What Are Exceptional Responders?

By Eva Kiesler,

Tuesday, March 24, 2015


Scientists are switching their thinking about “failed” clinical trials in which a drug doesn’t work for a majority of patients and shifting their focus onto the occasional patients who do benefit. The tumor DNA of these exceptional responders may offer clues about why the treatment worked for them and as investigators gain these insights, successful responses to the drug may eventually become closer to the norm.

  • Often few patients benefit from a trial of a new drug.
  • But there is hope for these generally unsuccessful treatments.
  • Sometimes exceptional patients have powerful responses.
  • DNA sequencing can reveal rare mutations driving their response.
  • This way, more people with the mutation can eventually benefit.

There is an exciting new movement in cancer research — often referred to as exceptional responder investigation — that appears to be transforming past disappointments into progress. Here, we discuss how this approach can resurrect therapies whose development was previously halted.

The history of oncology is full of “unique cases” — anecdotes doctors tell one another about the single patient who had an impressive response to a treatment that failed many others. Until recently, these puzzling phenomena usually didn’t get much attention, since there was no way of telling why a therapy helped certain people but not others.

If, for example, a new drug tested in a clinical trial worked remarkably well for one patient and ten others got no benefit, the therapy traditionally would have been written off as ineffective. And most likely the doctors who led the trial would have moved on to investigate another drug instead.

But in the past couple of years, researchers have been returning to failed trials to dust off data about those few exceptional responders. And increasingly, they are able to solve these mysteries thanks to powerful new sequencing technologies that make it possible to inspect the DNA of these patients’ tumors and find out what makes their cancers unique.

The approach has enabled us to resurrect [abandoned] therapies.
David Solit MSK physician-scientist

The goal of this research is to make patients’ successful responses to investigational drugs the norm, or closer to it, rather than the exception. If scientists are able to show that a particular gene mutation is making one person’s tumor vulnerable to a drug, and there’s a plausible explanation for why the drug is working, other patients with the same mutation — even in a different type of cancer — have a fair chance of benefiting from the treatment as well. Sometimes these patients can be offered the therapy in the context of a clinical trial.

A Breakthrough in Bladder Cancer

“Excitingly, many of these patients [with the same genetic mutations] are similarly responsive to the same therapy that was so effective in the outlier patient,” MSK clinician-scientist David Solit, who directs the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO), noted in a recent interview on this blog. “The approach has enabled us to resurrect therapies whose development was previously halted.”

In 2012, Dr. Solit and his co-workers published a groundbreaking study of a patient with advanced bladder cancer who participated in a clinical trial of a drug called everolimus (Afinitor®) and responded surprisingly well. The researchers decided to survey this patient’s disease in depth by sequencing the entire genome of her tumor. An examination of other patients on the trial showed that only those with TSC1 mutations in their tumors benefited from the drug.

Cancer genomics researchers Michael Berger and David Solit

Following this research, MSK scientists have conducted a number of similar investigations to identify extraordinary responders with different types of cancer with the goal of extending the treatments that helped them to other patients who might benefit. The bladder cancer study led by Dr. Solit also led the National Cancer Institute to launch the Exceptional Responder Initiative, a comprehensive effort to analyze the cancer genomes of up to 300 exceptional responders.

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Basket Studies

MSK doctors are also pioneering a new way to conduct clinical trials — called basket trials — to more quickly test promising precision treatments. Traditional clinical trials enroll patients according to a particular cancer type. Basket trials, on the other hand, are designed around gene changes and so may be open to patients with different tumor types. They have been particularly impactful for patients with rare cancer types for whom few clinical trial options have previously existed.

Research on exceptional responders can help identify small subgroups of patients diagnosed with different cancers — breast, lung, bladder, and endometrial cancer, for example — who are likely to benefit from a specific treatment because their tumors have the same rare mutation. “Opening up separate trials for each type of cancer is often not feasible and would take years,” Dr. Solit says. “Instead, we conduct one study in which patients with any of these cancers can enroll.” Researchers at MSK have initiated an increasing number of these basket trials in recent years.

