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Single-Cell Study Details Development of Chemoresistant Breast Cancer

NEW YORK (GenomeWeb) - A pilot study using single-cell sequencing to analyze the evolution of chemotherapy-resistant triple-negative breast cancer suggests that resistance arises from pre-existing clones with genetic mutations. However, transcriptional profiles associated with the cancer subtype can develop via reprogramming in response to chemotherapy.

The study was published today in Cell by researchers from the University of Texas MD Anderson Cancer Center and Sweden’s Karolinska Institute. The results, they wrote, have clinical implications for diagnosis, prognosis, and treatment of this cancer subtype.

“In this study, we investigated the genomic and phenotypic evolution of tumor cells in triple-negative breast cancer patients in response to neoadjuvant chemotherapy, which revealed two distinct classes of clonal dynamics: extinction and persistence," the authors wrote.

In some patients, chemotherapy eliminated all tumor cells, but the researchers found other patients with residual tumor cells, whose genotypes and phenotypes had changed following treatment.

Led by senior authors Nicholas Navin, of MD Anderson, and Theodoros Foukakis, of the Karolinska Institute, the researchers used single-cell DNA and RNA sequencing, as well as bulk exome sequencing, to profile 20 patients during treatment. In 10 patients, Illumina deep-exome sequencing found clonal extinction, while tumor cells persisted in the other 10. For eight of those, the researchers performed additional single-cell analyses.

In particular, they used a Becton Dickinson FACSAria II flow cytometer to sort single cells and analyzed them using pooled libraries and Illumina next-generation sequencing. In total, they analyzed 900 single cells by DNA sequencing and almost 7,000 by RNA sequencing, which showed that copy number aberrations emerging in response to chemotherapy were pre-existing and adaptively selected, while expression profiles were acquired through transcriptional reprogramming.

Triple-negative breast cancer is an aggressive subtype defined by a lack of estrogen, progesterone, and HER2 receptors, making it unresponsive to some treatments. It accounts for between 10 and 15 percent of all breast cancers. These tumors can be responsive to neoadjuvant chemotherapy, but often develop resistance. Previous studies of different tumor types have suggested that resistance to chemotherapy can arise through selection of pre-existing mutations or through acquisition of new genomic mutations during treatment. And previous studies on chemoresistance in triple-negative breast cancer patients “were based on targeted markers or bulk genomic tissue profiling and had limited ability to reconstruct clonal evolution during chemotherapy,” the authors wrote.

“Our data further suggest that a small fraction of genotypes selected by neoadjuvant chemotherapy were primed for transcriptional reprogramming and had subsets of chemoresistant genes expressed prior to treatment,” they noted, adding that while their study had a small sample size, it had important implications for the clinic.

“There may be diagnostic opportunities for detecting chemoresistant clones in triple-negative breast cancer patients prior to the administration of [chemotherapy] to predict which patients may benefit from chemotherapy," they wrote. "Second, the stratification of ... patients into clonal extinction and clonal persistence groups may have prognostic applications in patient outcome or survival beyond histopathological techniques. Third, our data on chemoresistant phenotypes raise the possibility of therapeutic strategies to overcome chemoresistance.”

Future studies will include analyses of matched primary and metastatic tumors in order to understand the role of chemoresistant clones in metastasis. Such projects will become more doable, they wrote, as the throughput of single-cell DNA sequencing increases and costs decline, and as single-cell DNA and RNA profiling in the same cell becomes feasible.

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