How Exceptional Responders Are Providing Clues to Personalizing Cancer Treatment

A Conversation With Louis M. Staudt, MD, PhD

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The findings from a recent study of patients with cancer who had an exceptional response to chemotherapy are yielding new clues on the molecular changes in patients’ tumors. These findings may explain the genetic alterations contributing to these patients’ dramatic and long-lasting responses to treatment—and could lead to achieving personalized treatment for more patients.

The study, led by Louis M. Staudt, MD, PhD, Director of the National Cancer Institute’s (NCI’s) Center for Cancer Genomics, analyzed the DNA of tumor tissue and normal tissue in 111 patients enrolled in the NCI’s Exceptional Responders Initiative. For this initiative, the NCI defines exceptional responders as patients who received a treatment in which fewer than 10% had a complete or durable partial response lasting at least 6 months based on clinical trial data; achieved either a complete or partial response lasting at least 6 months as defined by Response Evaluation Criteria in Solid Tumors (RECIST) or response criteria as defined where RECIST were not commonly used; or sustained a complete or partial response for at least three times longer than the median duration of response from literature resources for a specific treatment.

“Our findings are all coalescing around the theme of DNA damage response pathways and the drugs that can be made to target those pathways.”
— Louis M. Staudt, MD, PhD

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The majority of patients in this study had a variety of metastatic cancers, including glioblastoma multiforme, colorectal adenocarcinoma, and cholangiocarcinoma, and had received standard treatments. The researchers used multiple platforms to profile the patients’ tumor genetic and epigenetic aberrations as well as its microenvironment. They found plausible mechanisms for the therapeutic response in nearly one-quarter of the patients. The mechanisms were assigned to four broad categories: DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of a favorable prognosis.

For 26 of the patients, the researchers were able to identify molecular features that could explain their exceptional response to treatment. For example, one patient with glioblastoma multiforme who had been sequentially treated with surgery, localized carmustine and radiation therapy, and then treated with the DNA-damaging chemotherapy temozolomide upon disease recurrence achieved a complete response that has lasted more than 10 years. Another patient with metastatic colon cancer has achieved an ongoing, nearly complete response lasting almost 4 years after receiving temozolomide in combination with the investigational drug TRC102. These findings suggest that treating some patients with a combination of drugs, each blocking a different DNA repair pathway, may improve outcomes.1

Although the researchers could not determine the underlying mechanisms behind the exceptional responses of the remaining 85 patients in the study, the take-home message, said Dr. Staudt, is that all patients with cancer should have a genomic analysis performed on their tumor, not just in the metastatic stage setting, but at initial diagnosis as well.

The ASCO Post talked with Dr. Staudt about why some patients with advanced cancer survive significantly longer than patients with clinically comparable tumors; the role the immune system may play in making patients more responsive to therapy; and the importance of performing genomic analysis on tumors at diagnosis and in advanced-stage cancer.

What Gives Exceptional Responders Their Superpower?

You were able to identify the molecular features that may explain the exceptional responses to treatment for 26 of the 111 patients in your study. Please talk about the common mechanistic themes you observed in these patients.

Our goal was to find mechanistic themes in these exceptional responders, and there were some. Many of our patients had received DNA-damaging chemotherapy, and, therefore, many of the common mechanisms revolved around the DNA damage pathway. One particular drug, temozolomide, damaged DNA in a stereotypical way, and it turns out there are multiple backup systems needed to repair that damage. If the cell can repair the damage, it will keep on dividing despite having received temozolomide.

The glioblastoma tumor from one patient had two of the backup DNA repair pathways inactivated by genetic lesions. This patient had an exceptional complete response to temozolomide lasting more than 11 years.

The most mechanistically intriguing part of the study results has to do with the patients on the investigational drug TRC102. We found that TRC102 crippled DNA damage response pathways. A patient with metastatic colon adenocarcinoma in our study had received temozolomide in combination with TRC102 and achieved a long-term partial response lasting 45 months. When we analyzed the patient’s tumor, we found the therapy had crippled two DNA damage response pathways. So, our findings are all coalescing around the theme of DNA damage response pathways and the drugs that can be made to target those pathways. Future research will tell us how well these drugs can be combined to make cancer cells much more sensitive to DNA damage.

Another common mechanistic theme we found has to do with the rare mutations in some of these patients’ tumors. For example, we observed mutations in the BRCA1/2 genes in two patients: one with metastatic rectal cancer and one with metastatic cholangiocarcinoma. BRCA lesions are rarely observed in these types of tumors, and both of these patients had an exceptional response to platinum-based therapies. Thus, we concluded that their exceptional response to therapy may be due to the same molecular mechanism found in breast and ovarian tumors.

