“Exceptional responders” offer clues to potential cancer treatments

Nov. 23, 2020

In a comprehensive analysis of patients with cancer who had exceptional responses to therapy, researchers have identified molecular changes in the patients’ tumors that may explain some of the exceptional responses, according to researchers as reported in a press release from the National Institutes of Health (NIH).

The results demonstrate that genomic characterizations of cancer can uncover genetic alterations that may contribute to unexpected and long-lasting responses to treatment. The results appeared in Cancer Cell. Researchers at the National Cancer Institute (NCI), part of the NIH, conducted the study in collaboration with investigators from other institutions, including NCI-designated Cancer Centers.

“The majority of patients in this study had metastatic cancers that are typically difficult to treat, yet some of the patient responses lasted for many years,” said Louis Staudt, MD, PhD, director of NCI’s Center for Cancer Genomics. “Researchers and the doctors who treat these patients have long been curious about the mechanisms underlying these rare responses to treatment. Using modern genomic tools, we can now start to solve these fascinating puzzles.”

The retrospective study, which is now closed to accrual, included detailed medical histories and tumor samples from 111 patients with various types of cancer who had received standard treatments, such as chemotherapy. The patients had been identified by NCI’s Exceptional Responders Initiative, a national project launched in 2014 to explore the feasibility of collecting and analyzing the data and biospecimens needed to better understand the biological basis of exceptional responses in cancer.

For 26 of the 111 (24 percent) patients, the researchers were able to identify molecular features that could potentially explain exceptional responses to treatment, such as the co-occurrence of multiple rare genetic changes in the tumor genome or the infiltration of the tumor with certain types of immune cells.

The study defined an exceptional responder as someone who had a partial or complete response to a treatment that would be effective in less than 10 percent of similar patients. The duration of an exceptional response is one that lasts at least three times longer than the median response time.

To analyze the tumor tissue (and normal tissue, when available) from patients in the study, the researchers used multiple genomic approaches—including analysis of DNA mutations, RNA expression levels, DNA copy number alterations, and DNA methylation—as well as analysis of the immune cells in the tumor microenvironment.

The mechanisms underlying exceptional responses in the study fit into several broad categories, including the body’s ability to repair DNA damage and the immune system’s response to tumors. Another category described rare combinations of genomic alterations that resulted in the death of tumor cells during treatment — a concept known as synthetic lethality.

For example, the researchers identified mutations in the BRCA1 or BRCA2 genes in two patients with cancers that rarely involve alterations in these genes, which help repair DNA. But in these patients, the researchers suggested, the mutations may have impaired the tumor’s ability to fix damaged DNA, thereby increasing the effectiveness of treatments such as platinum-based chemotherapy that harm DNA.

The study also adds to the growing body of evidence highlighting the ability of the immune system to “kick in” and help eradicate tumors. In some patients in the study, increased levels of B lymphocytes, a type of immune cell, in tumors were associated with exceptional responses.

Results and hypotheses developed during this retrospective analysis will need to be confirmed by larger studies, according to the researchers. But if confirmed, the findings could potentially provide leads for investigators trying to develop treatments that exploit the vulnerabilities of tumor cells like those found in some exceptional responders, they noted.

Since the Exceptional Responders Initiative began, researchers have reviewed the medical histories of more than 500 patients who had been recommended to the initiative by a physician. Chemotherapy is among the most widely used treatments for cancer, and the vast majority of the patients considered for enrollment in the initiative had exceptional responses to chemotherapy agents.

For the majority of the patients in the analysis, multiple genomic approaches were needed to characterize the tumor samples. Focusing on DNA mutations alone would not have provided the clues the investigators needed to develop hypotheses about the biological underpinnings of the responses, the researchers said. 

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