October 15, 2014 (Vol. 34, No. 18)

Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Hope for Better Cancer Treatments May Lie in Those Patients Who Respond Exceptionally Well

We have all heard stories about the single patient who survives a deadly cancer in response to a particular drug, in contrast to other patients receiving the same drug who succumb to the disease.

These patients may include heavily pretreated cancer patients for whom other drugs have failed, but then who respond to a therapy not typically used to treat their type of cancer. Now, with novel genomics tools at their disposal, investigators say that by analyzing the drug responses of “n-of-1,” patients who are single outliers in clinical studies, new insights into cancer mechanisms and more effective treatments can be gained. 

The National Cancer Institute (NCI) is currently funding research to take such “super responder” patients out of the realm of the anecdotal to identify more patients who could respond to life-saving treatments but for whom it would have been unexpected.

While definitions of “exceptional responder” tend to move around a bit, the NCI defines these individuals as cancer patients who had a complete response or partial response for at least six months to treatment in a clinical trial in which less than 10% of patients responded. Thus far, about 100 exceptional responders have been identified by researchers poring through about 10 years of clinical trials, said Barbara Conley, M.D., associate director of the NCI’s Cancer Diagnosis Program.

The NCI is recruiting stories, tissue samples, and clinical data from up to 200 such individuals to find out how these patients benefited from drugs that failed most others. As Charles Sawyers, M.D., a cancer researcher at the Memorial Sloan-Kettering Cancer Center in New York and proponent of the approach, said in Nature, the idea initially met with some resistance. “It’s in vogue to talk about your n-of-1 study now,” he said. “But when I was in medical school this was called an anecdote—and it was a bad word.”

The NCI project will, given adequate tissue samples, perform whole-genome sequencing and repeated reads of the whole “exome”—the one percent of human DNA that is translated into protein sequences. 


The NCI is funding research to determine whether outliers from failed clinical trials can reveal hidden drug development possibilities. [francisblack/IStock Photos]

A Chaotic Brew

NCI’s Dr. Conley says both whole-genome and exome sequencing are required because cancer cells, even within a single tumor, often have a “hodgepodge” of mutations. Re-doing whole-exome sequencing dozens of times captures most of the significant genetic variation in one tumor, and it’s more practical than trying to sequence the whole genome over and over.

The investigators will also analyze RNA expression to provide a measure of which genes are expressed and how much protein they’re producing.

According to John Mendelsohn, M.D., co-director of the Institute for Personalized Cancer Therapy and former president of the MD Anderson Cancer Center, oncologists now recognize cancer as a “chaotic brew” of genetic rearrangements, mutations, deletions, and amplifications. When epigenetic influences on gene expression and evolution under therapeutic pressure are added to the mix, the recipe for devising effective treatments becomes considerably more complicated, he said.

David Solit, M.D., director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering. along with collaborators at the Weill Cornell Medical Center and New York Genome Center, will expand their program of integrated next-generation sequencing analyses of responding patients either enrolled in Phase I/II clinical trials or treated with standard systemic agents at Memorial Sloan Kettering and Weill Cornell.

Dr. Solit and his colleagues have been credited with “turning on the lightbulb” and encouraging funded programming to analyze outlier patients by James Doroshow, M.D., director of the Division of Cancer Treatment and Diagnosis of the NCI.

In 2012 investigators reported that they had used whole-genome sequencing to discover the genetic basis of a durable remission in a bladder cancer patient undergoing treatment in a clinical trial testing everolimus (Afinitor®), a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. The findings were made after an early-stage clinical trial in which Memorial Sloan Kettering physicians treated advanced bladder cancer patients with everolimus, a targeted therapy already used in the treatment of kidney cancer, among other cancer types.

While the drug failed to help did the vast majority of patients enrolled in the trial, one 73-year-old woman responded favorably to the drug.

“Her response is absolutely remarkable,” commented Dr. Solit, who led the study. “Most impressively, more than two years after starting the treatment, she continues to do well on everolimus, and all signs of her disease are gone.”

By comparison, the health of the other patients on the trial typically worsened two to three months into the study.

Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutations correlated with everolimus sensitivity. These results demonstrate, the investigators said, the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.

“This tells us that everolimus might be an option for the minority of bladder cancer patients whose tumors have TSC1 mutations, even though the drug was not effective in most patients with this disease,” explains Dr. Solit. The researchers are now planning a new clinical trial in which the drug will be offered only to patients whose cancer cells test positive for TSC1 mutations. He estimates that such mutations are likely to be present in approximately one out of ten people with bladder cancer.


Seeking the Outliers

Other cancer research and genome-sequencing centers have similar projects to find the outliers in clinical trials. The primary goal will be to ensure that the development of agents with profound, life-altering activity in only a minority of patients is not prematurely halted but rather redirected to the subset of patients most likely to benefit, he said.

“Studying exceptional responders can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents,” said Nikhil Wagle, M.D., of Dana-Farber Cancer Institute and first author of a paper describing such responders in the journal Cancer Discovery earlier this year. “We can use that information to identify patients whose tumors have genetic alterations similar to those found in exceptional responders, and treat them with those same agents.”

“We conducted a Phase I clinical trial of two anticancer agents—the mTOR inhibitor everolimus, and pazopanib, another drug used to treat kidney cancer—and one of our patients developed near-complete remission of his bladder cancer, which lasted for 14 months,” said Dr. Wagle. “We performed whole-exome sequencing of the patient’s tumor, and to our surprise, we identified two mutations in the gene mTOR, which is the target of everolimus.”

In this Phase I trial, the investigators recruited nine patients with advanced solid tumors, including five with bladder cancer, whose diseases had progressed despite treatment with standard therapies. Patients received one to 13 cycles of everolimus and pazopanib.

One of five patients with bladder cancer had a complete response, as evaluated by imaging, which lasted for 14 months. To understand why his tumor responded dramatically, the investigators performed complete sequencing of the coding regions of his tumor genome, which included about 25,000 genes, and identified two mutations in mTOR: mTOR E2419K and mTOR E2014K.

While these two mutations had never been noted in humans, according to Dr. Wagle, one of the mutations had previously been well described in yeast and in human cell lines. Through a series of studies, Dr. Wagle and his research team found that the two mutations activated the mTOR-mediated cell-signaling pathway.

Dr. Wagle explained that the two mutations made the patient’s tumor dependent on the mTOR pathway to survive, which is the most likely explanation for the tumor becoming quite sensitive to the mTOR inhibitor everolimus.

The NCI is soliciting submissions of exceptional responders from clinical trials in which only 1–10% of the patients responded to treatment.

And based on the data it collects, some researchers want the NCI to establish a public database of exceptional responders—a necessary step, they say, to better leverage the data because journals hesitate to publish results from a single individual.

Elaine Mardis, Ph.D., co-director of the Genome Institute at Washington University in St Louis, Missouri, has advocated establishment of an online journal for rapid publication of n-of-1 results, as a way to rapidly release information and give researchers incentive to study patients who seem to be outliers.