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Press release
Thursday, November 19, 2020
In a comprehensive analysis of cancer patients who had exceptional responses to treatment, researchers identified molecular changes in the patients’ tumors that may account for some of the exceptional responses. The results demonstrate that genomic characterizations of cancer can reveal genetic alterations that may contribute to unexpected and lasting responses to treatment, the researchers say.
The results appeared in Cancer Cell on November 19. Researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, conducted the study in collaboration with researchers from other institutions, including cancer centers designated by the NCI.
“The majority of patients in this study had metastatic cancers which are generally difficult to treat, but some of the patient’s responses lasted for many years,” said Louis Staudt, MD, Ph.D., director of NCI’s Center for Cancer Genomics, who co-led the study. “Researchers and physicians who treat these patients have long been curious about the mechanisms underlying these rare responses to treatment. Using modern genomic tools, we can now begin to solve these fascinating puzzles. “
“As clinical researchers, we have a lot to learn from these patients, and they have a lot to teach us,” said Percy Ivy, MD, of NCI’s Division of Cancer Treatment and Diagnosis, who co-led the research. . “The knowledge gained from studying outstanding stakeholders can help inform how we care for patients in the future and will help us move closer to the goal of precision oncology.
The retrospective study, which is now closed on an accrual basis, included detailed medical histories and tumor samples from 111 patients with various types of cancer who received standard treatments, such as chemotherapy. The patients had been identified by NCI’s Outstanding Stakeholder Initiative, a national project launched in 2014 to explore the feasibility of collecting and analyzing the data and biological samples needed to better understand the biological basis for exceptional responses to the disease. Cancer.
For 26 of 111 patients (24%), 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 infiltration of the tumor. the tumor with certain types of immune cells.
The study defined an exceptional responder as someone who had a partial or complete response to treatment that would be effective in less than 10% of similar patients. The duration of an exceptional response is that which lasts at least three times longer than the median response time.
To analyze tumor tissue (and normal tissue, if any) from study patients, the researchers used several genomic approaches – including analysis for DNA mutations, RNA expression levels , changes in DNA copy number and DNA methylation – as well as analysis of immune cells in the tumor microenvironment.
The mechanisms underlying the exceptional responses in the study fall into several broad categories, including the body’s ability to repair DNA damage and the immune system’s response to tumors. Another category describes rare combinations of genomic alterations that have resulted in tumor cell death during treatment – a concept known as synthetic lethality.
For example, researchers have identified mutations in the BRCA1 or BRCA2 genes in two cancer patients 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 repair damaged DNA, thereby increasing the effectiveness of treatments such as platinum-based chemotherapy that damage DNA.
“Our results demonstrate the importance of testing patients’ tumors for alterations that could indicate available treatments,” said Dr Staudt. “There is a need to move on to the molecular diagnosis of cancer which provides information that cannot be gleaned by looking at tumors under a microscope.”
The study also adds to the growing body of evidence showing 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.
The 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 clues to researchers trying to develop treatments that exploit vulnerabilities in tumor cells like those found in some exceptional responders, they noted.
For example, in two patients treated with the DNA-damaging drug temozolomide, researchers identified two DNA repair pathways that had to be simultaneously inactivated to elicit an exceptional response. This discovery supports the development of drugs that block these DNA repair mechanisms, which could generally improve the responses of cancer patients to temozolomide.
“This proof-of-concept study demonstrates that analysis of exceptional responder tumors is not only possible but necessary to learn as much as possible from these patients,” said Dr. Ivy. “We are extremely grateful to the many generous patients who participated in this study, even if they had nothing to gain personally from it, and to our many collaborators across the country, without whom this work would not have been possible.
Since the launch of the Outstanding Stakeholder Initiative, researchers have reviewed the medical histories of more than 500 patients who had been referred to the initiative by a physician. Chemotherapy is among the most widely used treatments for cancer, and the vast majority of patients considered for enrollment in the initiative have had exceptional responses to chemotherapy agents.
For the majority of patients in the analysis, several genomic approaches were necessary to characterize the tumor samples. Focusing only on DNA mutations would not have provided the clues investigators needed to develop hypotheses about the biological underpinnings of the responses, the researchers said.
Further research and additional analytical approaches are needed to describe the molecular underpinnings of the unresolved cases of non-exceptional respondents, they noted. To encourage the participation of researchers from around the world in this effort, the NCI team and colleagues have made public their molecular profiling results and clinical information in the NCI Genomic Data Commons.
About the National Cancer Institute (NCI): The NCI leads the National Cancer Program and NIH’s efforts to dramatically reduce cancer prevalence and improve the lives of cancer patients and their families, through cancer prevention research and cancer biology, the development of new interventions and training and mentoring of new investigators. For more information on cancer, please visit the NCI website at cancer.gov or call the NCI contact center, the Cancer Information Service, at 1-800-4-CANCER (1-800 -422-6237).
About the National Institutes of Health (NIH):NIH, the nation’s medical research agency, comprises 27 institutes and centers and is a component of the US Department of Health and Human Services. The NIH is the principal federal agency that conducts and supports basic, clinical and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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