Abstract
Angiosarcoma Project researchers have uncovered some details about the molecular underpinnings of angiosarcoma, pointing to potential therapeutic options. Their work also suggests that a research model based on direct patient participation can overcome common barriers to studying rare diseases.
In an analysis published in Nature Medicine, researchers report details on the molecular underpinnings of angiosarcoma and suggest possible therapeutic options (Nat Med 2020;26:181–7). The findings also suggest that a research model based on engaging patients through social media and patient networks can overcome common barriers to studying rare diseases.
The insights are the first from the Angiosarcoma Project, in which patients in the United States and Canada can enroll online and submit their medical history and biospecimens remotely (see https://ascproject.org). For this study, researchers conducted whole-exome sequencing on 47 donated tumor samples and discovered several recurrently mutated genes, including some—such as PIK3CA, GRIN2A, and NOTCH2—that had not been associated with angiosarcoma.
PIK3CA was one of the most frequently mutated genes, with alterations showing up in 10 of the samples, nine of which were from patients with breast angiosarcoma, suggesting that a PI3K inhibitor might be a viable therapeutic option for them. In addition, because PIK3CA mutations frequently arise in breast adenocarcinoma, researchers hypothesized in their report that “the site of tumor origin (breast), independent of tumor lineage, may be permissive for PI3K pathway activation and may aid tumor formation within breast tissue, perhaps due to interaction with the breast microenvironment.”
This “suggests a rationale for potentially treating these patients with a PI3K inhibitor recently approved for breast cancers [alpelisib (Piqray; Novartis)] with this mutation,” says senior investigator Nikhil Wagle, MD, of Dana-Farber Cancer Institute in Boston, MA.
Investigators also observed a high tumor mutation burden (TMB) in angiosarcomas of the head, neck, face, and scalp (HNFS), a molecular signature linked to ultraviolet radiation and sun exposure. High TMB is a possible biomarker of response to immune checkpoint inhibitors, and the researchers noted that three patients in the study with refractory metastatic HNFS angiosarcoma had been treated off-label with the PD-1 inhibitor pembrolizumab (Keytruda; Merck). Two of them have remained disease-free for 2 years, even after discontinuing the drug. The third patient did not have a durable response and stopped the drug after a single dose due to side effects.
“The fact that multiple targets were identified in a large set like this is very encouraging from a therapy standpoint,” says Vinod Ravi, MD, of The University of Texas MD Anderson Cancer Center in Houston. “It suggests we should start investigating the activity of these agents in select angiosarcoma patients.”
The Angiosarcoma Project is part of Count Me In, an initiative that aims to advance treatment for several types of cancer by engaging directly with patients to build extensive online databases of clinical and genomic information (see https://joincountmein.org). The approach can be particularly effective for studying cancers affecting relatively few patients across a large geographic area, which can limit enrollment in a traditional research study.
“There is a huge amount we can learn by studying tumor samples directly contributed by patients, particularly when accompanied by detailed clinical information,” says Wagle, who directs Count Me In. “This approach allows us to reach patients at community oncology clinics and hospitals throughout the country—where the vast majority receive their care—thus overcoming a major barrier of the traditional approaches.”
The take-home message of the Angiosarcoma Project, says Ravi, is that tailoring treatment for patients holds tremendous value. “These results suggest that we should consider checkpoint inhibitors for patients with high mutational burden when standard therapies fail,” he notes. “In terms of future research, we should think [about] separating patients into their respective molecular buckets in order to match them to appropriate targeted therapies.” –Janet Colwell
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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