What we are saying with our exceptional responders’ paper is that, even if a mutation is rare within a cancer type, the oncologist and the patient might consider a treatment regimen that targets that rare mutation.

Was there also something different or unusual about these patients’ immune systems that may have made them more likely to respond to the therapy?

We profiled the microenvironment of these patients’ tumors in a very uniform fashion. We found that many of these tumors were significantly enriched with certain types of immune cells, specifically tumor-infiltrating B lymphocytes and activated natural killer cells, which was a nice surprise. Several studies published over the past few years have shown that the presence of B cells within tumors may identify patients who are more likely to respond to therapy. Our findings fit the hypothesis that there is an immune mechanism involving tumor-infiltrating B cells that, in some way, may help patients respond to therapy.

Tailoring Treatment for Each Patient

You were not able to identify the molecular features of the other 85 exceptional responders in your study. Why not?

I would first say that is a glass-half-empty question. The glass-half-full way of looking at our results is that, wow, we were able to identify the molecular mechanisms for exceptional responses to therapy in 26 patients. In addition, we were also able to rule out the hypothesis that they were just random events that occurred rarely, and we do not know enough about cancer to figure out what made these patients exceptional responders, so we dispelled that hypothesis.

“Clinical research that includes rich molecular investigations can lead to good ideas about how best to treat difficult cancers.”
— Louis M. Staudt, MD, PhD

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However, the question of why we were unable to decipher the molecular mechanisms of exceptional response in the remaining patients presents us with an interesting puzzle. Is there something we missed in these patients? Maybe we didn’t conduct the right type of molecular test. For example, we did not study the proteomics of cancer in these patients, which is an active area of research now. Perhaps that could have yielded some insights.

There also may well be clinical factors that contributed to the exceptional response in some patients. For example, in many clinical trials, a quantitative measure of patients’ performance status is a strong predictor of therapeutic efficacy. Performance status may have more to do with the bulk of disease, the patient’s age, or other physiologic factors than the molecular profile of a patient’s tumor.

Is that why more patients do not have an exceptional response to therapy?

For some patients, we just don’t have the perfect drug to target the molecular lesions in their tumors. Or, even if the drug does target those molecular mechanisms, the tumor may have bypass pathways, allowing cells to easily evade the therapy, which is why the concept of combination therapy is so intriguing. At the NCI, we are starting studies on drug combinations to see how effective they are in a selected subset of patients, and we will continue to learn how to tailor treatment to achieve a better response.

One other aspect that makes the NCI’s Exceptional Responders Initiative so valuable is that sometimes, as bench research scientists, we are not smart enough to see what is really important in the treatment of human cancer and why some patients’ tumors respond well to treatment and others do not.

In our clinical trials of ibrutinib in aggressive lymphomas, we observed that tumors with mutations targeting the B-cell receptor and the signaling protein MYD88 had an exceptional response. The cooperation between the B-cell receptor and MYD88 was completely unknown from basic research, illustrating how clinical research that includes rich molecular investigations can lead to good ideas about how best to treat difficult cancers.

We are learning so much from our patients, including how human cancer cells operate at the molecular level and how to target those cells to elicit the most effective response.

Genomic Analysis of Both Early- and Late-Stage Tumors

One of the patients in your study has survived glioblastoma multiforme for 10 years. Is that patient cured of cancer?

We do not know. We know that patients can have good control of their cancer for a long time. If a patient lives for 10 years without a recurrence, for most cancers, that will mean the cancer will not recur, and the patient is cured. However, some cancers, such as breast cancer, can recur 10 or more years after initial diagnosis and treatment. In my mind, our goal should be to develop combination therapies that produce long-term complete remissions and not settle for just pushing the survival curve out by only a few months.

One theme from our exceptional responder study I would like to emphasize is what we call prognostic genetics. That means that although a cancer may have looked aggressive under the microscope, when you looked at its molecular features, they were similar to those in a more indolent, slow-growing version of that cancer. That is what we found in many patients with glioblastoma multiforme who had a long survival after therapy.

This is why we need to have genomic analysis done on more types of malignant tumors and not just in advanced tumors, but in early-stage disease as well. The knowledge from these genetic analyses could be used to inform how to treat patients more precisely even after their first diagnosis. 

DISCLOSURE: Dr. Staudt has received royalties for gene--expression profiling in lymphoma that has been licensed by NanoString Technologies.


1. Wheeler DA, Takebe N, Hinoue T, et al: Molecular features of cancers exhibiting exceptional responses to treatment. Cancer Cell 39:38-53.e7, 2021.