancer treatment among patients with various types of solid tumors, according to the results of a study from the National Cancer Institute (NCI) Exceptional Responders Initiative.1

“We’re curious to understand why exceptional responses happen, and eager to learn as much as we can from these patients,” Louis Staudt, MD, PhD, coleader of the study and director of the NCI’s Center for Cancer Genomics, told Cancer Therapy Advisor.

Exceptional responses — defined as responses that occur when a partial response (PR) or complete response (CR) is expected in less than 10% of patients treated, or a response that lasts at least 3 times longer than the median — are rare.1 The mechanisms underlying such responses are unknown, but experts hypothesize that exceptional responses are a result of oncogene addiction, genomic alterations in specific signaling pathways that control functions critical to the malignancy, or changes that promote immune system recognition and elimination of tumor cells.

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The present study aimed to identify the molecular mechanisms responsible for exceptional responses to anticancer treatments. “As clinical researchers, we have a lot to learn from these patients, and they have a lot to teach us,” Percy Ivy, MD, coleader of the study and associate chief of the Investigational Drug Branch of the NCI’s Division of Cancer Treatment and Diagnosis, said in a press release.2

“We wanted to understand why exceptional responses occurred in the cases that they did, and what role their genetic makeup had in [these responses], so that we can be smarter about cancer and develop combination therapies to build on that knowledge in the future,” Dr Staudt said.

Rationale and Approach

The NCI Exceptional Responders Initiative was developed based on several proof-of-concept studies published in the early to mid-2000s.3 One of these studies established that genomic alterations could explain an exceptional response.4 In this study, whole-genome sequencing of tumor DNA  from a patient with metastatic bladder cancer identified multiple nonsynonymous mutations. The patient achieved a CR on everolimus therapy that lasted at least 2 years, representing an exceptional response that was traced to mutations in TSC1 and NF2, a combination associated with enhanced sensitivity to mTORC1 inhibition in vitro. Results from several other studies have suggested that molecular mechanisms may play a role in exceptional responses.4

The NCI launched the Exceptional Responders Initiative to genotype tumors from patients who experienced exceptional responses, with the hope of discovering new pathways to inform the development of novel anticancer therapies. Clinicians from NCI-supported and non–NCI-supported institutions could submit cases to the Initiative.4 Cases were accepted if they met the criteria for an exceptional response and had pretreatment tumor tissue available for analysis. 

The present study included 111 patients from NCI-supported clinical trial sites with a range of tumor types that affected the brain, breast, lung, liver, endometrium, and gastrointestinal tract.1 The PRs and CRs achieved were, in most cases, highly durable, with a range of 6 to 145 months. Multiple platforms were used to assess genetic and epigenetic aberrations including mutations, copy number changes, aberrant methylation, outlier gene expression, and the molecular and cellular makeup of the tumor microenvironment.