A new type of clinical trial called a basket trial can speed the development of precision treatments.

Since last year, our pathologists have been analyzing the tumor DNA of essentially all MSK patients with advanced cancer using a new genomic sequencing test developed by MSK scientists. This routine testing allows doctors to detect clinically “actionable” tumor mutations that can help inform treatment choices — or, in some cases, identify patients who are candidates for a basket trial.

There are good indications that the approach is paying off. A recent study that explored the value of genomic testing for guiding lung cancer treatment showed that in two-thirds of patients, tumor sequencing led to the identification of actionable mutations. And those patients who were able to receive a therapy matched to their specific mutation had better outcomes than patients receiving standard treatment.

On March 26, MSK medical oncologist David Hyman was on WNYC’s Morning Edition to talk about a brain tumor patient who benefited from a drug originally tested for skin cancer. Learn more and listen to the program.

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Outliers have always been the most interesting individuals to study in most areas of biology, it's good the cancer community is now embracing this approach with the tumour and its actionable mutations. But how are we doing with those other outliers - those identifiable high risk individuals (eg very elderly BRCA2 carriers) who are possibly managing to pre-empt and prevent tumour growth in the first place? Now that there is finally excitement about immunotherapy, is there also sufficient focus on why (in terms of host DNA/epigenetics) some individuals might be more immunocompetent in fending off cancer than others? Has host DNA been compared yet between closely related high risk individuals with differing clinical outcomes over significant life spans? Aren't the interesting outliers also those who survive 9 or 10 decades without succumbing? In any evolving host/parasite relationship one needs to study both entities. Understandably as a first aid strategy there is still a bias towards studying the 'evolution' of mutations in the tumour so as to build an appropriate armoury of drugs, but perhaps the longer term goal should be to understand why some individuals, seemingly exposed to the same environmental and personal risk factors as their less fortunate kin, are never diagnosed with cancer and have extreme longevity - can we characterise the relevant genetic components of their immune system that affords this protection by comparison with kin? The challenge is obviously a very difficult one and an approach of finding elderly outliers without cancer and comparing to younger family members with cancer might polarise the familial differences whilst reducing the heterogeneity of the genomic haystack in which the difference is sought (as compared to GWA studies). I know of a large extended BRCA2 family where such a study might be feasible if anyone is able to pursue this approach.

When the book came out, I was too afraid to read it being too close to home. I am an ovarian stage one cancer survivor. This is my fifth year and I am counting my blessings. I am watching the series on PBS. Amazing and empowering information, I am so glad I am watching it. Great Documentary! I am thinking of all the people (children among them) who passed away and made some of treatments possible today. Thank you for bringing it to the public. I am surprised my husband is watching it. It is so tough for your loved ones to tackle cancer. And for us, the ones who battle with it, how do you stay calm in a turbulent sea? Hopefully, one day, there will be a cure, or at least a lifelong remission. Thank you.

my son-in-law has ACC which is a very rare cancer. Unfortunately, very few trials have been tested on this type of cancer. It has spread to many different areas of his body and they don't seem to know how to handle this. The family is of course extremely upset. He is only in his 50's.

Marie, we are sorry to hear about your son-in-law's diagnosis. Memorial Sloan Kettering does have an active clinical trial for metastatic ACC. More can be learned here:


Or he can contact Dr. Alan L. Ho at 646-888-4235 to inquire about eligibility.

This comment is pertaining to the basket trial: it is interesting to note the assumption/prediction that the "same mutation" in cancer in different organs would give the same response to the drug. However one is precluding the behaviour of the mutant protein in context i.e tumor microenvironment. if the same mutation behaves differently or signals differently in different tissues because the cellular environment is different then it cannot be predicted to give the same response in different organs to the same drug.

I didn't know the idea before I read the article. Informative details are included such as the same mutation in cancer.

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