Researchers from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard have shown that fusion RNAs are more common than previously thought in people with metastatic breast cancer and could potentially be targeted with drugs that are already available.
“The implication of our findings is that fusion RNAs—especially those that are patient-specific—are quite common in the treatment refractory setting and may be more widely expressed in patients with advanced cancers than traditional targets,” says Nolan Priedigkeit, MD, PhD, a medical oncology fellow and postdoctoral scholar at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard.
“At the same time, there may be low-frequency fusions—potentially targetable with drugs we already have—that we are missing with current testing standards as they are tricky to pick up with traditional sequencing platforms,” he tells Inside Precision Medicine.
Priedigkeit explains that breast cancer has a distinct genomic landscape, relative to other epithelial malignancies, that is characterized by a high degree of large structural changes in its genome. These alterations can bring two genes that are normally far apart closer together producing a fusion RNA or protein that is only expressed in the cancer cells. These fusion RNAs may serve as highly specific tumor biomarkers, have unique functions which may drive cancer progression, and potentially offer more personalized, cancer-specific targets.
Targeted therapies that can inhibit fusion proteins have been “remarkably successful in other malignancies,” Priedigkeit notes. Imatinib, which targets the bcr-abl fusion in chronic myelogenous leukemia, was the first to be used, but more recently there have been practice-changing advances in solid tumors with effective therapies against ALK, ROS1, NTRK, and RET fusions.
Yet, the prevalence and role of fusion RNAs in breast cancer has not been as comprehensively assessed.
To address this, Priedigkeit and colleagues performed a retrospective study using RNA sequencing data 423 patients with metastatic breast cancer. They ran the sequencing data through five different fusion-finding algorithms; highly expressed fusions identified by two or more algorithms that were not present in normal tissues were considered high-confidence and cancer-specific (HCCS).
Priedigkeit reported at the 2023 San Antonio Breast Cancer Symposium that around one-third of metastatic breast cancers harbored at least one highly expressed HCCS fusion RNA, a much higher proportion than expected. He described this finding as “striking” and said that unlike traditional alterations that drive cancer progression, many of these fusion RNAs are likely unique to individual patients.
The investigators found fusions were most common among tumors of the basal subtype and least common among tumors of the luminal A subtype.
In addition, the analysis showed that 64.5% of patients harboring HCCS fusions had at least one fusion involving a cancer-related gene, as defined by the OncoKB database, suggesting that some of these fusions may be cancer driver mutations.
In support of this hypothesis, the most common cancer-related gene involved in fusions was ESR1, encoding the estrogen receptor. Priedigkeit noted that the analysis uncovered both known and novel ESR1 fusions, many of which occurred during or after endocrine therapy and resulted in the loss of binding sites for estrogen receptor inhibitors. The frequency of ESR1 fusions was approximately 5% in estrogen receptor-positive disease.
The researchers also identified HCCS fusions involving known cancer-driving kinases that would likely be missed by current testing standards, some of which have FDA-approved small molecule inhibitors that may provide new treatment strategies for patients with heavily pretreated disease and few remaining options.
“The most immediately druggable fusions we found were FGFR family member fusions in hormone-receptor positive breast cancers,” says Priedigkeit. “More selective FGFR inhibitors are currently in development, and there is a compound, futibatinib, that received FDA-accelerated approval for advanced cholangiocarcinoma with FGFR2 fusions. Whether or not these compounds will have efficacy in breast cancer is something that needs to be proven; but is no doubt worth investing in.”
Priedigkeit cautions, however, that detecting these fusions is not easy and is crucially dependent on using the right technology. He points out there were eight patients who had estrogen receptor fusions identified by RNA-sequencing that were not detected on a standard DNA targeted sequencing panel.
“This is because oftentimes the fusions occur in regions that are in between genes—and thus not picked up on targeted panels simply because the region where they occur is not sequenced,” he explained. “With the right technology, such as whole-genome sequencing and/or RNA-sequencing on high quality specimens, our ability to pick up these fusions amplifies.”
He adds: “There is a critical need to understand optimal testing strategies so that we don’t overlook potentially actionable fusions in breast cancer.”
While the results are preliminary, and more research will be necessary to determine if these fusions are driving cancer progression, Priedigkeit and colleagues are now exploring innovative strategies using gene therapy techniques such as base editing to target fusion RNA sequences directly.
“The gene therapy revolution is knocking on our door—and there are new technologies that allow targeting nucleic acids directly rather than their protein products,” Priedigkeit said. “We have made several collaborations to credential some of these new technologies to exploit fusion RNAs, especially given how common they appear to be in metastatic breast cancers.”
