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Tumor characteristics in ‘exceptional responders’ may point to therapies for others

Cancer Cell
Reuters Health - 25/11/2020 - A molecular analysis of tumors from patients who had exceptionally good responses to cancer treatments has helped researchers identify potential targets for patients who don't respond as well to standard therapies, researchers say.

In a study of tumors from more than 100 exceptional responders, the study team identified genetic and microenvironment changes, many of which revealed plausible mechanisms for the response that could be exploited in the future, according to the report published in Cancer Cell.

"The major take home message from this study is that one can understand exceptional responses by molecular analysis of tumors," said Dr. Louis Staudt, director of the National Cancer Institute's Center for Cancer Genomics in Bethesda, Maryland.

"That didn't have to be the case," said Dr. Staudt, who co-led the research. "You could imagine that there was something about the patients' constitutions, whether they were healthier or there was something special about their immune systems, that made them different."

To take a closer look at what might have made these tumors more susceptible to current treatments, Dr. Staudt and his colleagues examined 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 the NCI's Exceptional Responder Initiative, a national project launched in 2014 to collect and analyze data and tumor specimens in order to better understand the biological basis of the exceptional responses.

The researchers used multiple genomic approaches - including analysis of DNA mutations, RNA expression levels, DNA copy number alterations, and DNA methylation. They also analyzed immune cells in the tumor microenvironment to try to understand potentially exploitable signaling pathways and weaknesses in the tumors.

For 26 (23.4%) of the patients, Dr. Staudt and his colleagues were able to identify tumor features - such as immune system engagement, intracellular signaling, or lack of ability to repair DNA damage caused by chemotherapy - that made the cancers vulnerable to standard therapies.

As an example of genes leaving the tumor unable to repair DNA damage, Dr. Staudt points to mutations in BRCA genes in some patients with prostate and colon cancers. Seeing exactly how these mutations affected the tumor's ability to repair damage from the standard chemotherapy used to treat prostate cancer, for example, suggested that adding in a medication usually used for breast cancer might improve survival.

"The results of this study revealed that in about 25% of cases a plausible mechanism was identified with a known treatment or a target that provided an explanation for the exceptional response,"," said Dr. Charles L. Shapiro, a professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City and director of Translational Breast Cancer Research for the Mount Sinai Health System.

"Two things are important from this study," Dr. Shapiro said in an email. "It underscores the importance of genomic testing to identify specific targets or treatments. The other importance of this work is it opens new approaches to cancer treatment."

"For example," Dr. Shapiro said, "converting immunologically non-responsive cancers - or cold tumors -into ones that respond to immunological therapies - or hot tumors). In fact, several clinical trials are in progress or on the drawing board to test this hypothesis. Making cancers vulnerable to existing therapies and the process of identifying new targets and treatments is a high priority."

SOURCE: https://bit.ly/37aM1zY Cancer Cell, online November 19, 2020.

By Linda Carroll

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