Rare Daily Staff
Scientists at the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, and Count Me In, working in partnership with patients, have identified new causes of angiosarcoma, a rare cancer of blood vessel walls.
The research also points to possible therapeutic options for patients with the disease, who often have a poor prognosis.
The findings grow out of the Angiosarcoma Project, a unique partnership between patients and scientists that empowers patients to contribute their medical records, biological samples, and voices to accelerate research. Launched in 2017, the Angiosarcoma Project is part of Count Me In, which aims to catalyze research on several cancer types by directly engaging cancer patients online to enroll in biomedical studies.
The researchers said the work, published in Nature Medicine, shows how a crowdsourced effort that unites a small and scattered group of patients can yield unexpected findings about a disease that has been difficult to study because it is so rare.
Angiosarcoma arises in endothelial cells, which form the inner linings of blood vessels and can occur anywhere in the body, but it is most commonly found in the skin, breast, liver, and spleen. It is an extremely rare cancer, with only 300 new cases each year in the United States, and prognosis is generally poor. Patients are scattered across the country, so large studies to find the illness’s molecular underpinnings have not been feasible until now.
The Angiosarcoma Project team established a social media working group to connect patients with angiosarcoma and loved ones online and invite them to help shape the project’s outreach strategy. The team built an online portal that allows patients in the United States and Canada to join the study and contribute their medical history and tumor or blood samples for DNA testing.
Within 18 months of launching, 338 patients had registered, a large proportion of all patients in the United States with angiosarcoma.
In the study, researchers analyzed the genomes of nearly 50 tumor samples donated by angiosarcoma patients from across the United States and Canada. The team found dozens of mutated genes in various forms of the cancer, as well as clues suggesting that drugs approved for other types of cancer might be useful in treating some kinds of angiosarcoma.
The Broad’s Genomics Platform sequenced the exome, or protein-coding regions, of 47 of these tumor samples along with germline (inherited) DNA from the same patients. Co-first author Esha Jain, a computational biologist in the Wagle lab, led the analysis of the data, which revealed 30 genes that were frequently mutated in several tumors. Some of these genes had never been associated with angiosarcoma, such as PIK3CA, GRIN2A, and NOTCH2.
Most of the samples with mutations in PIK3CA were in cases of angiosarcoma of the breast. The researchers looked at where the mutations fell in the gene itself and deduced that they were likely to be “activating” mutations, meaning they give the protein a new or enhanced function. This suggests that blocking the PIK3CA pathway with an FDA-approved drug known as a PI3 kinase inhibitor could be helpful for patients with breast angiosarcomas that carry one of these mutations.
The PIK3CA gene is also mutated in breast adenocarcinoma, a different type of cancer that happens to occur in the same tissue, suggesting that something about the cellular environment of the breast encourages these tumors to develop.
The team measured the tumors’ overall rate of mutation and learned that angiosarcomas of the head, neck, face, and scalp (HNFS) have a higher burden of mutations than the others. The pattern of those mutations has previously been linked to damage from ultraviolet radiation, suggesting that sun damage may have led to disease in these patients.
Because other tumors with excessive mutations have responded to treatment with drugs known as immune checkpoint inhibitors, the researchers hypothesized that these medicines might help patients with HNFS. In fact, they found two patients in the study with HNFS angiosarcoma who, after failing to respond to standard treatments, were given off-label immune checkpoint inhibitors and responded well to the therapy.
Despite needing to discontinue the treatment because of side effects, those patients remain disease-free today without any further treatment for their cancer. This suggests that immune checkpoint inhibitors could potentially help some patients with this subtype.
“This work was only possible with our patient partners,” said senior author Nikhil Wagle, an institute member at the Broad, a medical oncologist at Dana-Farber, an assistant professor at Harvard Medical School, and director of Count Me In. “The scientific insights they’ve helped generate have shed new light on the poorly understood roots of angiosarcoma, which urgently needs new treatment options for patients.”